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==== Front
Lancet Respir Med
Lancet Respir Med
The Lancet. Respiratory Medicine
2213-2600
2213-2619
Elsevier Ltd.
S2213-2600(22)00482-9
10.1016/S2213-2600(22)00482-9
Comment
Licensure laws and other barriers to telemedicine and telehealth: an urgent need for reform
Raghu Ganesh a
Mehrotra Ateev bc
a Department of Medicine and Department of Laboratory Medicine and Pathology, University of Washington, Seattle 98195, WA, USA
b Department of Health Care Policy, Harvard Medical School, Boston, MA, USA
c Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
12 12 2022
12 12 2022
© 2022 Elsevier Ltd. All rights reserved.
2022
Elsevier Ltd
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
==== Body
pmcA few weeks ago, a man in his mid-60s with worsening pulmonary fibrosis sought the expertise of a specialist physician (GR) via a telemedicine visit. The patient took the visit in his car by the roadside. Although a telemedicine visit in a car is never ideal, it was particularly difficult because he was using supplemental oxygen at 6 L/min and his oxygen saturation was only 90%; every cough during the conversation led his oxygen saturation to drop even further. The patient was not in the car by his choice or because his pulmonologist recommended it—both would have preferred the telemedicine visit from the comfort of the patient's home. The visit occurred in the car parked just within the border of Washington, USA (figure ) to comply with state licensure.Figure Map of northwestern states of the USA
To meet current licensure requirements for telemedicine, the patient travelled over 8 h (black arrow). The pulmonologist (GR) providing the telemedicine visit is in Seattle, Washington, USA (white star). The arrowhead of the black line indicates the patient's location at the time of telemedicine visit, over 5 h of additional travel would have been needed to reach Seattle (dotted grey line with the arrowhead). To ensure privacy, the patient's home is not at the point of the red star. The red star is placed in an arbitrary spot in the state of Idaho that corresponds to approximately the distance from Washington that the patient lives.
In the USA, and around the world, the onset of the COVID-19 pandemic triggered a sudden surge in the use of telehealth. This growth was facilitated by many temporary payment and regulatory changes made by governments and health plans to ensure that patients with acute and chronic illnesses receive the care they need.1 Telehealth was particularly important for physicians treating rarer and complex diseases and whose patients often live hundreds of kilometres away or in other states. For diseases such as interstitial lung diseases or pulmonary fibrosis, input from a specialist can be crucial for management2 but travel can be extremely taxing. It is not surprising that many patients and pulmonologists have turned to telemedicine.3
Historically in the USA, each state mandated that physicians must be licenced in the state where the patient is physically located at the time of encounter.4 Early in the pandemic, most states temporarily waived this requirement. Unfortunately, most of these waivers have now expired. This brings us back to our patient. The patient drove from where they live in Idaho to Clarkston, Washington (USA), which is just inside the border (figure). The patient was still more than 500km from Seattle, where the physician was located, but they now met the requirements of state law.
The negative consequences for patients of these reinstated restrictions to providing telemedicine across state borders are substantial, especially for patients confronting life and death decisions similar to our patient.5 This patient is not unique; many patients in the USA are now taking video appointments in their cars, on roadsides and in parking lots, travelling unnecessarily to the doctor's office, or simply skipping follow-up care. Our patient's trip required substantial planning, and the patient had to pack several tanks of oxygen to ensure that he had sufficient oxygen for the entire trip. Patients are now subject to accidents of geography. Two patients with the same lung disease who both live the same distance from their pulmonologist can have very different access to their physician. The patient who lives in the same state as the physician can have a telemedicine visit from the comfort of their home. The patient who lives in another state must travel or skip the appointment. The current situation also encourages patients to lie to their physician. To ensure they are compliant with state laws, physicians typically ask patients where they are at the time of the visit. For all practical purposes, the patient could be sitting in a car just outside the home and tell his physician that he was within the state border. Indeed, just the other week, a man in his mid-70s with pulmonary fibrosis considered this, as he thought it was pointless to drive approximately 4 km to be within the border of Washington just to sit in his car for a telemedicine encounter with GR.
Given that the current US licensure does not work for telemedicine, there is a clear need for reform. The medical conditions and management of patients are the same across state lines, and licenced physicians are all trained in accredited programmes in the USA. Ideally, a licenced physician could freely care for any patient in the nation. Many licensure reforms are being debated. One idea is that the federal government could create a single national licence that would allow a physician to care for any patient in person or via telemedicine. Unfortunately, this idea does not have substantial support. Reforms being considered by individual states include full licence reciprocity between states (rather than having physicians being licenced in each state), creating special telemedicine-only licences for physicians in another state, or creating exceptions for licensure when the patient and physician have previously had an in-person visit.4
The potential benefits of telemedicine visits, as well as home monitoring for the treatment of pulmonary disease, have been discussed elsewhere in this issue.6, 7 However, the benefits will not reach all patients unless challenges are addressed. We have focused on licensure, because of its sudden salience and need for reform, but we acknowledge that there are many other barriers. For example, there remains uncertainty on whether all telemedicine visits will be paid for in the future by government payers and private plans. With this uncertainty, pulmonologists and health systems might be reluctant to make investments in telehealth infrastructure. Relatedly, there is uncertainty on how telehealth should be paid and, specifically, whether physicians, providers, specialists such as pulmonologists, or subspecialists should receive reimbursement for each visit or capitated payments (eg, a monthly payment for a given patient).8 Another barrier is that the provider, physician, or specialist cannot provide high-quality care for all patients with just a video encounter on a computer or smartphone.9 Data such as oximetry for oxygen saturation, forced vital capacity and FEV1 by home spirometry, electrocardiograms, day-to-day physical activities such as ambulation (eg, steps per day or distance covered over a defined time), and auscultation from digital stethoscopes are often crucial for optimal diagnosis and management. It remains unclear whether the data collected by patients are similar to the measurements obtained by trained staff and supervised in a medical facility. It also remains uncertain how patients should access these digital tools, how society should pay for such home measurements and assessments by remote devices, and how these results should be incorporated into the electronic health record. Only when these, and other barriers to care, are addressed will all patients have access to the clinicians they need, regardless of their origin and location.
GR is a long-standing licenced physician in the state of Washington, USA, pulmonologist in clinical practice, and an expert in the field of interstitial lung diseases and pulmonary fibrosis; he reports research grants from the National Institute of Health (NIH); and is a consultant for Bristol Myers-Squibb, Bellerophan, Fibrogen, Gilead Sciences, Nitto, Novartis, Roche-Genentech, and Veracyte for studies outside of the submitted work. AM reports grants from NIH, Commonwealth Fund, and Arnold Foundation; personal fees from Black Opal Ventures, Commonwealth of Massachusetts, Pew Charitable Trusts, Sanofi-Pasteur, and HHS Assistant Secretary Planning evaluation outside of the submitted work.
==== Refs
References
1 Centers for Medicare and Medicaid Services COVID-19 emergency declaration blanket waivers for health care providers https://www.cms.gov/files/document/summary-covid-19-emergency-declaration-waivers.pdf Dec 1, 2020
2 Raghu G Remy-Jardin M Richeldi L Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline Am J Respir Crit Care Med 205 2022 e18 e47 35486072
3 Lee JYT Tikellis G Corte TJ The supportive care needs of people living with pulmonary fibrosis and their caregivers: a systematic review Eur Respir Rev 29 2020 190125
4 Mehrotra A Nimgaonkar A Richman B Telemedicine and medical licensure –potential paths for reform N Engl J Med 384 2021 687 690 33626604
5 Macdonald SM Berv J Losing contact—covid-19, telemedicine and the patient-provider relationship N Engl J Med 387 2022 775 777 36026588
6 Wijsenbeek MS Moor CC Johannson KA Home monitoring in interstitial lung diseases Lancet Respir Med 2022 published online Oct 4. 10.1016/S2213-2600(22)00228-4
7 Holland AE Glaspole I Lockdown as the mother of invention: disruptive technology in a disrupted time Lancet Respir Med 2022 published online Oct 4. 10.1016/S2213-2600(22)00291-0
8 Adler-Milstein J Mehrotra A Paying for digital health care—problems with the fee-for-service system N Engl J Med 385 2021 871 873 34449187
9 Romanick-Schmiedl S Raghu G Telemedicine—maintaining quality during times of transition Nat Rev Dis Primers 6 2020 45 32483168
| 36521508 | PMC9744441 | NO-CC CODE | 2022-12-15 00:01:45 | no | Lancet Respir Med. 2022 Dec 12; doi: 10.1016/S2213-2600(22)00482-9 | utf-8 | Lancet Respir Med | 2,022 | 10.1016/S2213-2600(22)00482-9 | oa_other |
==== Front
Lancet Infect Dis
Lancet Infect Dis
The Lancet. Infectious Diseases
1473-3099
1474-4457
Elsevier Ltd.
S1473-3099(22)00732-0
10.1016/S1473-3099(22)00732-0
Articles
Effectiveness of BNT162b2 and CoronaVac COVID-19 vaccination against asymptomatic and symptomatic infection of SARS-CoV-2 omicron BA.2 in Hong Kong: a prospective cohort study
Tsang Nicole Ngai Yung MPH a
So Hau Chi MNurs a
Cowling Benjamin J Prof PhD a
Leung Gabriel M Prof MD a
Ip Dennis Kai Ming MD a*
a WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
* Correspondence to: Dr Dennis Kai Ming Ip, WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region 999077, China
12 12 2022
12 12 2022
© 2022 Elsevier Ltd. All rights reserved.
2022
Elsevier Ltd
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Background
COVID-19 vaccines provide protection against symptomatic infection that might require medical attention and against severe outcomes; however, there is a paucity of evidence regarding the effectiveness of the BNT162b2 and CoronaVac vaccines and their booster regimens against asymptomatic or mild omicron infections in the community. We aimed to measure the effectiveness of BNT162b2 and CoronaVac vaccines against asymptomatic and symptomatic SARS-CoV-2 omicron infections, during a period of omicron BA.2 predominance in Hong Kong.
Methods
In this prospective cohort study in a population that was generally infection-naive before the large omicron BA.2 wave between January and late May, 2022, we established a public health surveillance platform to monitor the evolving activity of SARS-CoV-2 infections in the community. We recruited a cohort of individuals aged 5 years and older between March 1 and March 7, 2022, from the general population. Individuals were enrolled from all 18 districts of Hong Kong, according to a predefined age-stratified quota, primarily by random digit dialing (generating suitable eight-digit local telephone numbers by randomly picking sets of the first four digits from a sampling frame, and randomly generating the last four digits), and supplemented by our existing cohorts (which included cohorts for studying influenza vaccination from school-based vaccination programmes and cohorts for SARS-CoV-2 seroprevalence from the community), to ensure representativeness of the population in Hong Kong. Participants did weekly rapid antigen testing with a self-collected pooled nasal and throat swab, regardless of symptom and exposure status, from March 1 to April 15, 2022. Individuals reporting a history of SARS-CoV-2 infection confirmed by laboratory PCR testing before enrolment were excluded from the vaccine effectiveness analysis to avoid potential bias due to infection-induced immunity. The primary outcomes of the study were the incidence of SARS-CoV-2 infection, including asymptomatic and symptomatic infections, and the vaccine effectiveness of BNT162b2 and CoronaVac vaccines. The effectiveness of one, two, and three doses of vaccination was estimated with a Cox proportional hazards regression model with time-dependent covariates, allowing for changes in vaccination status over time, after adjustment for demographic factors and pre-existing medical conditions.
Findings
Of the 8636 individuals included in the analysis, 7233 (84%) received at least two doses of vaccine, 3993 (46%) received booster doses, and 903 (10%) reported SARS-CoV-2 infection. Among these infections 589 (65·2%) were symptomatic and 314 (34·8%) were asymptomatic at the time of testing. Statistically significant protection against asymptomatic and symptomatic SARS-CoV-2 omicron infection was found only for those who received a BNT162b2 or CoronaVac booster dose, with a vaccine effectiveness of 41·4% (23·2 to 55·2; p=0·0001) and 32·4% (9·0 to 49·8; p=0·0098), respectively. The vaccine effectiveness of BNT162b2 and CoronaVac boosters was further increased to 50·9% (95% CI 31·0–65·0; p<0·0001) and 41·6% (15·0–59·8; p=0·0049), respectively, for symptomatic omicron infections. A similar pattern of vaccine effectiveness (55·8%, 22·9–74·6; p=0·0040) was also conferred after receipt of a BNT162b2 booster by individuals who received a CoronaVac primary vaccination series.
Interpretation
Two doses of either vaccine did not provide significant protection against COVID-19 infection. However, receipt of a BNT162b2 booster or CoronaVac booster was associated with a significantly lower risk of omicron BA.2 infection and symptomatic infection. Our findings confirm the effectiveness of booster doses to protect against mild and asymptomatic infection.
Funding
Henry Fok Foundation and Hong Kong Health Bureau.
==== Body
pmcIntroduction
With the current global predominance of the omicron variant of SARS-CoV-2, previous understanding of the effectiveness of different COVID-19 vaccines against the ancestral strain and earlier variants is no longer sufficient to inform the way forward during the evolving COVID-19 pandemic.1 Literature has generally suggested that a primary series plus booster doses of mRNA vaccine shows modest to high effectiveness against severe COVID-19 outcomes, including hospitalisation, mechanical ventilation, and death,2, 3, 4, 5, 6, 7 and effectively prevents symptomatic infections.4, 5, 7, 8, 9 However, evidence of the effectiveness of vaccines in preventing mild and asymptomatic infections, which have potential public health implications for seeding downstream secondary transmission, are generally lacking.
Research in context
Evidence before this study
With the evolving omicron variants of SARS-CoV-2, previous understanding of the effectiveness of COVID-19 vaccines against the ancestral strain and earlier variants is becoming increasingly insufficient. Newer omicron-specific vaccine-effectiveness estimates are needed to inform the way forward, especially for individuals who present with asymptomatic infection, who might either have no symptoms or develop symptoms later (pre-symptomatic), because of the potential public health implications for seeding downstream secondary transmission. We searched PubMed and MedRxiv, with no language restrictions, from database inception up to Sept 14, 2022, using the search terms “((vaccine effectiveness) AND (omicron)) AND (((BNT162b2) OR (Comirnaty)) OR (CoronaVac))”, and found 133 published articles and 791 preprints. 118 of these publications reported vaccine effectiveness against omicron outcomes, with 100 studies focused only on symptomatic infection or severe complications. Among the 18 studies that attempted to examine asymptomatic infections, only ten reported aggregated vaccine effectiveness rather than the vaccine effectiveness of specific vaccine types, three used only a risk-based testing approach, which was not optimal in ascertaining asymptomatic infections, and five were of restricted generalisability, as they focused on specific population subgroups (one each on haemodialysis patients, people who were incarcerated, and university students and employees, and two on children). To our knowledge, to date, no study has reported the vaccine effectiveness of the BNT162b2 booster or CoronaVac vaccines and booster regimens against omicron BA.2 asymptomatic infection.
Added value of this study
The population of Hong Kong was generally omicron-infection-naive before a large BA.2 wave extending from January 1 to April 30, 2022, and peaking in early March. Our prospective observational cohort study examined and compared the vaccine effectiveness of BNT162b2 and CoronaVac against asymptomatic and symptomatic SARS-CoV-2 omicron BA.2 infections. The systematic use of weekly SARS-CoV-2 rapid antigen testing for outcome ascertainment, regardless of exposure status and symptoms, allowed for identification of asymptomatic infections, including in those who remained asymptomatic and those who went on to develop symptoms (pre-symptomatic), and improved generalisability to community infections. To our knowledge, our study is the first to report the effectiveness of CoronaVac vaccines against SARS-CoV-2 omicron BA.2 asymptomatic infections. Our results suggest that no significant protection was observed for one or two doses of BNT162b2 and CoronaVac. Significant protection against SARS-CoV-2 asymptomatic and symptomatic omicron infection was shown for those who received a BNT162b2 booster or CoronaVac booster. A similar pattern of vaccine effectiveness was also conferred by administering a BNT162b2 booster dose to individuals who received a CoronaVac primary vaccination series.
Implications of all the available evidence
Our results suggest that a booster dose of COVID-19 vaccine is needed to achieve significant protection against omicron infection, by either an inactivated or mRNA vaccine, which highlights the importance of achieving high coverage of booster doses. Our study shows the experimental feasibility for examining vaccine effectiveness against asymptomatic and mild infections using a systematic outcome-ascertainment approach, irrespective of exposures status and symptoms.
However, examination of the effectiveness of vaccines in preventing mild and asymptomatic COVID-19 infections is inherently challenging. Common study designs used for studying vaccine effectiveness, including test-negative design, depend on symptomatic cases presenting in various settings.9 Therefore, such designs can be biased towards the more severe end of the clinical spectrum and might not be generalisable to all cases in the community. Moreover, previous observational vaccine effectiveness studies that do not have a prescribed similar testing schedule might be biased by the potential differential testing frequencies and behaviours among people with different vaccination status.10, 11 Previous vaccine effectiveness studies against omicron infections have focused mainly on various mRNA vaccine candidates, including BNT162b2 (Pfizer–BioNTech) and the mRNA-1273 (Moderna) vaccine, or adenoviral vector vaccines, such as ChAdOx1 nCoV-19 (AstraZeneca),4, 5, 7, 8, 9, 12 and, to our knowledge, the effectiveness of inactivated vaccine (eg CoronaVac [Sinovac]) against omicron infections has yet to be investigated. Although previous studies have reported the effectiveness of BNT162b2 among children and adolescents,9, 12 the comparative effectiveness of BNT162b2 and CoronaVac vaccines among different age groups remains unclear. We did a study examining the effectiveness of BNT162b2 and CoronaVac vaccines against SARS-CoV-2 infection, using a prospective and systematic approach to outcome ascertainment, regardless of risk or symptoms, and therefore capturing mild and asymptomatic infections, during a period of omicron BA.2 predominance in Hong Kong.
Methods
Study design and participants
From early January to late May, 2022, Hong Kong had its fifth and the largest wave of the COVID-19 pandemic, with daily reported positive SARS-CoV-2 cases rising progressively to a maximum of more than 50 000 per day, and largely caused by the omicron variant sublineage BA.2. From March 1, 2022, we established a public health surveillance platform to monitor the evolving activity of SARS-CoV-2 infections in the community. We recruited a cohort of individuals aged 5 years and older between March 1 and March 7, 2022, from the general population. Individuals were enrolled from all 18 districts of Hong Kong, according to a predefined age-stratified quota, primarily by random digit dialing, and supplemented by our existing cohorts, to ensure representativeness of the population in Hong Kong. Random digit dialing involved generating suitable eight-digit local telephone numbers for recruitment by randomly picking sets of the first four digits from a sampling frame, and randomly generating the last four digits using Microsoft Excel. The existing cohorts included cohorts maintained for studying protection from influenza vaccination in school-based vaccination programmes and cohorts for studying SARS-CoV-2 seroprevalence recruited from the community. Eligible participants had to consent to do regular scheduled rapid antigen tests and be competent at self-reporting testing results to our online system to be recruited to the study. An incentive of supermarket coupon of US$50 would be given to participants submitting 100% of scheduled weekly tests for achieving a high compliance.
Before the study period, COVID-19 infections in the community were confirmed using PCR by either the government laboratory or another officially recognised laboratory in Hong Kong. History of any previous PCR-confirmed infection before joining the study was ascertained by self-reporting in a baseline questionnaire on recruitment. Individuals reporting a history of COVID-19 infection confirmed by laboratory PCR testing before enrolment were excluded from the vaccine effectiveness analysis to avoid potential bias due to natural immunity13 as, given a very low seroprevalence of infection before the omicron wave,14 most people reporting a previous infection would have had a recent infection with the omicron BA.2 strain, thus were presumed to be immune to this strain.
The community surveillance programme was reviewed and commissioned by the Health Bureau of the Hong Kong Special Administrative Region Government as an emergency public health initiative during the rapid upswing of the fifth wave of the COVID-19 pandemic in Hong Kong and thus was exempted from a full ethics review. Written informed consent was obtained from all individuals, allowing collection, storage, and use of information for surveillance and anonymised research purposes.
Procedures
Outcome ascertainment of COVID-19 infection was done using a COVID-19 lateral flow rapid antigen test (INDICAID; PHASE Scientific, Hong Kong) for the qualitative detection of SARS-CoV-2 nucleocapsid protein. A rapid antigen test assay brand that met the WHO priority target product profiles for COVID-19 diagnostics (ie, sensitivity ≥80% and specificity ≥97%)15 and the US Food and Drug Administration (FDA) Emergency Use Authorization16 was chosen to address the issue of variable sensitivity between assay brands.17, 18 Rapid antigen tests were provided to all consenting individuals for weekly testing with a self-collected pooled nasal and throat swab, regardless of symptom and exposure status, and participants submitted the test results (positive, negative, or invalid) with rapid antigen test photographs to an online platform. Additional rapid antigen tests done at the participants' discretion were also captured. Demographic information, including sex, age, chronic illness history, COVID-19 infection history, household size, housing type, district, and residential address, was collected at enrolment. Corresponding estimates from the overall population were extracted from the 2021 and 2016 Hong Kong Population Census from the Census and Statistics Department. COVID-19 infection was defined as any positive rapid antigen test result reported during the study period, irrespective of symptoms. Symptomatic COVID-19 infections were defined as those receiving a positive rapid antigen test result and reporting at least one of 19 surveyed symptoms (appendix p 1). Asymptomatic infections were defined as positive rapid antigen test without any symptoms at the time point of the test. Participants were stratified into quartiles of socioeconomic levels according to the published monthly domestic household rent of the Hong Kong tertiary planning unit (TPU) that their residential addresses belong to (Q1 [lowest]: ≤HK$1510; Q2: HK$1511–2050; Q3: HK$2051–5300; Q4 [highest]: ≥HK$5301). Vaccination records were collected at baseline and updated regularly and verified by individual official vaccination documents submitted via the same online platform as for rapid antigen test reporting.
Outcomes
The primary outcomes of the study were the incidence of SARS-CoV-2 infection, including asymptomatic and symptomatic infections, and the vaccine effectiveness of BNT162b2 and CoronaVac.
Statistical analysis
Cohen's w effect size, defined as
w=∑i=1m(p1i-p0i)2p0i
—where P 0i represents the proportion in cell i posited by the population overall according to the 2021 Population Census from the Hong Kong Census and Statistics Department, P 0i represents the proportion in cell i posited by the cohort, and m is the number of cells—was used to estimate the degree of discrepancy between the distribution of our cohort and the Hong Kong population, where a small departure (w=0·1) represents weak discrepancy, a medium departure (w=0·3) represents medium discrepancy, and a larger departure (w=0·5) denotes large discrepancy.19
We studied the risk of infection using the community surveillance data during the peak of the epidemic wave in Hong Kong between March 1 and April 15, 2022, to examine the effectiveness of COVID-19 vaccination. Individuals were included in the analysis until the day of infection as confirmed by a positive rapid antigen test, or the end of study period (April 15, 2022), whichever occurred first. Time to infection was measured from the respective date of enrolment for all individuals to control for time-varying confounders (eg, amount of community transmission and prevalence of the omicron variant) when comparing the risk of COVID-19 between vaccinated and unvaccinated people.20 To address the potential for immortal time bias, we continuously ascertained and updated the classification of the vaccination status of each individual dynamically, as unvaccinated, first dose, second dose, or third dose during the entire study period. Individuals reported their updated vaccination status and date of vaccination in the weekly scheduled submission. Only vaccine doses completed more than 14 days before the rapid antigen testing were counted.21
Since the independent variable (vaccination status) varied over time, univariate and multivariate survival analyses were done with time-dependent covariates (vaccination status) according to the study design. Kaplan-Meier analysis was done for univariate analyses. The association between vaccination and risk of infection was estimated by a multivariate Cox proportional hazards regression model after adjustment for age,22 gender,23 coexisting illnesses,24 and other sociodemographic factors that might confound rapid antigen test positivity—eg, household size, district, housing type, and TPU median monthly domestic household rent—which were associated with test positivity in univariate regression models. All covariates were tested for the proportional hazards assumption by Schoenfeld's global test. 95% CIs were estimated using robust SEs.
We estimated vaccine effectiveness as 1 minus the adjusted hazard ratio (HR), where the adjusted HR was obtained from a multivariate Cox proportional hazards regression model with time-dependent covariates to estimate the risk of rapid antigen test positivity for individuals who were unvaccinated, or who had received one, two, or three doses of vaccination using the Mantel-Byar method.25 Using information on the time between the start of follow-up and exposure initiation, individuals were followed up from the time of cohort entry, with infection status (rapid antigen test result) and vaccination status updated on a weekly basis. Data from individuals with time-varying vaccination status were split into multiple data segments, each with the corresponding interval of follow-up period for assessing the effectiveness of different vaccination status in the regression model. The effectiveness of one, two, and three doses of vaccination was estimated with unvaccinated people as a reference group. Vaccine effectiveness for the primary series (two doses) was assessed by stratification into either completed within 3 months (14–89 days) or completed 3 months or longer (90 or more days) after the second dose. Most people who received only one dose and those who had received three doses had received their latest dose within the past 3 months so participants were not further stratified. The outcome of infection was ascertained at the time of first rapid antigen test positivity. We estimated vaccine effectiveness for preventing any SARS-CoV-2 infection, irrespective of clinical symptoms (symptomatic and asymptomatic infection), as well as for symptomatic infection. Individual data were censored 14 days after the receipt of a vaccine in the unvaccinated group, after receipt of a further dose in the one-dose and two-dose groups, at 3 months after the second dose if no further doses were received, or at the end of follow-up.
Vaccine effectiveness was also estimated with stratification by age group (children aged 5–17 years, adults aged 18–59 years, and older adults ≥60 years) and vaccine type (BNT162b2 and CoronaVac),13, 26 with the effectiveness of primary series and booster vaccination for different vaccine types (BNT162b2 and CoronaVac) examined and compared among each age group. Relative vaccine effectiveness was estimated by comparing the relative protection additionally conferred by CoronaVac, using BNT162b2 as a reference. As the local Hong Kong vaccine policy required the same vaccine type to be used in both doses in the primary series, the small proportion of individuals who received the first two doses with different vaccine types from elsewhere were not included in the analysis. As switching to a different vaccine type was allowed for the booster dose, regimens of different vaccine combinations for those who received a third dose were included in the analysis if sample size permitted.
p<0·05 was considered to indicate a statistically significant difference. To achieve 80% power with a 0·05 type I error rate in the survival analysis, 334 positive rapid antigen tests were needed with a HR of 0·60 between vaccinated and unvaccinated groups. All data processing and analyses were done in R (version 4.1.0), using the packages survival and tidyverse.
Role of the funding source
The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Results
1560 (15·3%) of 10 196 individuals in the cohort had reported themselves to be previously infected with SARS-CoV-2 before enrolment and thus were excluded from the vaccine effectiveness analysis. Among the 8636 individuals included in the vaccine effectiveness analysis, 903 (10·5%) were infected during the surveillance period, with a median of 10 days (IQR 6–17) between enrolment and infection; among these infections 589 (65·2%) were symptomatic and 314 (34·8%) were asymptomatic. 7233 (84%) individuals had received at least two doses of vaccine and 3993 (46%) received booster doses. The distribution of positive and negative cases according to sex, age, and comorbidity status was similar (table 1 ). Sociodemographic factors associated with test positivity included household size, district, housing type, and TPU level median monthly domestic household rent (appendix p 2). High compliance with weekly testing was maintained in 8419 (97·5%) individuals, with a similar pattern across different characteristics (appendix p 3).Table 1 Characteristics of people tested for SARS-CoV-2 with rapid antigen test, according to test positivity or negativity
Hong Kong population* Study cohort
Number of individuals (n=7 182 991) Number of individuals (n=8636) Effect size† Negative rapid antigen test (n=7733) Positive rapid antigen test (n=903)
Gender 0·0001
Female 3 918 820 (54·6%) 4723 (54·7%) .. 4230 (54·7%) 493 (54·6%)
Male 3 264 171 (45·4%) 3913 (45·3%) .. 3503 (45·3%) 410 (45·4%)
Age group, years .. .. 0·0068 .. ..
5–17 738 609 (10·3%) 886 (10·3%) .. 787 (10·2%) 99 (11·0%)
18–59 4 379 236 (61·0%) 6014 (69·6%) .. 5383 (69·6%) 631 (69·9%)
≥60 2 065 146 (28·8%) 1736 (20·1%) .. 1563 (20·2%) 173 (19·2%)
Hong Kong region .. .. 0·0018 .. ..
Hong Kong 1 161 636 (16·2%) 1300 (15·1%) .. 1168 (15·1%) 132 (14·6%)
Kowloon 2 166 850 (30·2%) 2482 (28·7%) .. 2204 (28·5%) 278 (30·8%)
New Territories and Marine 3 854 505 (53·7%) 4854 (56·2%) .. 4361 (56·4%) 493 (54·6%)
Hong Kong district .. .. 0·0040 .. ..
Central and Western 228 370 (3·2%) 203 (2·4%) .. 179 (2·3%) 24 (2·7%)
Wan Chai 161 585 (2·2%) 118 (1·4%) .. 114 (1·5%) 4 (0·4%)
Eastern 515 623 (7·2%) 648 (7·5%) .. 575 (7·4%) 73 (8·1%)
Southern 256 058 (3·6%) 331 (3·8%) .. 300 (3·9%) 31 (3·4%)
Yau Tsim Mong 298 791 (4·2%) 280 (3·2%) .. 253 (3·3%) 27 (3·0%)
Sham Shui Po 417 242 (5·8%) 451 (5·2%) .. 415 (5·4%) 36 (4·0%)
Kowloon City 397 230 (5·5%) 450 (5·2%) .. 387 (5·0%) 63 (7·0%)
Wong Tai Sin 397 585 (5·5%) 479 (5·5%) .. 423 (5·5%) 56 (6·2%)
Kwun Tong 656 002 (9·1%) 822 (9·5%) .. 726 (9·4%) 96 (10·6%)
Kwai Tsing 482 396 (6·7%) 578 (6·7%) .. 473 (6·1%) 105 (11·6%)
Tsuen Wan 308 481 (4·3%) 462 (5·3%) .. 402 (5·2%) 60 (6·6%)
Tuen Mun 490 910 (6·8%) 598 (6·9%) .. 535 (6·9%) 63 (7·0%)
Yuen Long 643 865 (9·0%) 811 (9·4%) .. 746 (9·6%) 65 (7·2%)
North 300 183 (4·2%) 352 (4·1%) .. 320 (4·1%) 32 (3·5%)
Tai Po 306 046 (4·3%) 347 (4·0%) .. 320 (4·1%) 27 (3·0%)
Sha Tin 672 418 (9·4%) 882 (10·2%) .. 809 (10·5%) 73 (8·1%)
Sai Kung 471 901 (6·6%) 623 (7·2%) .. 571 (7·4%) 52 (5·8%)
Islands and Marine 178 305 (2·5%) 201 (2·3%) .. 185 (2·4%) 16 (1·8%)
Have a chronic illness 1 799 100 (25·0%) 1783 (20·6%) 0·0035 1593 (20·6%) 190 (21·0%)
Median monthly domestic household rent quartile‡ .. .. 0·0021 .. ..
1 (lowest) 1 738 085/7 334 200 (23·7%) 1966 (22·8%) .. 1711 (22·1%) 255 (28·2%)
2 1 841 942/7 334 200 (25·1%) 2199 (25·5%) .. 1968 (25·4%) 231 (25·6%)
3 1 891 657/7 334 200 (25·8%) 2428 (28·1%) .. 2194 (28·4%) 234 (25·9%)
4 (highest) 1 862 516/7 334 200 (25·4%) 2043 (23·7%) .. 1860 (24·1%) 183 (20·3%)
Household size§, people .. .. 0·0298 .. ..
1–2 1 307 784/2 674 161 (48·9%) 2146 (24·8%) .. 1975 (25·5%) 171 (18·9%)
3–4 1 097 254/2 674 161 (41·0%) 4689 (54·3%) .. 4167 (53·9%) 522 (57·8%)
≥5 269 123/2 674 161 (10·1%) 1801 (20·9%) .. 1591 (20·6%) 210 (23·3%)
Housing type¶ .. .. 0·0055 .. ..
Public rental housing 2 120 704/7 047 963 (30·1%) 2414 (28·0%) .. 2032 (26·3%) 382 (42·3%)
Subsidised home ownership scheme housing 1 129 933/7 047 963 (16·0%) 1635 (18·9%) .. 1482 (19·2%) 153 (16·9%)
Private permanent housing 3 710 508/7 047 963 (52·7%) 4356 (50·4%) .. 4005 (51·8%) 351 (38·9%)
Others 86 818/7 047 963 (1·2%) 231 (2·7%) .. 214 (2·8%) 17 (1·9%)
Have COVID-19 symptoms .. 632 (7·3%) .. 43 (0·6%) 589 (65·2%)
Vaccination status‖ .. .. 0·0049 .. ..
Unvaccinated 731 112/7 394 700 (9·9%) 764 (8·8%) .. 641 (8·3%) 123 (13·6%)
One dose 656 086/7 394 700 (8·9%) 639 (7·4%) .. 545 (7·0%) 94 (10·4%)
Two doses 3 105 353/7 394 700 (42·0%) 3240 (37·5%) .. 2771 (35·8%) 469 (51·9%)
Three doses 2 902 149/7 394 700 (39·2%) 3993 (46·2%) .. 3776 (48·8%) 217 (24·0%)
Data are n (%) or n/N (%), unless otherwise indicated. Only individuals aged 5 years and older were included.
* Estimates from the overall population were extracted from the 2021 Hong Kong Population Census from the Census and Statistics Department.
† Cohen's w effect size: small 0·1; medium 0·3; large 0·5.
‡ Tertiary planning unit-level median monthly domestic household rent was based on the latest available census data in 2016 for the Hong Kong population.
§ Number of households with the corresponding household size for the Hong Kong population.
¶ Total population in domestic households for the Hong Kong population.
‖ Total population in 2021, without excluding those younger than 5 years, for the Hong Kong population.
764 (8·8%) of 8636 individuals were unvaccinated, 639 (7·4%) had only one dose of vaccine, 3240 (37·5%) had two doses, and 3993 (46·2%) had three doses (table 1). Differences in monthly domestic household rent, housing type, and geographical district were observed between vaccination status; in particular, individuals who received three doses of vaccine had a higher likelihood of being male, older, having a chronic illness, having a smaller household size, and being asymptomatic (appendix p 4). 2308 (71·2%) of 3240 individuals who received two doses of vaccine had received the second dose more than 3 months before testing, so vaccine effectiveness was stratified by those who had completed the second dose within 3 months or 3 months or longer before testing. For the primary series of two vaccine doses, 2353 (27·2%) of 8636 individuals received BNT162b2 and 875 (10·1%) individuals received CoronaVac. For the primary series using BNT162b2, 1884 (21·8%) of 8636 individuals completed the two doses 3 months before testing and 469 (5·4%) completed the two doses within 3 months of testing (table 2 ). For the primary series using CoronaVac, 458 (5·3%) of 8636 individuals completed the two doses 3 months before testing and 417 (4·8%) completed the two doses within 3 months of testing (table 2). As switching of vaccine between the two doses was not allowed in the primary series, only 12 (0·1%) of 8636 individuals had two doses with other vaccine combinations, and were not included in the primary analysis (table 2).Table 2 Vaccination status by age group
Population Cohort
Total (n=7 394 700) Aged 0–19 years (n=1 108 900) Aged 20–59 (n=4 251 700) Aged ≥60 (n=2 034 100) Total (n=8636) Aged 5–17 (n=886) Aged 18–59 (n=6014) Aged ≥60 (n=1736) Effect size*†
Unvaccinated 731 112 (9·9%) 343 882 (31·0%) 36 758 (0·9%) 350 472 (17·2%) 764 (8·8%) 216 (24·4%) 390 (6·5%) 158 (9·1%) 0·0678
One dose 656 086 (8·9%) 274 057 (24·7%) 208 505 (4·9%) 173 524 (8·5%) 639 (7·4%) 287 (32·4%) 232 (3·9%) 120 (6·9%) 0·0055
≥3 months .. .. .. .. 71 (0·8%) 40 (4·5%) 28 (0·5%) 3 (0·2%) ..
<3 months .. .. .. .. 568 (6·6%) 247 (27·9%) 204 (3·4%) 117 (6·7%) ..
Two doses 3 105 353 (42·0%) 412 728 (37·2%) 1 921 045 (45·2%) 771 580 (37·9%) 3240 (37·5%) 323 (36·5%) 2404 (40·0%) 513 (29·6%) 0·0083
≥3 months .. .. .. .. 2308 (26·7%) 133 (15·0%) 1899 (31·6%) 276 (15·9%) ..
<3 months .. .. .. .. 932 (10·8%) 190 (21·4%) 505 (8·4%) 237 (13·7%) ..
Three doses 2 902 149 (39·2%) 78 233 (7·1%) 2 085 392 (49·0%) 738 524 (36·3%) 3993 (46·2%) 60 (6·8%) 2988 (49·7%) 945 (54·4%) 0·0033
≥3 months .. .. .. .. 852 (9·9%) 1 (0·1%) 555 (9·2%) 296 (17·1%) ..
<3 months .. .. .. .. 3141 (36·4%) 59 (6·7%) 2433 (40·5%) 649 (37·4%) ..
One dose BNT162b2 285 584 (3·9%) 143 169 (12·9%) 108 969 (2·6%) 33 446 (1·6%) 329 (3·8%) 152 (17·2%) 145 (2·4%) 32 (1·8%) 0·0042
≥3 months .. .. .. .. 61 (0·7%) 36 (4·1%) 23 (0·4%) 2 (0·1%) ..
<3 months .. .. .. .. 268 (3·1%) 116 (13·1%) 122 (2·0%) 30 (1·7%) ..
One dose CoronaVac 370 502 (5·0%) 130 888 (11·8%) 99 536 (2·3%) 140 078 (6·9%) 310 (3·6%) 135 (15·2%) 87 (1·4%) 88 (5·1%) 0·0060
≥3 months .. .. .. .. 10 (0·1%) 4 (0·5%) 5 (0·1%) 1 (0·1%) ..
<3 months .. .. .. .. 300 (3·5%) 131 (14·8%) 82 (1·4%) 87 (5·0%) ..
Two dose BNT162b2 1 818 926 (24·6%) 232 148 (20·9%) 1 316 777 (31·0%) 270 001 (13·3%) 2353 (27·2%) 175 (19·8%) 1914 (31·8%) 264 (15·2%) 0·0074
≥3 months .. .. .. .. 1884 (21·8%) 124 (14·0%) 1589 (26·4%) 171 (9·9%) ..
<3 months .. .. .. .. 469 (5·4%) 51 (5·8%) 325 (5·4%) 93 (5·4%) ..
Two dose CoronaVac 1 237 279 (16·7%) 175 799 (15·9%) 566 889 (13·3%) 494 591 (24·3%) 875 (10·1%) 146 (16·5%) 481 (8·0%) 248 (14·3%) 0·0063
≥3 months .. .. .. .. 417 (4·8%) 8 (0·9%) 305 (5·1%) 104 (6·0%) ..
<3 months .. .. .. .. 458 (5·3%) 138 (15·6%) 176 (2·9%) 144 (8·3%) ..
Two dose other combinations 49 148 (0·7%) 4781 (0·4%) 37 379 (0·9%) 6988 (0·3%) 12 (0·1%) 2 (0·2%) 9 (0·1%) 1 (0·1%) 0·0042
≥3 months .. .. .. .. 7 (0·1%) 1 (0·1%) 5 (0·1%) 1 (0·1%) ..
<3 months .. .. .. .. 5 (0·1%) 1 (0·1%) 4 (0·1%) 0 ..
Three dose BNT162b2 1 580 623 (21·4%) 64 639 (5·8%) 1 213 564 (28·5%) 302 420 (14·9%) 2432 (28·2%) 56 (6·3%) 1913 (31·8%) 463 (26·7%) 0·0036
≥3 months .. .. .. .. 296 (3·4%) 1 (0·1%) 198 (3·3%) 97 (5·6%) ..
<3 months .. .. .. .. 2136 (24·7%) 55 (6·2%) 1715 (28·5%) 366 (21·1%) ..
Three dose CoronaVac 905 449 (12·2%) 5128 (0·5%) 571 478 (13·4%) 328 843 (16·2%) 1050 (12·2%) 0 734 (12·2%) 316 (18·2%) 0·0052
≥3 months .. .. .. .. 371 (4·3%) 0 241 (4·0%) 130 (7·5%) ..
<3 months .. .. .. .. 679 (7·9%) 0 493 (8·2%) 186 (10·7%) ..
Two dose CoronaVac plus BNT162b2 416 077 (5·6%)‡ 8466 (0·8%) 300 350 (7·1%) 107 261 (5·3%) 463 (5·4%) 0 310 (5·2%) 153 (8·8%) 0·0070
≥3 months .. .. .. .. 178 (2·1%) 0 112 (1·9%) 66 (3·8%) ..
<3 months .. .. .. .. 285 (3·3%) 0 198 (3·3%) 87 (5·0%) ..
Two dose BNT162b2 plus CoronaVac .. .. .. .. 29 (0·3%) 4 (0·5%) 18 (0·3%) 7 (0·4%) ..
≥3 months .. .. .. .. 3 (<0·1%) 0 2 (<0·1%) 1 (0·1%) ..
<3 months .. .. .. .. 26 (0·3%) 4 (0·5%) 16 (0·3%) 6 (0·3%) ..
Three dose other combinations .. .. .. .. 19 (0·2%) 0 13 (0·2%) 6 (0·3%) ..
≥3 months .. .. .. .. 4 (0·1%) 0 2 (<0·1%) 2 (0·1%) ..
<3 months .. .. .. .. 15 (0·2%) 0 11 (0·2%) 4 (0·2%) ..
Data are n (%), unless otherwise indicated.
* Overall effect size for the cohort 0·0084.
† Cohen's w effect size: small 0·1; medium 0·3; large 0·5.
‡ Included three doses with any vaccine combinations in local population.
For individuals who received three doses of vaccine, 2432 (28·2%) of 8636 received three doses of BNT162b2 and 1050 (12·2%) received CoronaVac. A small proportion of individuals received a combination, either of a primary series of CoronaVac followed by a BNT162b2 booster (463 [5·4%] of 8636 individuals), or a primary series of BNT162b2 followed by a CoronaVac booster (29 [0·3%] individuals). 19 (0·2%) of 8636 individuals received three vaccine doses in other combinations and were not included in the analysis (table 2).
Among the 886 participants aged 5–17 years, 323 (36·5%) received two doses of vaccine and 287 (32·4%) received one dose of vaccine. As only 60 (6·8%) of 886 individuals aged 5–17 years had received three doses of vaccination, the effectiveness of booster vaccination was not examined in this age group. Among the 6014 individuals aged 18–59 years, 2988 (49·7%) received three doses of vaccine and 2404 (40·0%) received two doses of vaccine. Among the 1736 individuals aged 60 years and older, 945 (54·4%) received three doses of vaccine and 513 (29·6%) received two doses of vaccine. The observed differential distribution of vaccination status by age group was largely consistent with the territory-wide figures of vaccine coverage for the population in Hong Kong (table 2).
Table 3 shows the differential risk of SARS-CoV-2 infection stratified according to vaccination status. The lowest positivity rate was observed among individuals who received three doses (5·4%, 95% CI 4·8–6·2), followed by those who received two doses within 3 months (6·8%, 5·3–8·6). Higher positivity rates were observed among individuals who received only one dose (14·7%, 12·2–17·7) or two doses at least 3 months previously (17·6%, 16·1–19·2). Detailed vaccination status by age group is shown in the appendix were shown in the appendix (pp 5–7). For all age groups, the positivity rate was lower for individuals with a more recent primary series of vaccination within 3 months compared with those who completed vaccination at least 3 months ago.Table 3 Vaccination status and risk of infection
Total (n=8636) Test negative (n=7733) Test positive (n=903) Positivity (95% CI)*
Unvaccinated 764 (8·8%) 641 (8·3%) 123 (13·6%) 16·1% (13·7–18·9)
One dose 639 (7·4%) 545 (7·0%) 94 (10·4%) 14·7% (12·2–17·7)
≥3 months 71 (0·8%) 58 (0·8%) 13 (1·4%) 18·3% (11·0–28·9)
<3 months 568 (6·6%) 487 (6·3%) 81 (9·0%) 14·3% (11·6–17·4)
Two doses 3240 (37·5%) 2771 (35·8%) 469 (51·9%) 14·5% (13·3–15·7)
≥3 months 2308 (26·7%) 1902 (24·6%) 406 (45·0%) 17·6% (16·1–19·2)
<3 months 932 (10·8%) 869 (11·2%) 63 (7·0%) 6·8% (5·3–8·6)
Three doses 3993 (46·2%) 3776 (48·8%) 217 (24·0%) 5·4% (4·8–6·2)
≥3 months 852 (9·9%) 814 (10·5%) 38 (4·2%) 4·5% (3·3–6·1)
<3 months 3141 (36·4%) 2962 (38·3%) 179 (19·8%) 5·7% (4·9–6·6)
One dose BNT162b2 329 (3·8%) 289 (3·7%) 40 (4·4%) 12·2% (9·1–16·1)
≥3 months 61 (0·7%) 51 (0·7%) 10 (1·1%) 16·4% (9·2–27·6)
<3 months 268 (3·1%) 238 (3·1%) 30 (3·3%) 11·2% (8·0–15·5)
One dose CoronaVac 310 (3·6%) 256 (3·3%) 54 (6·0%) 17·4% (13·6–22·0)
≥3 months 10 (0·1%) 7 (0·1%) 3 (0·3%) 30·0% (10·8–60·3)
<3 months 300 (3·5%) 249 (3·2%) 51 (5·6%) 17·0% (13·2–21·7)
Two dose BNT162b2 2353 (27·2%) 1996 (25·8%) 357 (39·5%) 15·2% (13·8–16·7)
≥3 months 1884 (21·8%) 1561 (20·2%) 323 (35·7%) 17·1% (15·5–18·9)
<3 months 469 (5·4%) 435 (5·6%) 34 (3·8%) 7·3% (5·2–10·0)
Two dose CoronaVac 875 (10·1%) 765 (9·9%) 110 (12·2%) 12·6% (10·5–14·9)
≥3 months 417 (4·8%) 336 (4·3%) 81 (9·0%) 19·4% (15·9–23·5)
<3 months 458 (5·3%) 429 (5·5%) 29 (3·2%) 6·3% (4·4–9·0)
Two dose others 12 (0·1%) 10 (0·1%) 2 (0·1%) 16·7% (4·7–44·8)
≥3 months 7 (0·1%) 5 (0·1%) 2 (0·1%) 28·6% (8·2–64·1)
<3 months 5 (0·1%) 5 (0·1%) 0 0·0% (0·0–43·5)
Three dose BNT162b2 2432 (28·2%) 2322 (30·0%) 110 (12·2%) 4·5% (3·8–5·4)
≥3 months 296 (3·4%) 291 (3·8%) 5 (0·6%) 1·7% (0·7–3·9)
<3 months 2136 (24·7%) 2031 (26·3%) 105 (11·6%) 4·9% (4·1–5·9)
Three dose CoronaVac 1050 (12·2%) 978 (12·6%) 72 (8·0%) 6·9% (5·5–8·6)
≥3 months 371 (4·3%) 352 (4·6%) 19 (2·1%) 5·1% (3·3–7·9)
<3 months 679 (7·9%) 626 (8·1%) 53 (5·9%) 7·8% (6·0–10·1)
Two dose CoronaVac plus BNT162b2 463 (5·4%) 429 (5·5%) 34 (3·8%) 7·3% (5·3–10·1)
≥3 months 178 (2·1%) 164 (2·1%) 14 (1·6%) 7·9% (4·7–12·8)
<3 months 285 (3·3%) 265 (3·4%) 20 (2·2%) 7·0% (4·6–10·6)
Two dose BNT162b2 plus CoronaVac 29 (0·3%) 29 (0·3%) 0 0·0% (0·0–11·7)
≥3 months 3 (<0·1%) 3 (<0·1%) 0 0·0% (0·0–56·2)
<3 months 26 (0·3%) 26 (0 3%) 0 0·0% (0·0–12·9)
Three dose others 19 (0·2%) 18 (0·2%) 1 (0·1%) 5·3% (0·9–24·6)
≥3 months 4 (<0·1%) 4 (0·1%) 0 0·0% (0·0–49·0)
<3 months 15 (0·2%) 14 (0·2%) 1 (0·1%) 6·7% (1·2–29·8)
Data are n (%), unless otherwise indicated.
* Overall positivity (95% CI) was 10·5% (9·8–11·1).
A potential attenuation of infection severity was shown in those who received a booster BNT162b2 dose compared with unvaccinated individuals, both in terms of a lower number of symptoms (6·21, SD 3·64 vs 8·09, 4·13; p=0·0040) and a lower mean severity score was found (8·35, 6·31 vs 11·56, 7·93; p=0·0068). No impact on symptom profile was observed for those who received two doses or fewer of BNT162b2 (appendix p 8).
Using unvaccinated people as the reference group in the multivariate model, the first dose of BNT162b2 vaccine provided a vaccine effectiveness of 16·5% (95% CI –19·5 to 41·6; p=0·32) against asymptomatic and symptomatic SARS-CoV-2 omicron infection (table 4 ). Vaccine effectiveness after two doses (ie, primary series) was not significant (27·6%, –6·3 to 50·7; p=0·10) within 3 months, and point estimates declined to a very low level of 1·1% (–22·4 to 20·1; p=0·92) at 3 months and beyond. A BNT162b2 booster vaccine improved the effectiveness to 41·4% (23·2 to 55·2; p=0·0001; figure ; table 4).Table 4 Effectiveness of the BNT162b2 and CoronaVac vaccines against COVID-19 omicron BA.2 infection
Median length of follow-up (person-days) Total length of follow-up (person-days) Number of events Adjusted hazard ratio (95% CI) Vaccine effectiveness (95% CI) p value
Asymptomatic and symptomatic infection
Unvaccinated 31 31 166 123 1 (ref) 1 (ref) ..
BNT162b2
One dose 22 13 143 40 0·84 (0·58 to 1·19) 16·5% (−19·5 to 41·6) 0·32
Two doses (≥3 months) 32 85 088 323 0·99 (0·80 to 1·22) 1·1% (−22·4 to 20·1) 0·92
Two doses (<3 months) 27 14 524 34 0·72 (0·49 to 1·06) 27·6% (−6·3 to 50·7) 0·10
Three doses 32 66 787 110 0·59 (0·45 to 0·77) 41·4% (23·2 to 55·2) 0·0001
CoronaVac
One dose 24 13 892 54 1·02 (0·74 to 1·40) −1·6% (−39·8 to 26·2) 0·92
Two doses (≥3 months) 21 19 891 81 0·95 (0·71 to 1·26) 5·4% (−25·6 to 28·8) 0·70
Two doses (<3 months) 21 11 367 29 0·77 (0·52 to 1·15) 22·7% (−15·2 to 48·2) 0·21
Three doses 36 32 882 72 0·68 (0·50 to 0·91) 32·4% (9·0 to 49·8) 0·0098
CoronaVac plus BNT162b2
Two-dose CoronaVac plus BNT162b2 36 14 809 34 0·69 (0·47 to 1·01) 31·3% (−1·0 to 53·3) 0·056
Two-dose BNT162b2 plus CoronaVac 36 824 0 .. .. ..
Other vaccine combination
One dose 0 0 0 .. .. ..
Two doses (≥3 months) 21 377 2 1·17 (0·27 to 5·12) −16·8% (−412·1 to 73·4) 0·84
Two doses (<3 months) 27 129 0 .. .. ..
Three doses 29 537 1 0·77 (0·12 to 4·78) 23·3% (−377·9 to 87·7) 0·78
Symptomatic infection only
Unvaccinated 31 31 166 82 1 (ref) 1 (ref) ..
BNT162b2
One dose 22 13 143 25 0·77 (0·49 to 1·21) 22·9% (−21·4 to 51·0) 0·26
Two doses (≥3 months) 32 85 088 219 0·95 (0·73 to 1·24) 4·7% (−23·5 to 26·6) 0·71
Two doses (<3 months) 27 14 524 23 0·68 (0·43 to 1·09) 31·6% (−9·3 to 57·2) 0·11
Three doses 32 66 787 66 0·49 (0·35 to 0·69) 50·9% (31·0 to 65·0) <0·0001
CoronaVac
One dose 24 13 892 38 1·09 (0·74 to 1·61) −9·3% (−60·5 to 25·6) 0·65
Two doses (≥3 months) 21 19 891 55 0·94 (0·66 to 1·32) 6·4% (−32·1 to 33·7) 0·71
Two doses (<3 months) 21 11 367 22 0·88 (0·55 to 1·40) 12·2% (−40·0 to 44·9) 0·59
Three doses 36 32 882 43 0·58 (0·40 to 0·85) 41·6% (15·0 to 59·8) 0·0049
CoronaVac plus BNT162b2
Two-dose CoronaVac plus BNT162b2 36 14 809 15 0·44 (0·25 to 0·77) 55·8% (22·9 to 74·6) 0·0040
Two-dose BNT162b2 plus CoronaVac 36 824 0 .. .. ..
Other vaccine combination
One dose 0 0 0 .. .. ..
Two doses (≥3 months) 21 377 1 0·92 (0·12 to 7·08) 7·6% (−608·2 to 88·0) 0·94
Two doses (<3 months) 27 129 0 .. .. ..
Three doses 29 537 0 .. .. ..
Data are n, unless otherwise indicated. Data were adjusted for age group, gender, chronic illness, household size, district, housing type, Hong Kong tertiary planning unit level, and monthly household rent. Symptomatic infections were defined as those with a positive rapid antigen test result after an individuals reported at least one of 19 surveyed symptoms.
Figure Cumulative risk of infection with the SARS-CoV-2 omicron variant according to vaccination status in asymptomatic and symptomatic infection (A) and symptomatic infection only (B)
Shading indicates 95% CIs.
A similar pattern of vaccine effectiveness for any SARS-CoV-2 infection, but with a slightly lower magnitude of protection, was given by the CoronaVac vaccine. The first dose of CoronaVac provided a vaccine effectiveness of –1·6% (95% CI –30·8 to 26·2; p=0·92) against asymptomatic and symptomatic SARS-CoV-2 omicron infection (table 4). Vaccine effectiveness after two doses was not significant within 3 months (5·4%, –25·6 to 28·8; p=0·70) or at 3 months and beyond (22·7%, –15·2 to 48·2; p=0·21). A CoronaVac booster improved the vaccine effectiveness to 32·4% (9·0 to 49·8; p=0·0098; figure; table 4). A similar amount of protection was observed for CoronaVac and BNT162b2, with non-significant relative vaccine effectiveness (appendix p 13).
The vaccine effectiveness against any infection of a booster dose using a switched vaccine type was also examined. For people who received a primary series of CoronaVac, the vaccine effectiveness for a booster dose using BNT162b2 was 31·3% (95% CI –1·0 to 53·3; p=0·056), similar to the values for a booster with the same vaccine (table 4). No significant difference in vaccine effectiveness was found in the estimation of relative effectiveness for the types of booster dose (p=0·86; appendix p 13). The effectiveness of a CoronaVac booster after a primary series of BNT162b2 was not examined because of the small sample size.
For vaccine effectiveness against symptomatic SARS-CoV-2 omicron infection, a booster dose generally showed a similar pattern of effectiveness but conferred a higher level of protection, with vaccine effectiveness of 50·9% (95% CI 31·0–65·0; p<0·0001) for a BNT162b2 booster and 41·6% (15·0–59·8; p=0·0049) for a CoronaVac booster (table 4). A BNT162b2 booster for those who received a primary series of CoronaVac also conferred a similar significant vaccine effectiveness of 55·8% (22·9–74·6; p=0·0040) against symptomatic infection (table 4). The relative vaccine effectiveness against symptomatic infection between CoronaVac and BNT162b2 was not significant (appendix p 13).
To address the potential confounding effect of differential vaccine coverage in subpopulations, the age-specific effectiveness of different vaccine types was further examined. For all SARS-CoV-2 omicron infections, a similar non-significant protection of the first dose and primary series within 3 months was observed across all age groups (appendix pp 17, 20, 23). For adults aged 18–59 years, we observed no significant protection for the first dose of BNT162b2 (20·4%, 95% CI –30·9 to 51·6; p=0·37), first dose CoronaVac (–0·6%, –72·2 to 41·3; p=0·98), two BNT162b2 doses within 3 months (35·3%, –4·2 to 59·8; p=0·073), two CoronaVac doses within 3 months (38·2%, –19·5 to 68·0; p=0·15), or a second dose received beyond 3 months (2·5, –29·0 to 26·2; p=0·86 for BNT162b2 and –3·0, –45·9 to 27·3; p=0·87) for CoronaVac; appendix p 17). Significant protection was only observed for those who received a BNT162b2 booster vaccine, with a vaccine effectiveness of 42·1% (19·5 to 58·4; p=0·0012; appendix p 17). For symptomatic SARS-CoV-2 omicron infection, the significant protection of a BNT162b2 booster was also maintained, with a slightly higher vaccine effectiveness of 51·6% (27·7 to 67·6; p=0·0004) for those receiving a BNT162b2 primary series and 60·0% (20·8 to 79·8; p=0·0085) for those receiving a CoronaVac primary series.
For adults aged 60 years and older, no significant protection against SARS-CoV-2 omicron infection was shown after either one dose of BNT162b2 (–69·7%, 95% CI –353·1 to 36·5; p=0·29), one dose of CoronaVac (–65·0%, –219·6 to 14·8; p=0·14), two BNT162b2 doses within 3 months (–39·3%, –236·4 to 42·4; p=0·46), or two CoronaVac doses within 3 months (–65·7%, –228·5 to 16·5; p=0·15; appendix p 20). A booster vaccine of either BNT162b2 or CoronaVac did not provide significant protection against SARS-CoV-2 omicron infection for this older population, with a vaccine effectiveness of –1·5% (–101·0 to 48·7; p=0·97) and 25·2% (–56·0 to 64·1; p=0·44), respectively (appendix p 20). A similarly negligible protection for older people was observed for symptomatic omicron infection (appendix p 20).
For individuals aged 5–17 years, no significant protection against SARS-CoV-2 omicron infection was shown after one dose of BNT162b2 (32·4%, 95% CI –29·0 to 64·6; p=0·24), one dose of CoronaVac (22·7%, –38·3 to 56·8; p=0·39), two BNT162b2 doses within 3 months (3·2%, –220·7 to 70·8; p=0·96), or two CoronaVac doses within 3 months (55·6%, –50·3 to 86·9; p=0·19; appendix p 23). A similarly negligible protection for this population was observed for symptomatic omicron infection (appendix p 23). The age-specific protection conferred by either a BNT162b2 or CoronaVac booster after a primary series was not examined for those aged 5–17 years because of the small sample size.
Discussion
This prospective cohort study adopted a comprehensive non-symptom and risk-based outcome-ascertainment approach by regular rapid antigen testing to evaluate the vaccine effectiveness of the primary series and booster dose of vaccination against SARS-CoV-2 during omicron BA.2 predominance. A representative cohort that covered different population subgroups by age, gender, monthly income, and district was recruited to increase the generalisability of our findings, and stratified analysis provided an age-specific and vaccine-type-specific estimate for different vaccination statuses. Our surveillance initiative, with regular testing regardless of symptom status or exposure history, allowed assessment of vaccine effectiveness against both symptomatic and asymptomatic infection. The provision of free rapid antigen tests to all enrolled participants helped to minimise the potential effect of changing testing policy and capacity on outcome ascertainment. The exclusion of 15·3% of individuals who were previously infected was consistent with the reported local seroprevalence against BA.2 of 7·3% before the fifth wave of SARS-CoV-2 in November to December, 2021,27 and 23·4% after the peak of the fifth wave of infection in May, 2022,28 and might have helped us avoid wrongly attributing protection to previous infection in the vaccine effectiveness analysis. Understanding the updated effectiveness of available vaccines against infection, including asymptomatic infection, in relation to the evolving omicron variants is essential for guiding vaccination policies and informing future vaccine development.
Our findings showed that a booster dose of vaccination conferred substantial protection against SARS-CoV-2 infection by the omicron variant, including mild and asymptomatic cases. Significant protection against infection was observed only for three doses of vaccine. This finding supports the need for a booster dose for protection against the omicron variant, and fits with the current recommendation for booster doses in Hong Kong,29 Ontario, Canada,30 Australia,31 and the USA.32
We also observed differential vaccine effectiveness for the booster dose for different age groups. Specifically, moderate and statistically significant protection from a BNT162b2 booster dose was only achieved in those aged 18–59 years, whereas no significant protection was conferred in those aged 60 years and older, which is compatible with the general finding of a lower vaccine effectiveness for older individuals in the literature.33, 34, 35, 36 This differential vaccine effectiveness highlights the need to explore the potential feasibility and benefit of more targeted vaccination regimens for optimising protection of different subpopulations in the community.
For the primary series of two doses of either BNT162b2 or CoronaVac completed within 3 months or at least 3 months ago, our results showed no significant protection was achieved in all age groups. Compared with a previous study on symptomatic omicron infection, our finding of no significant protection from the primary series of BNT162b2 contrasted with that study's finding of high vaccine effectiveness (65·5%, 95% CI 63·9–67·0) assessed at 4 weeks,8 but was more similar to the study's finding of much lower vaccine effectiveness (8·8%, 7·0–10·5) at 6 months or more after vaccination.8 Although a BNT162b2 primary series completed within 3 months did not show significant vaccine effectiveness, the higher vaccine effectiveness compared with a course completed 3 or more months ago (27·6% vs 1·1%) was compatible with the rapid waning of effectiveness reported in previous studies.37 This observed difference might also have been partly due to our adjustment for immortal time bias to avoid potential wrongful attribution of protective effects to a more recent vaccination event.
Our findings showed that significant vaccine effectiveness against symptomatic or asymptomatic omicron infection was conferred by a third dose of either BNT162b2 or CoronaVac. The protection conferred by a BNT162b2 or CoronaVac booster was further increased when considering only symptomatic omicron infections. Our results were generally much lower than previously reported vaccine effectiveness of booster doses against the more severe outcomes of omicron infection, including an effectiveness of 86% against hospital admission2 and more than 90% effectiveness against severe disease or death,3, 38, 39, 40 but were consistent with the vaccine effectiveness of 52·2% (95% CI 48·1–55·9) of three doses of BNT162b2 against symptomatic omicron BA.2 infection reported in Qatar, where universal testing allowed detection of cases of all severities.4 Although our results were lower than the reported vaccine effectiveness in a previous study (70·2–73·5% for BNT162b2 and 32·4–51·0 % for CoronaVac) of patients with mild or moderate COVID-19 who were admitted to hospital during the same epidemic wave in Hong Kong using an ecological study design,3 our study might capture the milder end of the spectrum of infection in the community, with most individuals not requiring medical attention. With this understanding, our findings are consistent with the overall picture of a rapidly attenuating vaccine effectiveness effect size when the examined outcomes were shifted from the more severe to the milder end of the clinical spectrum in the published literature.1, 4, 39 However, as previous studies suggested that vaccination might shorten the viral shedding duration,41, 42 our study design with regular scheduled testing might help to avoid potential differential outcome ascertainment related to the duration of viral shedding, reducing the likelihood of detecting an infection among vaccinated people, and the resultant bias towards an overestimation of the vaccine effectiveness effect size.
Despite the low level of protection against infections with mild or no symptoms, the high proportion of mild infections might still impose a non-trivial collective clinical burden in the community during a rapid surge of an evolving epidemic, as in the fifth SARS-CoV-2 wave in Hong Kong. However, the high proportion of asymptomatic cases that might have been prevented by booster vaccination, which otherwise might have potentially seeded downstream secondary transmission, might help to prevent further propagation of the epidemic in the community due to the shedding of virus in the absence of awareness, appropriate management, isolation, or quarantine measures. This potential public health implication might become even more important as newer SARS-CoV-2 variants with higher transmissibility and milder clinical symptoms emerge,43 including the new omicron variants.44, 45 Besides the indirect effect on transmission through preventing the incidence of infection, transmission might also be prevented through reduced transmissibility of infection in breakthrough cases in vaccinated people. Although current literature generally regards the vaccine effectiveness of two doses for preventing omicron transmission to be minimal,44, 46 some studies have reported modest effectiveness of a booster dose for reducing secondary transmission related to breakthrough cases in vaccinated people in households or institutional settings,44, 46, 47 signifying the value and implications of the vaccine even if effectiveness against mild infection is not high. Although our study did not directly examine the outcome of transmission or viral shedding, our data did reveal a potential attenuation of infection severity in those who received a booster BNT162b2 vaccine compared with unvaccinated individuals, both in terms of a lower number of symptoms and a lower mean severity score. However, similar to the existing literature, no effect on symptom profile was observed for those who received two doses or fewer of vaccine.
The similar magnitude of vaccine effectiveness of the mRNA vaccine (BNT162b2) and inactivated vaccine (CoronaVac) implies that both vaccine types are effective against omicron infection. The similar protection achieved with either the same or different booster regimens also supports the current recommendation of BNT162b2 boosters in Hong Kong and some other countries,48, 49, 50 which might give the advantage of facilitating higher booster dose uptake, with the enhanced autonomy of personal preference, and lead to less issues with vaccine availability during an evolving pandemic.
This surveillance initiative is an observational study with some possible biases and should be interpreted with caution. As a history of previous PCR-confirmed infection was ascertained by self-reporting, some under-ascertainment of previous infection might have been present and affected our vaccine effectiveness estimation. However, given the straightforward and official nature of the case definition, and the lack of obvious benefit for untruthful reporting, substantial inaccurate recall might be unlikely. Government mandatory testing orders in relation to community exposure risk, which were instituted independent of vaccination status, might serve to capture some people with no symptoms and to prevent substantial differential under-ascertainment among people with different vaccination statuses.
Imperfect performance in terms of suboptimal sensitivity and specificity of rapid antigen testing might cause misclassification of infection status,18 which is likely to be non-differential, as suggested in a systematic review of 155 studies on rapid antigen test diagnostic performance.51 This fact might bias the estimation of the HR towards the null, and result in a potentially over-estimated vaccine effectiveness.52 Adopting rapid antigen test brands that meet the WHO priority target product profiles for COVID-19 diagnostics15 and FDA Emergency Use Authorization,16 as in our study, would thus be an important step to minimise potential bias in vaccine effectiveness estimation.
The availability of rapid antigen testing kits for regular self-testing, irrespective of symptom status or exposure risk, should facilitate early identification of both symptomatic and asymptomatic cases.53 However, case counting on the basis of PCR testing or voluntary rapid antigen test result reporting might underestimate the risk of infection and case ascertainment, as testing can be affected by any change in testing policy, health seeking behaviour, laboratory testing capacity, or incomplete reporting practices due to the fear of isolation or quarantine order being imposed.
As the changing symptom pattern after rapid antigen test positivity was not continuously monitored in our surveillance platform, classification as either symptomatic or asymptomatic in the current study was based primarily on the data at the time of the positive rapid antigen test. As some people who were asymptomatic on original testing might develop symptoms later (ie, pre-symptomatic), this strategy might affect precise estimation of the vaccine effectiveness against symptomatic infection; however, this should have no effect on the estimation of vaccine effectiveness against both symptomatic and asymptomatic infection.
Although behavioural factors, such as wearing a mask and physical distancing, might affect infection risk and be potential residual confounders in this study, a substantial difference between vaccinated and unvaccinated participants, or between individuals who received two doses of vaccine and those who received three doses, was not expected, as universal mask wearing and stringent social distancing requirements were legally required for the whole community during the study period in Hong Kong, irrespective of vaccination.54 Another limitation was our inability to estimate vaccine effectiveness for some subgroups, due to the relatively small number of individuals who received some vaccine regimens. As the local population had recently started to receive booster doses, and booster doses had only recently been approved for children, the additional protection achievable by a booster dose in children, and the waning effectiveness of booster doses over time, were not evaluated. A further study examining the effect of booster doses on younger age groups and the waning effectiveness of booster doses is warranted, to inform the assessment of and optimise vaccine policy in the evolving pandemic.
In conclusion, we assessed the vaccine effectiveness of the BNT162b2 and CoronaVac vaccines in different regimens and age groups and found that a BNT162b2 or CoronaVac booster dose achieved significant protection against omicron infection in Hong Kong. These updated vaccine effectiveness estimates allow assessment of the public health impact of COVID-19 vaccines for preventing transmission of symptomatic and asymptomatic infections in the community. We found similar effectiveness for both vaccine types, and a potential association of effectiveness with age. Our findings support the use of different booster vaccination regimens from the primary series during the evolving pandemic.
Data sharing
The data are available from the corresponding author upon reasonable request.
Declaration of interests
BJC reports honoraria from AstraZeneca, Fosun Pharma, GlaxoSmithKline, Moderna, Pfizer, Roche, and Sanofi Pasteur. All other authors declare no competing interests.
Supplementary Material
Supplementary appendix
Acknowledgments
This project was supported by the Henry Fok Foundation, and a special commissioned fund (reference number COVID-19FHB) from the Health Bureau of the Hong Kong Special Administrative Region Government. We acknowledge contribution to the design and acquisition of data by Michael Ni, IT support by Wong Hoi Wa, and research support by Jerome Leung, Grace Ng, Oscar Kwok, Christine Ning, Kenny Mok, Clarice Guo, Kaki Chen, and Cynthia Yau.
Contributors
GML and DKMI conceived and designed the study. NNYT and HCS collected the data. NNYT and DKMI accessed and verified the data. BJC advised on the statistical analysis. NNYT did the statistical analysis. NNYT and DKMI interpreted the data. NNYT and DKMI wrote the first draft of the manuscript, and all authors provided critical review and revision of the text and approved the final version for publication. All authors had full access to all the data in the study and accept final responsibility for the decision to submit for publication.
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| 36521506 | PMC9744442 | NO-CC CODE | 2022-12-15 00:01:45 | no | Lancet Infect Dis. 2022 Dec 12; doi: 10.1016/S1473-3099(22)00732-0 | utf-8 | Lancet Infect Dis | 2,022 | 10.1016/S1473-3099(22)00732-0 | oa_other |
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Epidemiol Infect
Epidemiol Infect
HYG
Epidemiology and Infection
0950-2688
1469-4409
Cambridge University Press Cambridge, UK
36440638
10.1017/S0950268822001777
S0950268822001777
Expressions of Emotion
Original Paper
Epidemiological evaluation of mass testing in a small municipality in the Netherlands during the SARS-CoV-2 epidemic
https://orcid.org/0000-0003-2477-8661
Heijmink Lisanne 12*
Tönis Juul 12*
Gilhuis Niek 1
Gerkema Maartje 12
Hart Lotte 3
Raven Stijn 124
van den Boogaard Jossy 2
Hofhuis Agnetha 2
van den Hof Susan 2
Visser Olga 14
1 Municipal Health Service Utrecht region, Zeist, the Netherlands
2 Center for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands
3 Seeder de Boer, Amsterdam, the Netherlands
4 Department of Primary and Community Care, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands
Author for correspondence: Stijn Raven, E-mail: [email protected]
* These authors contributed equally.
2022
15 11 2021
15 11 2021
150 e19315 6 2022
18 9 2022
02 11 2022
© The Author(s) 2022
2022
The Author(s)
simple This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means subject to acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.
During 6 weeks in February–March 2021, the Dutch municipal health service Utrecht studied the epidemiological effects on test incidence and the detection of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with mass testing (MT). During MT, inhabitants of Bunschoten could repeatedly test regardless of symptoms and as often as desired at the close-by test facilities in the municipality. Data from the regular COVID-19 registration was used for analysis. In Bunschoten, MT caused a significant increase in test incidence and an immediate increase in the number of detected active infections, in contrast to a stabilisation in the rest of the province of Utrecht. Age distribution of test incidence shifted to the older population in Bunschoten during MT. During MT, there was a 6.8 percentage point increase in detected asymptomatic cases, a 0.4 percentage point increase in pre-symptomatic cases and a decrease of 0.5 days between onset of symptoms and test date. This study has shown that MT increases test incidence and helps to obtain a more complete view of the presence of SARS-CoV-2 in a community, which can be useful in specific situations with a defined target group or goal. However, the question remains open whether the use of MT is proportionate to the overall gain.
Key words
COVID-19
COVID-19 testing
mass screening
Netherlands
SARS-CoV-2
The Dutch Ministry of Health, Welfare and Sports
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pmcIntroduction
Transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be successfully suppressed by non-pharmaceutical interventions (NPIs) [1]. An active testing strategy is part of several NPIs against SARS-CoV-2 that can contribute to the control of COVID-19 [2]. Since June 2020, the Netherlands has chosen for a large-scale symptom-based testing and contact tracing programme. The merits of a mass testing (MT) programme, to actively offer frequent testing to all residents of a community, are not fully known as it has not been frequently used as an approach to control COVID-19 [3].
In December 2020, Bunschoten was one of the municipalities with the highest registered incidence of SARS-CoV-2 infections in the Netherlands [4]. In week 52 of 2020, the infection incidence and the percentage of positive tests (PPTs) in Bunschoten was much higher than that in the rest of the province of Utrecht in that same period, Figure 1. Bunschoten is a municipality in the middle of the ‘Dutch Bible belt’, in the province of Utrecht [5, 6]. This community is characterised by a high proportion of orthodox protestants with strong social relationships. Even though the municipal health service (MHS) Utrecht region performed source and contact tracing, a specific explanation for the high number of infections was not found. Due to the inexplicable high number of infections at the end of 2020 in Bunschoten, MHS Utrecht region implemented MT [7]. Fig. 1. SARS-CoV-2 test incidence, infection incidence and PPTs in the province of Utrecht (excluding Bunschoten) as well as in Bunschoten, situation in week 52 of 2020.
The aim of this study was to investigate the epidemiological effects of the implementation of MT in Bunschoten. Two main objectives were composed: to study the effect of MT on (1) test incidence and (2) the detection and the spread of SARS-CoV-2. It was hypothesised that the test incidence would increase rapidly due to the changed eligibility criteria for testing during MT and easily accessible test facilities. Furthermore, with more tests being executed, a slight increase in SARS-CoV-2 infection incidence was expected.
Methods
Design
Timeframe and place
Test incidence as well as infection incidence in Bunschoten were analysed before, during and after MT in order to investigate the effect of MT. MT lasted 6 weeks, from 8 February to 19 March 2021. Also, to study the effects before and after MT, data of a period of 6 weeks before MT (pre-MT period), from 27 November 2020 to 7 February 2021, as well as 6 weeks after MT (after-MT period), from 22 March 2021 to 2 May 2021, were analysed. Figures show 12 weeks before MT in order to show the trend and the situation in the last weeks of 2020. The other municipalities in the province of Utrecht were chosen as a reference because of its wide variety of municipalities with different population groups. Before MT, at the end of 2020, there were restrictive non-pharmaceutical measures in place which were gradually lifted from April 2021 onwards [8]. Additionally, the number of detected infections increased nationally since February, caused by the emergence of the alpha variant (B.1.1.7) [9].
In the regular test policy of the Netherlands at the time, only symptomatic individuals and contacts of confirmed cases were tested by the MHS and SARS-CoV-2 home-testing kits were not available. During the 6 weeks of MT, all inhabitants of Bunschoten aged 6 years and older were invited to test for SARS-CoV-2 as often as they wished and regardless of the presence of symptoms or contact with a positive case. To facilitate MT, two additional permanent test facilities were set-up in addition to an already existing facility, evenly distributed throughout the municipality, to improve accessibility for all inhabitants. As a fourth testing facility, a mobile test unit alternated between two remote neighbourhoods. Aside from these MT test facilities with extended opening hours, inhabitants of Bunschoten could still test at other MHS test facilities across the Netherlands under similar conditions as for other civilians living outside of Bunschoten.
Test method
During MT, the collected nasopharyngeal swabs were analysed using real-time polymerase chain reaction (RT-PCR), which is the main test method used in the Netherlands for detection of SARS-CoV-2 [10]
Ethics
The Medical Research Ethics Committee of the University Medical Centre Utrecht assessed the study protocol and confirmed that the Medical Research Involving Human Subjects Act (WMO) did not apply. Therefore, this study was exempt from formal medical-ethical approval (reference number: MvdL/mb/21/500143).
Data collection
Effect of MT on test incidence
Data regarding test incidence were extracted from the Dutch national registration system for COVID-19 tests and vaccinations performed by the MHS Utrecht region. This system contains test dates, laboratory results and demographic data [11]. Data of inhabitants of Bunschoten who tested during MT were compared to the data of inhabitants of the rest of the province of Utrecht who were tested within the regular test facilities during the same period.
Effect of MT on detection and spread of SARS-CoV-2
To investigate the effect of MT on detection of SARS-CoV-2, anonymised data were extracted from HPZone, the regular Dutch national registration system used for source and contact tracing by all MHS in the Netherlands [11]. This database entailed the MHS medical file of all SARS-CoV-2-infected individuals in the province of Utrecht including important characteristics, such as the symptoms experienced during SARS-CoV-2 infection. Cases were contacted immediately after a positive test as part of routine source and contact investigation and 5 and 10 days later for follow-up. Again, data of infected inhabitants of Bunschoten were compared to the data of inhabitants of the rest of the province of Utrecht during the same period.
Data analysis
Outcome measures
Test incidence (number of performed tests per 100 000 inhabitants) and SARS-CoV-2 infection incidence (number of detected active infections per 100 000 inhabitants) in Bunschoten were the primary outcome measures, which were analysed over time and compared to the rest of the province of Utrecht. Incidences were calculated per 100 000 inhabitants and per week. The PPT was calculated by dividing the number of positive test results by the total number of tests performed with valid outcome. Besides, an alternative PPT calculation based on individuals instead of tests was performed. With this method, the number of inhabitants with an active infection was divided by the unique number of individual test facility visitors per week.
To study whether MT had motivated other population groups to get tested than in the pre-MT period, the distribution of gender and age regarding test incidence between Bunschoten and the other municipalities in the province of Utrecht was compared in the pre-MT period and during MT. To study whether infections were detected differentially across the population before and during MT, gender and age distributions were also compared. The distribution of age category was calculated as a percentage of the total population in that age category.
Positive test outcomes were classified in three types, distinguished based on symptoms: a symptomatic case, a pre-symptomatic case and an asymptomatic case. A symptomatic case is defined as a patient who develops symptoms, whether prior to the test appointment or after the test appointment. A pre-symptomatic case is defined as a patient who develops symptoms after the test appointment. An asymptomatic case is defined as a patient experiencing no symptoms at least 5 days after the positive test [12]. The number of detected pre-symptomatic and asymptomatic cases in Bunschoten during MT was described as a proportion of the total number of inhabitants with an active infection and compared to the pre-MT period. To assess whether infections were detected earlier due to MT, the difference in days between date of onset of symptoms and the moment of testing was calculated per week.
Since RT-PCR for detection of SARS-CoV-2 is very sensitive (estimated sensitivity of 89% [13]), in some individuals viral RNA can be detected for more than 8 weeks after an infection, which can be a disadvantage in case of MT (indirectly encouraging people to test repetitively, regardless of previous test results) [14]. Detection of residual viral RNA could lead to unjustified isolation of persons with a positive RT-PCR test result, while the person is not contagious anymore [15]. In order to specify the current status of the patient's infection, inhabitants with a positive RT-PCR result were strongly advised to return for a second test within 3 days after the first positive test. The viral load of the first positive test, determined by the number of replication cycles (Ct), was compared to the viral load of the second test result in order to distinguish (early) active infections from recent or late/old SARS-CoV-2 infections, according to Table 1 [25]. Table 1. Interpretation of number of Ct to determine the policy of someone that tested positive for SARS-CoV-2
Viral load first positive test Ct ≤ 32 Ct > 32
Viral load second test (max. 3 days after first positive test) Ct ≤ 32 Ct > 32 or negative test result Ct ≤ 32 Ct > 32 or negative test result
Interpretation Active infection Recent inactive infection (Early) active infection Late/old (inactive) infection
Policy Isolation No isolation Isolation No isolation
Statistical analysis
All statistical analyses over time, as well as the comparison between Bunschoten and the other municipalities of the province of Utrecht, were performed using the 95% confidence interval (CI). Visualisations have been made using Microsoft PowerBI Desktop (version April 2021).
Results
Test incidence
In total, 12 910 SARS-CoV-2 tests were executed in 8321 inhabitants of Bunschoten aged 6 years and older during MT. Of the total 21 189 inhabitants of Bunschoten, 39.2% got tested during MT. Among the tested individuals, 64% got tested once, 23.3% got tested twice and 12.1% got tested more than twice. In Figure 2, test incidence for Bunschoten as well as the province of Utrecht is displayed per 100 000 inhabitants per week. When MT started in week 6 of 2021, there was an almost 12-fold increase in test incidence compared to week 5 in Bunschoten. During MT, the test incidence in Bunschoten (9900 (95% CI 8525– 11 275)) was significantly higher compared to the province of Utrecht (2274 (95% CI 1665–2883) (Table 2). In the pre-MT period, there was no significant difference in test incidence between Bunschoten (1890 (95% CI 1140–2640)) and the province of Utrecht (1573 (95% CI 1257–1889)), the same accounts for the after-MT period (Bunschoten: 2537 (95% CI 2169–2906); province of Utrecht: 3097 (95% CI 2801–3393)). Also, no significant difference in test incidence in Bunschoten between pre-MT period (1890 (95% CI 1140–2640)) and after-MT period (2537 (95% CI 2169–2906)) was detected. Fig. 2. SARS-CoV-2 test incidence in Bunschoten and the province of Utrecht per week from week 47 in 2020 until week 17 in 2021 per 100 000 inhabitants.
Table 2. Mean weekly SARS-CoV-2 test and infection incidence and mean PPTs, with 95% CI, in Bunschoten and the province of Utrecht (excluding Bunschoten), in the pre-MT period, during MT and in the after-MT period
Mean weekly test incidence per 100 000 inhabitants (95% CI) Mean weekly infection incidence per 100 000 inhabitants (95% CI) Mean PPTs (95% CI)
Bunschoten Province Utrecht (excl. Bunschoten) Bunschoten Province Utrecht (excl. Bunschoten) Bunschoten Province Utrecht (excl. Bunschoten)
Pre-MT period 1890 (1140–2640) 1573 (1257–1889) 486 (209–764) 182 (132–233) 18.5% (14.1–22.9) 9.9% (8.9–10.42)
MT 9900 (8525–11 275) 2274 (1665–2883) 504 (396–612) 158 (125–190) 7.1% (5.7–8.5) 7.0% (5.7–8.1)
After-MT period 2537 (2169–2906) 3097 (2801–3393) 400 (361–439) 254 (234–274) 15.1% (12.8–17.3) 7.5% (6.4–8.5)
Infection incidence
In total, 646 inhabitants with an active infection (as defined in Table 1) were found during MT. In Figure 3, the trend of the infection incidence for Bunschoten as well as the province of Utrecht is presented. In the pre-MT period, Bunschoten (486 (95% CI 209–764)) had a higher infection incidence compared to the province of Utrecht (182 (95% CI 132–233)), but this was not significant (Table 2). During MT, the infection incidence was significantly higher in Bunschoten (504 (95% CI 396–612)) than in the province of Utrecht (158 (125–190)). Moreover, there was a significant difference in infection incidence between Bunschoten (400 (95% CI 361–439)) and the province of Utrecht (254 (95% CI 234–274)) in the after-MT period. Furthermore, there was no significant difference in average detected infection incidence in Bunschoten between the pre-MT period (486 (95% CI 209–764)) and after-MT period (400 (95% CI 361–439)). Assuming that infection incidence during the study period (weeks 6–11) in Bunschoten would have stayed at the same level as before the intervention (week 5), MT caused a 3.3-fold increase in detected active infections. Second, assuming that the course of infection incidence in Bunschoten would have been the same as in the rest of the province of Utrecht during the intervention (weeks 6–11), MT caused a 3.2-fold increase in detected active infections. Fig. 3. SARS-CoV-2 infection incidence in Bunschoten and the province of Utrecht per week from week 47 in 2020 until week 17 in 2021 per 100 000 inhabitants.
Percentage of positive tests
In the pre-MT period, Bunschoten (18.5% (95% CI 14.1–22.9)) had a very high PPT which was significantly higher compared to the province of Utrecht (9.9% (95% CI 8.9–10.4)). In the first week of MT, the PPT in Bunschoten dropped to 4.0% (Fig. 4), mostly due to the high number of performed tests in that week. This effect diminished when MT progressed, to an average of 7.1% (95% CI 5.7–8.5) during MT. In the province of Utrecht, there was an average PPT of 7.0% (95% CI 5.7–8.1) during MT, which was approximately equal to the average of Bunschoten. In the after-MT period, the PPT in Bunschoten (15.1% (95% CI 12.8–17.3)) was again significantly higher compared to the province of Utrecht (7.5% (95% CI 6.4–8.5)). Bunschoten showed an increasing PTT pattern, while the PPT of the rest of the region stayed at the same level. When calculating PPT per individual instead of per test, the average PPT in Bunschoten was 5.5% (95% CI 4.2–6.8) and 7.3% (95% CI 6.3–8.3) in the province of Utrecht during MT, also not significantly different. Fig. 4. Percentage of positive SARS-CoV-2 tests (regular calculation) per week in Bunschoten and the province of Utrecht from week 47 in 2020 until week 17 in 2021.
Asymptomatic cases, pre-symptomatic cases and difference between onset of symptoms and test date
In total, 80 inhabitants of Bunschoten with an active infection were asymptomatic (as per the definition in the methods) during MT. This accounts for an average of 12.4% of the detected individuals with an active infection. In the pre-MT period, an average of 5.6% was asymptomatic, indicating a 6.8 percentage point (233%) increase during MT. Fourteen inhabitants of Bunschoten with an active infection were pre-symptomatic during MT, which is 2.1% of the detected individuals with an active infection, compared to 1.7% pre-symptomatic cases in the pre-MT period. Therefore, there was a 0.4 percentage point (124%) increase in pre-symptomatic cases during MT. Since 12.4% of the detected active infections were found in asymptomatic individuals and 2.1% of the individuals were pre-symptomatic, 85.5% of infections were found in symptomatic individuals. In the pre-MT period, the difference between the onset of symptoms and the date of testing was on average 2.1 days. During MT, the difference between onset of symptoms and date of testing was 1.6 days on average, which was 0.5 days less.
Population groups
To study whether MT had motivated other population groups to test and whether it led to differential distribution of positively tested persons, age and gender distribution was analysed for both (data not shown). There were no substantial differences in gender distribution regarding test and infection incidence between Bunschoten and the province of Utrecht in the pre-MT period and during MT. The distribution of age in test incidence between Bunschoten and the province of Utrecht was comparable in the pre-MT period. However, there was a relatively higher test incidence in the age groups older than 50 years in Bunschoten compared to the province of Utrecht during MT. The test incidence in Bunschoten shifted to the older population in the period of MT compared to the pre-MT period.
Discussion
In this study, we assessed the effects of MT on test incidence and the detection of SARS-CoV-2 in Bunschoten, a Dutch municipality in the province of Utrecht. It was shown that MT had a major effect on test incidence in Bunschoten, which was significantly higher compared to the province of Utrecht during MT. In the pre-MT and after-MT periods, the test incidence in Bunschoten was comparable to the province of Utrecht. Furthermore, there was an immediate increase in the number of detected active infections in Bunschoten during MT, in contrast to a stabilisation of the detected infection incidence in the province of Utrecht. Also, we showed that there was a shift in age distribution of test incidence to the older population during MT, a relative increase in asymptomatic cases, and in pre-symptomatic cases. Additionally, there was a decrease of 0.5 days between onset of symptoms and test date. This study has shown that MT increases test incidence and helps to get a more complete view of the presence of SARS-CoV-2 in a community.
Adequate surveillance and a thorough test, trace and isolate (TTI) policy are the cornerstones of an effective infection prevention strategy [16]. It is hypothesised that MT offers a major contribution to both surveillance and TTI and could thereby have a great impact on the spread of SARS-CoV-2. Experimental evidence is, however, limited to a setting with low incidence of SARS-CoV-2 [17]. An MT campaign in Slovakia showed a decrease in infection incidence, but their modelling suggested that the decrease did not exclusively result from MT and also required the impact of isolation and quarantine measures [18]. Furthermore, a Dutch modelling study has shown that a strategy based solely on MT would require unrealistically high test frequencies to effectively stop spread of SARS-CoV-2 when control measures, e.g. social distancing and usage of face masks, were to be relaxed [19, 20]. The use of MT as an additional measure in a high-incidence community has to our knowledge not been studied before. The results of this study match the results of the Slovakian study, by showing a better representation of the number of active infections in the community. This improved detection also improves isolation and quarantine possibilities, the effect of which could be shown by studying various viral spread indicators (e.g. number of detected clusters and outbreaks, secondary attack rate). However, it turned out to be impossible to reliably document these indicators in our setting. So, while we were unable to support the effect on the spread of COVID-19 with reliable data in this setting, it is likely that timely isolating infected individuals and quarantining their households should also lower infection incidence over time.
Although we carefully claim some positive effects of MT in a setting of high COVID-19 incidence, there are several practical implications to take into consideration. First, the speed of implementation of MT is very important. Once MT was operational in Bunschoten, the infection incidence had already decreased to the average levels of the province of Utrecht and hence, MT seemed no longer as urgent as before in the view of the inhabitants. As a result, the willingness of the inhabitants of Bunschoten to get tested may have dropped in the aftermath of the December outbreak. Therefore, when considering implementing MT to control an outbreak, it is important to start MT as soon as an inexplicable rapid increase in infection incidence occurs. Clear communication regarding the goal and necessity of MT campaign adapted to target groups is helpful in increasing voluntary test willingness [21, 22]. Furthermore, the protocol regarding late inactive infections with long lasting RNA shredding should be carefully developed in advance. Offering a re-test to every individual with a positive test result could prevent unnecessary quarantine and self-isolation of contacts, when including RT-PCR test in the MT test policy. Finally, implementation of MT is very expensive regarding costs and MHS capacity and could also be burdensome for the assigned population [23].
Limitations
Our study has limitations. First, in the results we made two assumptions regarding infection incidence on the effectiveness of MT, e.g. (1) infection incidence in Bunschoten would stay similar to what it was before the intervention started and (2) infection incidence in Bunschoten would be similar to the province of Utrecht during the intervention. These assumptions suggested that MT caused up to a 3.3-fold increase in detected active infections. It is not possible to validate these assumptions, but it does indicate a bandwidth of possible effectiveness of MT. Second, a regularly used measurement to indicate the infection rate in a population is the PPT. In these circumstances this measurement was less useful since part of the positive test results could be related to old infections, which could have led to an overrepresentation of the number of positive tests. At the same time, inhabitants could get tested more than once, which could lead to an underestimation of the PPT. Therefore, the PPT was not an effective measurement to express the infection pressure in this case. To overcome this, we showed an alternative PPT calculation, which was more reliable. However, since this calculation is not used in national SARS-CoV-2 surveillance, it is not possible to relate this outcome to national PPT calculations.
Third, viral spread indicators (secondary attack rate and registered cluster and outbreaks) were influenced by many factors, including the infection rate at a given moment, changes in general control measures and the capacity and quality of the source investigation, contact tracing process and quality of registered data. Consequently, it was impossible to distinguish the effect of MT in the spread of SARS-CoV-2 from other influencing factors. Further research should be performed to determine the effect of MT on viral spread. Fourth, a questionnaire was included in the study design for analysis of social demographic characteristics. Yet, results were not representative due to a small control group and overrepresentation of certain population groups. Future research should look further into the effect of MT on different population groups. Finally, during a pandemic, the epidemic phase and the implemented control measures vary constantly, which may have influenced the results [8]. For example, primary schools opened at the start of MT after being closed for more than 1 month, which could have led to higher infection incidence. Therefore, we compared our results with the province of Utrecht as a reference, as well as time periods before and after MT.
Conclusions
A strategy of MT is successful to detect a larger number of active COVID-19 cases and could be a useful tool in specific situations with a defined target group or goal to get a more complete view of the presence of SARS-CoV-2 in a community, including the early spread of a variant of concern in a population or an outbreak in a specific population. However, the effect on the spread of SARS-CoV-2 remains inconclusive. Furthermore, MT should be implemented with other control measurements, including isolation of infected individuals, personal hygiene and social distancing [24]. Since the effect on viral spread remains inconclusive, MT has a large impact on MHS capacity and is costly; the question remains open whether the use of MT is proportionate to the overall gain.
Acknowledgements
The authors acknowledge the work of all mass testing organisers within the municipal health service Utrecht region, the municipality of Bunschoten and UMC Utrecht. Furthermore, the authors thank all inhabitants of Bunschoten who got tested during the MT.
Financial support
This work was funded by the Dutch Ministry of Health, Welfare and Sports.
Conflict of interest
All authors report no potential conflicts of interest.
Data availability statement
The datasets generated during this study are not publicly available because publicly sharing the data would not be in accordance with participant's consent obtained for this study. Data are available from the corresponding author on reasonable request.
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| 36440638 | PMC9744447 | NO-CC CODE | 2022-12-15 00:01:45 | no | Epidemiol Infect. 2021 Nov 15; 150:e193 | utf-8 | Epidemiol Infect | 2,021 | 10.1017/S0950268822001777 | oa_other |
==== Front
Can J Neurol Sci
Can J Neurol Sci
CJN
The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques
0317-1671
2057-0155
Cambridge University Press New York, USA
36321540
S0317167122003079
10.1017/cjn.2022.307
Letter to the Editor: New Observation
Severe Anterior Ischemic Optic Neuropathy Due to COVID-19-Related Epistaxis
Vosoughi Amir R. 1
https://orcid.org/0000-0003-4911-9152
Micieli Jonathan A. 2 3 4 5
1 Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
2 Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada
3 Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
4 Kensington Vision and Research Centre, Toronto, Ontario, Canada
5 Department of Ophthalmology, St. Michael’s Hospital, Unity Health, Toronto, Ontario, Canada
Corresponding author: Dr. Jonathan A. Micieli, Kensington Vision and Research Centre, 501-340 College Street, Toronto, Ontario, M5T3A9, Canada. Email: [email protected]
02 11 2022
02 11 2022
12
12 9 2022
07 10 2022
16 10 2022
© The Author(s) 2022
2022
The Author(s)
simple This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means subject to acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.
Keywords:
Epistaxis
Optic neuropathy
NAION
Hemorrhage
==== Body
pmcNon-arteritic ischemic anterior optic neuropathy (NAION) is the most common cause of optic neuropathy in older patients. It is frequently associated with a “disc at risk” appearance and vascular risk factors. Rarely, NAION occurs following non-surgical blood loss, most typically in context of gastrointestinal and uterine bleeding. 1 A far less common cause of NAION is epistaxis. We present a 60-year-old woman who developed bilateral visual deficits following an episode of severe epistaxis related to COVID-19 lasting for over 5 days. This case highlights a potential risk of COVID-19 infection – severe vision loss through a unique mechanism of epistaxis.
A 60-year-old woman with a past medical history of type 2 diabetes, hypertension, and takotsubo cardiomyopathy presented with sudden upper visual field loss in the right eye (RE) and complete vision loss in the left eye (LE). A month prior to her presentation, she tested positive for COVID-19 (polymerase chain reaction test from nasopharyngeal swab). She was asymptomatic from this except for nasal congestion. Two weeks after testing positive for SARS-CoV2, she developed severe epistaxis lasting over 5 days which required balloon angioplasty on the second day to control. On fifth day, she woke up with partial visual loss in the RE and complete visual loss in the LE. She subsequently presented to the emergency department where she was found to have a hemoglobin of 55 g/L and mean corpuscular volume of 86 fL and subsequently transfused with two units of packed red blood cells. Her complete blood count 4 months prior was normal with a hemoglobin of 138 g/L. She denied any constitutional symptoms or symptoms of giant cell arteritis.
Initial ophthalmological exam revealed a visual acuity of 20/20 RE and counting fingers LE, with a left afferent pupillary defect. Fundus examination demonstrated bilateral optic disc edema. The macula and retina were unremarkable. Humphrey 24-2 SITA-Fast visual fields demonstrated superior hemifield defect in RE and dense complete visual field defect LE (Figure 1). Magnetic resonance imaging showed no enhancement or signal change in the optic nerves and CRP was 3.2 mg/L (normal <5 mg/L). She was diagnosed with NAION, and optimization of her hematological parameters to prevent further episodes of anemia and appropriate control of blood pressure and blood sugars were recommended. The optic disc edema resolved after 2 months and 1 year after onset her visual function remained stable.
Figure 1: Humphrey visual fields demonstrating superior hemifield defect in the right eye and complete defect in the left eye.
We here present a unique case of NAION following epistaxis related to COVID-19. NAION in temporal relation to COVID-19 may occur after several mechanisms, and this case adds epistaxis to this list. The proposed mechanisms for NAION from COVID-19 include microangiopathic/thrombotic phenomenon, 2,3 hypoxia, 2,4 and endothelial dysfunction resulting in decreased optic nerve head vascular compliance. 5,6 NAION can develop in early stages to 4 weeks after COVID-19 infection, primarily in patients with underlying vascular risk factors. 6 Our patient did not have any signs/symptoms suggestive of other mechanisms resulting in post-COVID-19 NAION. The temporal association with severe epistaxis and anemia implies hemorrhagic-induced NAION as the most likely mechanism.
A literature search revealed six case reports of NAION after epistaxis. 7–12 The cause of epistaxis was spontaneous, and all but one patient were older with underlying vascular risk factors. 10 In a study of 198 patients by Singer et al., the most common source of hemorrhage was gastrointestinal bleeding (40.2%), followed by uterine bleeding (32.8%), phlebotomy (14.3%), epistaxis (7.4%), wounds (3.2%), hemoptysis (1.05%), and urethral bleeding (1.05%). 1
Our case highlights multiple features characteristically associated with hemorrhage-induced ischemic optic neuropathy. It is frequently bilateral – in the review by Hollenhorst et al., 87.4% of cases were bilateral. It rarely occurs immediately at the time of hemorrhage. In the review by Hollenhorst et al., 8.3% cases occurred at the time of hemorrhage, 11.6% immediately following hemorrhage, 14.2% within 12 hours, 19.2% within 12–48 hours, 39.2% within 3–10 days, and 7.5% occurred after 14 days. 1 Interestingly, a single episode of hemorrhage rarely results in ischemic optic neuropathy; rather, the main culprit is multiple episodes of recurrent bleeding. 1 Post-hemorrhagic NAION often occurs in patients with underlying vascular risk factors. 1 The majority of patients will not recover vision; however, numerous cases have demonstrated visual improvement following immediate correction of anemia. 1 Therefore, immediate transfusions must be provided to prevent further visual deficits as well as provide a chance for visual recovery.
The etiology of NAION is not known. The main theory focuses on an acute event leading to hypoperfusion to posterior ciliary arteries – which are susceptible due do their small size – resulting in ischemia and subsequent inflammation. This is followed by the development of compartment syndrome in patients with a small cup to disc ratio or “disc at risk appearance.” Hemorrhagic NAION may result in hypoperfusion through either anemia or hypotension. Many authors consider anemia to be the main risk factor, as the visual symptoms often develop hours to days following a hemorrhagic event. The timing would be in keeping with anemia as the main culprit, as the recovery of hemoglobin levels is gradual, while blood volume rapidly returns to normal following hemorrhage. 1
In summary, post-hemorrhagic NAION may rarely develop after epistaxis. It often results in bilateral visual deficits, compared to NAION not preceded by hemorrhage, which is frequently unilateral. Patients with underlying vascular risk factors and multiple episodes of recurrent bleeding are at risk. The rapid correction of anemia and hypotension is important to prevent further visual deficits and may also result in visual recovery.
Statement of Authorship
Category 1: a. Conception and design: Amir R. Vosoughi and Jonathan A. Micieli; b. Acquisition of data: Amir R. Vosoughi, Jonathan A. Micieli; c. Analysis and interpretation of data: Amir R. Vosoughi and Jonathan A. Micieli. Category 2: a. Drafting the manuscript: Amir R. Vosoughi and Jonathan A. Micieli; b. Revising it for intellectual content: Amir R. Vosoughi and Jonathan A. Micieli. Category 3: a. Final approval of the completed manuscript: Amir R. Vosoughi and Jonathan A. Micieli.
Financial Support
None.
Conflicts of Interest
The authors do not have any conflicts of interest to disclose.
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References
1. Hollenhorst RW , Wegener HP. Loss of vision after distant hemorrhage. Am J Med Sci. 1950;219 :209–18. DOI 10.1097/00000441-195002000-00012.
2. Rho J , Dryden SC , McGuffey CD , Fowler BT , Fleming J. A case of non-arteritic anterior ischemic optic neuropathy with COVID-19. Cureus. 2020;12 :e11950. DOI 10.7759/cureus.11950.33425529
3. Babazadeh A , Barary M , Ebrahimpour S , Sio TT , Mohseni Afshar Z. Non-arteritic anterior ischemic optic neuropathy as an atypical feature of COVID-19: a case report. J Fr Ophtalmol. 2022;45 :e171–e173. DOI 10.1016/j.jfo.2021.12.001.35031149
4. Yüksel B , Bıçak F , Gümüş F , Küsbeci T. Non-arteritic anterior ischaemic optic neuropathy with progressive macular ganglion cell atrophy due to COVID-19. Neuroophthalmology. 2022;46 :104–8. DOI 10.1080/01658107.2021.1909075.
5. Moschetta L , Fasolino G , Kuijpers RW. Non-arteritic anterior ischaemic optic neuropathy sequential to SARS-CoV-2 virus pneumonia: preventable by endothelial protection? BMJ Case Rep. 2021;14 :e240542. DOI 10.1136/bcr-2020-240542.
6. Sitaula S , Poudel A , Gajurel BP. Non-arteritic anterior ischemic optic neuropathy in COVID-19 infection - a case report. Am J Ophthalmol Case Rep. 2022;27 :101684. DOI 10.1016/j.ajoc.2022.101684.35990799
7. Michaelides M , Riordan-Eva P , Hugkulstone C. Two unusual cases of visual loss following severe non-surgical blood loss. Eye. 2002;16 :185–9. DOI 10.1038/sj.eye.6700094.
8. Harbridge DF. Optic atrophy manifested by visual disturbance following distant hemorrhage. Trans Am Ophthalmol Soc. 1923;21 :239–46.
9. Long AE. Amaurosis following nasal hemorrhage: report of a case. Am J Ophthalmol. 1943;26 :1179–82. DOI 10.1016/S0002-9394(43)90495-7.
10. Grimminger W. III. über Atrophia nervi optici partialis nach schweren Blutungen. Ophthalmologica. 1925;57 :106–20. DOI 10.1159/000295977.
11. Chisholm IA. Optic neuropathy of recurrent blood loss. Br J Ophthalmol. 1969;53 :289–95. DOI 10.1136/bjo.53.5.289.5775576
12. Waldeck HJS. Post hæmorrhagic optic atrophy as complication of severe epistaxis. J Laryngol Otol. 1960;74 :491–2. DOI 10.1017/S0022215100056851.14413610
| 36321540 | PMC9744450 | NO-CC CODE | 2022-12-15 00:01:45 | no | Can J Neurol Sci.;:1-2 | utf-8 | Can J Neurol Sci | 2,022 | 10.1017/cjn.2022.307 | oa_other |
==== Front
Epidemiol Infect
Epidemiol Infect
HYG
Epidemiology and Infection
0950-2688
1469-4409
Cambridge University Press Cambridge, UK
36345840
10.1017/S0950268822001704
S0950268822001704
Original Paper
Snapshot of COVID-19 superinfections in Marseille hospitals: where are the common pathogens?
Le Glass Elisabeth 12
Raoult Didier 12
https://orcid.org/0000-0002-5772-7628
Dubourg Grégory 12
1 IHU-Méditerranée Infection, Marseille, France
2 Aix Marseille Univ., IRD, AP-HM, MEPHI, Marseille, France
Author for correspondence: Grégory Dubourg, E-mail: [email protected]
2022
08 11 2021
08 11 2021
150 e19507 9 2022
25 10 2022
26 10 2022
© The Author(s) 2022
2022
The Author(s)
simple This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means subject to acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.
Episodes of bacterial superinfections have been well identified for several respiratory viruses, notably influenza. In this retrospective study, we compared the frequency of superinfections in COVID-19 patients to those found in influenza-positive patients, and to controls without viral infection. We included 42 468 patients who had been diagnosed with COVID-19 and 266 261 subjects who had tested COVID-19 negative between 26 February 2020 and 1 May 2021. In addition, 4059 patients were included who had tested positive for the influenza virus between 1 January 2017 and 31 December 2019. Bacterial infections in COVID-19 patients were more frequently healthcare-associated, and acquired in ICUs, were associated with longer ICU stays, and occurred in older and male patients when compared to controls and to influenza patients (P < 0.0001 for all). The most common pathogens proved to be less frequent in COVID-19 patients, including fewer cases of bacteraemia involving E. coli (P < 0.0001) and Klebsiella pneumoniae (P = 0.027) when compared to controls. In respiratory specimens Haemophilus influenzae (P < 0.0001) was more frequent in controls, while Streptococcus pneumoniae (P < 0.0001) was more frequent in influenza patients. Likewise, species associated with nosocomial transmission, such as Pseudomonas aeruginosa and Staphylococcus epidermidis, were more frequent among COVID-19 patients. Finally, we observed a high frequency of Enterococcus faecalis bacteraemia among COVID-19 patients, which were mainly ICU-acquired and associated with a longer timescale to acquisition.
Key words
Bacterial infections
bloodstream infections
COVID-19
respiratory infections
Agence Nationale de la Recherche http://dx.doi.org/10.13039/501100001665 10-IAHU-03
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pmcIntroduction
Among the factors that could contribute to COVID-19 mortality and morbidity, the role of bacterial superinfections remains unclear. The latter were common during pandemics such the Spanish flu pandemic in 1918 [1] and H1N1 influenza A in 2009 [2], in which invasive species such as Staphylococcus aureus, Streptococcus pyogenes or S. pneumoniae were identified. Comprehensive data regarding superinfections which complicate COVID-19 would allow rationalisation of the prescription of antimicrobial agents. In the literature, one meta-analysis covering 30 studies reported rates of bacterial superinfections of 7% in hospitalised patients and 14% of ICU patients; figures that appeared to be lower than those with influenza [3]. Surprisingly, in the latter study, Mycoplasma pneumoniae was the most frequent pathogen detected in COVID-19 patients followed by Gram-negative bacterial species. Moreover, a retrospective of patients hospitalised with COVID-19 reported acquisitions of superinfections to be both community-acquired and healthcare associated [4]. Interestingly, S. pneumoniae and S. aureus were the most frequent aetiological agents of community-acquired bacterial pneumonia, while enterobacteria and Pseudomonas aeruginosa were mostly found in healthcare-associated infections. Although a number of published studies have reported cases of co-infections with COVID-19 [5–10], they were conducted with a limited number of patients, often without a control group, thereby rendering it difficult to deduce whether such infections are actually associated with the acquisition of COVID-19 [11].
Since the beginning of the pandemic, we have diagnosed over 40 000 patients with COVID-19 and have access to microbiological results from patients admitted to public hospitals in Marseille. In this retrospective study, we aimed to provide a snapshot of bacterial superinfections in all COVID-19 patients for which microbiological investigations were conducted. To assess whether SARS-CoV-2 infection is associated with a specific epidemiology, we compared these results with those obtained from controls during the same period, as well as to a control group of influenza-positive patients between 2017 and 2019.
Methods
Study design and patients
This retrospective study was conducted at the IHU Méditerranée Infection in Marseille, France. We first extracted records of all patients with a positive diagnosis of COVID-19 (cases) between 26 February 2020 and 1 May 2021. A COVID-19 diagnosis was confirmed by real-time reverse transcription PCR (RT-PCR) testing performed on nasopharyngeal throat swab specimens, as previously described [12]. Firstly, to compare infections among the cases with controls, we extracted the list of patients who had had at least one COVID-19 PCR test, and for whom all tests were negative (controls). Finally, we aimed to compare COVID-19 superinfections with influenza superinfections through extraction of all positive PCR results for influenza A, B or H1N1 [13] between 1 January 2017 and 31 December 2019. All microbiological tests results from cases, controls and influenza patients were analysed.
Data collection and outcomes
For all cases, controls, and influenza patients for whom a bacterial infection had been identified, information was collected from electronic health records concerning demographics (age, gender), length of hospital stay, outcomes including death, and admission to the intensive care unit (ICU).
Microbiological procedures
Microbiological investigations included standard culture for urinary samples and blood cultures [14]. Respiratory specimens (i.e. sputa, pleural fluids, bronchoalveolar lavages (BALs), bronchial aspirates and pulmonary biopsies) were examined by standard cultures [15]; urine specimens were tested for pneumococcal antigen [16], and BAL by S. aureus (PCR) [17].
Definitions
We defined a superinfection by a positive sample to any bacteria and collected between two days before and 30 days after the diagnosis of the viral infection among COVID-19 and influenza patients. We did not consider the detection of Candida albicans and Enterococcus spp. from respiratory samples in this study. Bacteraemia was defined as the growth of a commensal non-skin flora in at least one blood culture vial, and involving a common skin coloniser (coagulase-negative staphylococci or Corynebacterium species) when at least two vials sampled within 48 h were positive for the same species. When the timescale between sampling the positive specimen exceeded 48 h after initial admission, these were defined as healthcare-associated infections. We removed duplicate data when a patient was positive to the same bacterial pathogen from the same anatomical site. The positivity rate for each category (i.e. respiratory infections and bacteraemia) was calculated by dividing the number of positive patients by the number of patients for which at least one blood or respiratory specimen was taken following their admission.
Statistical analysis
Statistical analyses were performed using Graphpad 6 (La Jolla, USA) and XLSTAT 2019 (Addinsoft, New York, USA). Continuous and categorical variables were presented as median (interquartile range) and absolute number (percentage) respectively. The Mann–Whitney U test, chi-square test and Fisher exact test were used when appropriate. Significance was set at P < 0.05.
Results
Patients included
In total, 42 468 subjects were positive according to a COVID-19 RT-PCR test during the study period and were considered as cases. Of these, 631 had at least one superinfection, accounting for 1321 episodes. During the same period, 266 261 subjects tested negative for COVID-19 amplification and were used as controls. A total of 4731 infections were identified among 2884 controls. Finally, from 2017 to 2019 we identified 4059 patients with at least one positive PCR for influenza virus; of these, 124 had at least one superinfection, as previously defined.
Patients’ characteristics
The cases were older (68 years old vs. 58.9 years old and 56.6 years old; P < 0.0001) and were significantly more frequently male (sex ratio M/F: 2.9) compared to controls and influenza patients (sex ratio M/F: 1.6 and 1, respectively) (P < 0.0001) (Table 1). Among cases, the sex ratio of patients admitted to the ICU did not differ from that of patients hospitalised in other units. The proportion of ICU-acquired infections was significantly higher among cases (83.9%) compared to control and influenza groups (46.9% and 34.9%, respectively) (P < 0.0001) as well as to the proportion of hospital-acquired infections (82% vs. 61.1% and 44.1%, respectively) (P < 0.0001). The median length of stay in the ICU preceding the infection was longer among cases (9.63 days) compared to controls (6.71 days) and influenza patients (5.17 days). Table 1. Characteristics of infections occurring in COVID-19 patients and those occurring in uninfected subjects between 26 February 2020 and 1 May 2021, and those occurring among influenza-positive patients between 1 January 2017 and 31 December 2019s (***P < 0.001)
COVID-positive COVID-negative FLU-positive
N = 42 468 N = 266 261 4059
Overall coinfections
Total number of coinfections (N) 1321 4731 166
Number of positive patients (N) 631 2884 124
Ratio M/F 471/160 (2.9)*** 1791/1093 (1.64) 63/61 (1.03)
Median hospital stay (days) 8.69*** 3.61 1.34
Healthcare-associated (N, %) 1081/1318 (82)*** 2862/4687 (61.1) 71/161 (44.1)
Median age (years) 67.33*** 64.5 60.73
Time to coinfection (days) 9.7*** NA 5.53
Number of coinfections in ICU (n′/N, %) 1108/1321 (83.9)*** 2219/4728 (46.9) 58/166 (34.9)
Ratio M/F in ICU 362/104 (3.48)*** 665/358 (1.38) 19/14 (1.36)
Median ICU stay (days) 9.63*** 6709 5.17
Respiratory infections
Number of coinfections (N) 1069 2697 87
Number of positive patients (N′) 535 1492 68
Number of tested patients (N″) 1503 3632 638
Positivity rate (N′/N″, %) 535/1503 (35.6) 1492/3632 (41.1)*** 68/638 (10.7)
Ratio M/F 842/227 (3.7)*** 1812/885 (2.1) 46/41 (1.1)
Median hospital stay (days) 8731*** 4.64 1817
Healthcare-associated (n/N, %) 899/1066 (84.3)*** 1894/2680 (70.7) 41/85 (48.2)
Mean age (years) 66.16 61.6 64.3
Time to coinfection (days, mean) 9.8 – 5.95
Number of coinfections in ICU (n′/N, %) 948/1069 (88.7)*** 1640/2694 (60.9) 40/87 (46)
Median ICU stay (days) 9.2*** 6.8 3.9
Blood cultures
Number of coinfections (N) 252 2034 79
Number of positive patients (N′) 209 1686 67
Number of tested patients (N″) 5580 11 526 1864
Positivity rate (N′/N″, %) 209/5580 (3.75) 1686/11 526 (14.6)*** 67/1864 (3.6)
Ratio M/F 160/49 (3.3)*** 1028/658 (1.6) 44/35 (1.3)
Median hospital stay (days) 8.632*** 1.761 0.06111
Healthcare-associated (n/N, %) 182/252 (72.2)*** 968/2007 (48.2) 30/76 (39.5)
Median age (years) 66.9 66.9 52.06***
Time to coinfection (days) 9.1 – 5.1
Number of coinfections in ICU (n′/N, %) 160/252 (63.5)*** 579/2034 (28.5) 18/79 (22.8)
Median ICU stay (days) 12.95*** 6.48 14.3
Values in bold indicate the group for which the difference is the most significant.
Respiratory infections
We identified a total of 1069, 2697 and 87 respiratory infections among 535 cases, 1492 controls, and 68 influenza patients, respectively (Table 1). When compared to control and influenza groups, respiratory infections were more frequent among controls (41.1%) than among cases and influenza patients (35.6% and 10.7%, respectively) (P < 0.001). However, respiratory infections among cases were more frequently healthcare-associated (84.3% vs. 70.7% and 48.2%, respectively) (P < 0.0001) and more frequently ICU-acquired (88.7% vs. 60.9% and 40.6%, respectively) (P < 0.0001) compared to the control and influenza groups, respectively. Cases with respiratory infections were significantly more frequently male (sex ratio M/F: 3.7 vs. 2.1 and 1.1, respectively), and were older (mean age: 65.3 years old) than the controls only (55.4 years old) (P < 0.0001). The median length of stay in the ICU preceding the infection was higher among cases (9.2 days) when compared to that of controls (6.8 days) and influenza patients (3.9 days), while the mean timescale for acquiring respiratory superinfections was higher among cases (9.8 days) than influenza patients (5.95 days). Regarding the species identified, S. epidermidis (P < 0.0001), K. aerogenes (P = 0.004) and Hafnia alvei (P = 0.001) were more frequently recovered from respiratory specimens of cases, while Haemophilus influenzae (P < 0.0001), Enterobacter cloacae complex (P = 0.003) and Escherichia coli (P = 0.001) were more frequent among while S. pneumoniae (P = <0.0001) was more frequently detected from influenza patients (Fig. 1a). Regarding ICU-acquired infections, H. alvei (P = 0.03) and S. epidermidis (P = 0.03) were more predominant in cases, while E. cloacae complex (P = 0.0001), E. coli (P = 0.0001) S. pneumoniae (P = 0.001) and H. influenzae (P < 0.0001) were more frequent among controls (Fig. 1b). The only observed difference in non-ICU settings was the significantly higher detection of S. pneumoniae among influenza patients (P < 0.0001) (data not shown). The latter species was also more common in community settings (i.e. 62.5%) out of the 10 most frequent species associated with COVID-19 respiratory superinfections. Fig. 1. Microorganisms detected in respiratory specimens, the frequency of which is significantly different among COVID-19 patients, controls and influenza-positive subjects (*P < 0.05; **P < 0.01; ***P < 0.001). (a) All units and (b) ICU only.
Bacteraemia
We identified a total of 252, 2034 and 79 bacteraemia among 209 cases, 1686 controls, and 67 influenza patients, respectively (Table 1). Bacteraemia was significantly more frequent among controls (14.6%) than cases (3.75%) and influenza patients (3.6%) (P < 0.0001). However, bacteraemia among cases were predominantly healthcare-associated (72.2% vs. 48.2% and 39.5%, respectively), more frequently ICU-acquired (63.5% vs. 28.5% and 22.8%, respectively, P < 0.0001), with an overrepresentation of male subjects (sex ratio M/F = 3.3 vs. 1.6 and 1.3, respectively, P < 0.0001) (Table 1). The median length of stay in the ICU preceding the infection was longer among cases (13 days) compared to controls (6.5 days) but not for influenza patients (14.3 days), while the mean timescale between viral diagnosis and acquisition of bacteraemia was longer among cases (9.1 days) than influenza patients (5.1 days). Regarding the species identified, S. epidermidis (P < 0.0001), E. faecalis (P < 0.0001) and P. aeruginosa (P = 0.002), were more frequently isolated from blood cultures of cases while E. coli (P ≪ 0.0001) and K. pneumoniae (P = 0.03) were more frequent among controls, and S. pneumoniae among influenza patients (P = 0.02) (Fig. 2a). Similar findings were apparent with ICU-acquired infections for S. epidermidis (P = 0.005), E. faecalis (P = 0.002), P. aeruginosa (P = 0.016), and E. coli (P < 0.0001), but not for K. pneumoniae and S. pneumoniae (Fig. 2b). In non-ICU settings, S. pneumoniae was, however, more frequent among influenza patients (P = 0.014), as well as E. coli among controls (P < 0.001). Of the 10 species most frequent among cases, only E. coli and S. hominis were more associated with community settings. Among COVID-19 patients, bacteraemia due to E. faecalis generally occurred later when compared to those due to other pathogens (13.7 days vs. 8.5 days, respectively) (P < 0.0001), and more frequently in ICU settings (87% vs. 52.8%, respectively, P < 0.0001), but were not associated with more deaths. Fig. 2. Microorganisms detected from blood cultures, the frequency of which is significantly different among COVID-19 patients, controls, and influenza-positive subjects between 1 January 2017 and 31 December 2019 (*P < 0.05; **P < 0.01; ***P < 0.001). (a) All units and (b) ICU only.
Discussion
In this study, we provide a snapshot of the superinfections (associated with COVID-19 over a 13-month period). Our data rely on microbiologic investigations that were assessed by microbiologists and validated by two study operators. First, we found that bacterial infections in COVID-19 patients were more frequently healthcare-associated, often acquired in ICUs, associated with a longer ICU stay, and occurred in older male patients, compared to controls and influenza subjects (Table 1). The usual main pathogens were less frequent in COVID-19 patients as illustrated by fewer bacteraemias involving E. coli and K. pneumoniae than among controls (Fig. 2a). Most importantly, the respiratory pathogens such as H. influenzae and S. pneumoniae, commonly involved in viral superinfections, were under-represented in COVID-19 patients compared with controls and influenza patients (Fig. 1a and b). These findings are in line with other studies agreeing that community-acquired superinfections are more common in COVID-19 positive subjects [18]. The present work showed that infections in COVID-19 patients are generally dominated by nosocomial-transmitted microorganisms, such as Gram-negative bacteria in respiratory infections, and coagulase negative staphylococci and P. aeruginosa in bacteraemia.
Nevertheless, it was surprising to observe the high frequency of E. faecalis bacteraemia among COVID-19 patients that were mainly ICU-acquired (87%) with a longer timescale of acquisition when compared to the other microorganisms. We wondered whether empirical antimicrobial therapy could have contributed to selecting enterococcal species, but fewer than the half of the patients with a positive blood culture for E. faecalis had received either cephalosporins or carbapenems prior to sampling (data not shown). Nevertheless, gut microbiota enrichment with E. faecalis has been associated with an abnormal immune response in COVID-19 patients [19].
We did not find increased mortality in patients with bloodstream infections involving E. faecalis although other studies have also noted an unexpected frequency of bacteraemia involving enterococci [20], particularly in ICU settings with often equal distribution between E. faecalis and E. faecium [21, 22], One of the hypotheses raised is the possible increased permeability of the gut barrier induced by the virus when replicating in enterocytes. However, patients developed E. faecalis bacteraemia within a mean timescale of 13.7 days in our series, when the virus replicates little, rendering this hypothesis less probable.
The rate of superinfection during COVID-19 has been reported to be usually low, ranging from 6% to 8% depending on the studies [3, 4, 23, 24]. Our study shows that COVID-19 patients experience more respiratory superinfections than individuals with influenza, due to a high proportion of pathogens with nosocomial transmission, whereas the rate of bloodstream infections is similar. Discrepant results were also reported which found similar rates of superinfection between COVID-19 patients and influenza-positive individuals, but it remains difficult to extract how many infections were ICU-acquired [24].
We acknowledge that the clinical application of our findings could be limited by the fact that the study was conducted primarily from a microbiological viewpoint, and that patients were not classified according to the severity of their illness. However, stringent inclusion criteria were used for the definition of bacteraemia to avoid inclusion of contaminants when collecting our data, and interpreted the results according to relevant parameters, including the proportion of ICU admissions, and the length of stay in the ICU. It is also acknowledged that only standard cultures and two rapid assays (i.e. pneumococcal antigen detection in urine and molecular detection of MRSA) were utilised and possibly may have missed pathogens detected by other approaches such as serological testing or other specific PCRs. Finally, we did not analyse the antibiotic treatments administered during the patient's stay. Indeed, antimicrobial agents were largely prescribed for COVID-19 patients, which could have thereby reduced the incidence.
Overall, this study shows that the superinfections occurring with COVID-19 are more frequent than with influenza primarily due to prolonged stays in the ICU. Pathogens that are commonly isolated from patients presenting with routine clinical infections are under-represented, while those most often associated with nosocomial transmission were predominant. Notably, there was an unexpectedly high frequency of Enterococcus faecalis bacteraemia among COVID-19 patients, a finding which warrants further investigation.
Acknowledgements
None.
Author contributions
Conceptualisation: G. D., D. R.; Methodology: D. R., G. D., E. L. G.; Validation: G. D., D. R.; Formal analysis: E. L. G., G. D.; Investigation: E. L. G., G. D.; Writing: E. L. G., G. D., D. R.; Visualisation: E. L. G., G. D.; Supervision: G. D., D. R.
Financial support
This work was supported by the French Government under the ‘Investments for the Future’ programme managed by the National Agency for Research (ANR), Méditerranée-Infection 10-IAHU-03 and was also supported by Région Provence Alpes Côte d'Azur and European FEDER PRIMMI funding (European Regional Development Fund–Plateformes de Recherche et d'Innovation Mutualisées Méditerranée Infection), ERDF PA 0000320 PRIMMI.
Conflict of interest
Didier Raoult has been a consultant for Hitachi High-Technologies Corporation, Tokyo, Japan, from 2018 to 2020. He is a scientific board member of Eurofins company and a founder of a microbial culture company (Culture Top). Other authors declare no conflicts of interest.
Ethical standards
All data were generated as part of routine work at the Assistance Publique-Hôpitaux de Marseille (APHM) (Marseille university hospitals), and this study results from routine standard clinical management. Access to the patients’ biological and registry data issued from the hospital information system was approved by the data protection committee of the APHM and was recorded in the European General Data Protection Regulation registry under number RGPD/APHM 2021-131.
Consent to participate
Not applicable.
Consent for publication
All authors have approved the manuscript and gave their consent for submission and publication.
Data availability statement
The data that support the findings of this study are not openly available, as requested by the data protection committee of APHM.
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| 36345840 | PMC9744451 | NO-CC CODE | 2022-12-15 00:01:46 | no | Epidemiol Infect. 2021 Nov 8; 150:e195 | utf-8 | Epidemiol Infect | 2,021 | 10.1017/S0950268822001704 | oa_other |
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Epidemiol Infect
Epidemiol Infect
HYG
Epidemiology and Infection
0950-2688
1469-4409
Cambridge University Press Cambridge, UK
36325838
10.1017/S0950268822001686
S0950268822001686
Original Paper
Association between physical activity status and severity of COVID-19 in older adults
https://orcid.org/0000-0001-5732-846X
Tsuzuki Shinya 123
Akiyama Takayuki 2
Matsunaga Nobuaki 2
Ohmagari Norio 12
1 Disease Control and Prevention Center, Tokyo, Japan
2 AMR Clinical Reference Center, National Center for Global Health and Medicine, Tokyo, Japan
3 Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
Author for correspondence: Shinya Tsuzuki, E-mail: [email protected]
2022
03 11 2021
03 11 2021
150 e18902 8 2022
11 10 2022
24 10 2022
© The Author(s) 2022
2022
The Author(s)
simple This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means subject to acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.
The risk factors specific to the elderly population for severe coronavirus disease 2019 (COVID-19) caused by the Omicron variant of concern (VOC) are not yet clear. We performed an exploratory analysis using logistic regression to identify risk factors for severe COVID-19 illness among 4,868 older adults with a positive severe acute respiratory coronavirus 2 (SARS-CoV-2) test result who were admitted to a healthcare facility between 1 January 2022 and 16 May 2022. We then conducted one-to-one propensity score (PS) matching for three factors – dementia, admission from a long-term care facility and poor physical activity status – and used Fisher's exact test to compare the proportion of severe COVID-19 cases in the matched data. We also estimated the average treatment effect on treated (ATT) in each PS matching analysis. Of the 4,868 cases analysed, 1,380 were severe. Logistic regression analysis showed that age, male sex, cardiovascular disease, cerebrovascular disease, chronic lung disease, renal failure and/or dialysis, physician-diagnosed obesity, admission from a long-term care facility and poor physical activity status were risk factors for severe disease. Vaccination and dementia were identified as factors associated with non-severe illness. The ATT for dementia, admission from a long-term care facility and poor physical activity status was −0.04 (95% confidence interval −0.07 to −0.01), 0.09 (0.06 to 0.12) and 0.17 (0.14 to 0.19), respectively. Our results suggest that poor physical activity status and living in a long-term care facility have a substantial association with the risk of severe COVID-19 caused by the Omicron VOC, while dementia may be associated with non-severe illness.
Key words
COVID-19
dementia
long-term care facility
physical activity
propensity score
Ministry of Health Labour and Welfare 20HA2003 Japan Society for the Promotion of Science http://dx.doi.org/10.13039/501100001691 20K10546
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pmcIntroduction
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), has become a global health threat [1–3]. Since the first case of COVID-19 was identified in Wuhan, China [4], there have been various changes in the approaches to clinical management of COVID-19. The risk factors for severe disease now seem to have been identified [5, 6] and the pharmaceutical treatments for COVID-19 cases are at least somewhat established [7–9]. However, the SARS-CoV-2 B.1.1.529 variant of concern (VOC) that causes COVID-19 has somewhat different clinical characteristics from the pre-existing variants. This variant, which was first identified in South Africa on 24 November 2021 [10] and was subsequently named Omicron, has now spread worldwide. Fewer patients develop serious illness with this variant and vaccines are less effective [11–13].
In Japan, the Omicron VOC has spread rapidly, as in many countries, although there have been fewer severe cases than when the Delta variant was dominant [14]. Nevertheless, the higher infectivity of the Omicron VOC compared with previous variants led to a huge number of new confirmed cases and a corresponding increase in the number of severe cases. This has burdened our health systems and society further [15].
Although previous studies have identified the risk factors associated with severe illness caused by other variants [5, 16–18], the same factors may not be applicable to the disease caused by the Omicron VOC. Examining the risk factors associated with severe COVID-19 caused by the Omicron VOC is therefore desirable especially since, throughout the entire pandemic period, older Japanese adults have accounted for a large proportion of the severe COVID-19 cases that required hospitalisation [19, 20]. Because Japan is fast becoming an extremely aged society, an evaluation of the risk factors specific to the elderly population would be extremely valuable. For instance, the US Centers for Disease Control and Prevention (CDC) reported that living in a long-term care facility was an independent risk factor for mortality [21]. Moreover, dementia or pre-existing Alzheimer's disease was reported to be associated with late mortality due to COVID-19 [22, 23]. According to Steenkamp et al., a moderate or high level of physical activity had a preventive effect on severe COVID-19 [24]. However, the influence of these factors on the severity of COVID-19 caused by the Omicron VOC is not clear.
The main objectives of this study were to identify the risk factors for severe COVID-19 caused by the Omicron VOC and to assess the relevance of three factors specific to the elderly population – dementia, living in a long-term care facility, and physical activity status – for the severity of the disease.
Methods
Study population and data
Healthcare facilities that voluntarily participated in the COVID-19 Registry Japan (COVIREGI-JP) [19, 25], which is managed by the REBIND (Repository of Data and Biospecimen of Infectious Disease) project, enroled the patients. Research collaborators in each facility manually entered the data into the registry. The inclusion criteria for enrolment were (i) a positive SARS-CoV-2 test result and (ii) admittance to a healthcare facility between 1 January 2022 and 16 May 2022. The exclusion criteria were positive test results for any of the N501Y, E484K, E484Q and L452R mutants in SARS-CoV-2 genome tests. Also, although not all the patients had the results of genome tests in our registry, most cases in January 2022 in Japan were caused by the Omicron VOC and some other studies regarded all the patients from the beginning of 2022 as having a disease caused by the Omicron VOC [26, 27]. Therefore, we also excluded patients who showed any evidence suggesting a disease caused by strains other than the Omicron VOC (i.e. N501Y, E484K, E484Q and L452R during the study period).
Statistical analysis
As a descriptive analysis of the whole data, which included patients younger than 65 years old, continuous variables are presented as median and interquartile range (IQR) and categorical variables as number of cases and percentages. We then performed an exploratory analysis using logistic regression to identify risk factors for severe illness for elderly patients (age 65 or older). In this study, we defined severe illness as a need for supplementary oxygen during admission. The following variables were included in the regression model: age, sex, vaccinated at least twice, current smoking habit, cardiovascular disease, cerebrovascular disease, chronic lung disease, asthma, liver disease, renal failure and/or dialysis, diabetes mellitus, solid tumour, blood cancer, collagen disease, physician-diagnosed obesity, dementia, admission from a long-term care facility and physical activity. In this study, we use the term ‘long-term care facility’ to refer to not only healthcare facilities but also nursing homes and other facilities that provide accommodation for elderly people, including those who are healthy, because there is no equivalent English term to cover this category of patients used in Japan. We defined physical activity as a dichotomous variable and patients were considered to have good physical activity status if they could (i) eat a normal diet, (ii) walk independently and (iii) take care of themselves; otherwise, they were considered to have poor physical activity status. Each of the three criteria was assessed by a treating physician at each facility, and then we judged the physical activity of each patient based on these three factors.
Next, we conducted one-to-one propensity score (PS) matching [28] using three categorisations: presence/absence of dementia, admission from a long-term care facility/home or an acute healthcare facility; and good/poor physical activity status. The PS was calculated by logistic regression analysis with the same variables included in the exploratory analysis. All matching processes were based on nearest neighbour matching with a caliper width of 0.05 and no replacement was allowed. The standardised difference was used to measure the covariate balance, and an absolute standardised difference above 0.1 was interpreted as a meaningful imbalance. Fisher's exact test was used to compare the proportion of severe and fatal COVID-19 cases in matched data. In addition, we estimated the average treatment effect on treated (ATT) in each PS matching analysis.
Two-sided P values of < 0.05 were considered to show statistical significance. All analyses were conducted with R version 4.1.3 [29].
Results
The characteristics of participants are shown in Table 1. We included 4,868 patients in the analysis, 1,380 of whom had severe COVID-19. The age distribution of the severe group was about 20 years older than that of the non-severe group (median 79.0 and 57.0 years old, mean 74.3 and 53.9 years old, respectively). Both the severe and non-severe groups showed comparatively high vaccination coverage, with 61.1% and 65.0% vaccinated at least twice, respectively. The severe group showed a higher proportion of past medical history and comorbidity; for instance, 14.3% of the severe group had cardiovascular disease, compared with only 5.8% of the non-severe group. Poorer physical activity and higher case fatality rate were other characteristics of the severe group. Table 1. Demographic characteristics of hospitalised patients for COVID-19 caused by the Omicron VOC
Supplementary oxygen during admission No Yes P value
Cases (n) 3,488 1,380
Age [median, IQR] (mean, range) 57.0 [31.0–78.0]
53.9 (0–103) 79.0 [68.0–87.0]
74.3 (0–107) <0.001
Male sex (%) 1,693 (48.5) 802 (58.1) <0.001
Vaccinated at least twice (%) 2,267 (65.0) 843 (61.1) 0.011
Booster dose (%) 314 (9.0) 121 (8.8) 0.824
Current smoking (%) 442 (12.7) 117 (8.5) <0.001
Cardiovascular disease (%) 202 (5.8) 198 (14.3) <0.001
Cerebrovascular disease (%) 297 (8.5) 286 (20.7) <0.001
Chronic lung disease (%) 120 (3.4) 172 (12.5) <0.001
Asthma (%) 211 (6.0) 100 (7.2) 0.135
Liver disease (%) 73 (2.1) 51 (3.7) 0.002
Diabetes mellitus (%) 591 (16.9) 344 (24.9) <0.001
Obesity (%) 229 (6.6) 111 (8.0) 0.071
Renal failure/dialysis (%) 119 (3.4) 80 (5.8) <0.001
Solid tumour (%) 227 (6.5) 138 (10.0) <0.001
Blood cancer (%) 70 (2.0) 38 (2.8) 0.130
Collagen disease (%) 71 (2.0) 35 (2.5) 0.278
Dementia (%) 349 (10.0) 315 (22.8) <0.001
Living in LTCF (%) 311 (8.9) 357 (25.9) <0.001
Normal diet (%) 3,045 (87.3) 929 (67.3) <0.001
Independent walking (%) 2,813 (80.6) 723 (52.4) <0.001
Self-care ability (%) 2,802 (80.3) 710 (51.4) <0.001
Poor physical activity status (%) 800 (22.9) 728 (52.8) <0.001
Outcome NA
Discharged to home (%) 2,732 (78.3) 664 (48.1)
Isolated (%) 267 (7.7) 16 (1.2)
Discharged to LTCF (%) 348 (10.0) 310 (22.5)
Transfer (%) 130 (3.7) 183 (13.3)
Transfer to higher-level facility (%) 2 (0.1) 21 (1.5)
Death (%) 9 (0.3) 181 (13.1)
Other (%) 0 (0.0) 5 (0.4)
IQR, interquartile range; LTCF, long-term care facility; NA, not applicable.
Table 2 and Figure 1 show the results of the logistic regression analysis. Age, male sex, cardiovascular disease, cerebrovascular disease, chronic lung disease, physician-diagnosed obesity, admission from a long-term care facility and poor physical activity status were identified as risk factors for severe illness (i.e. need for supplementary oxygen during admission). Vaccination was identified as the only factor associated with non-severe illness. Fig. 1. Results of multivariable logistic regression analysis. Black circles indicate median. Whiskers indicate 95% confidence intervals. LTCF, long-term care facility.
Table 2. Results of logistic regression analysis
Variable Odds ratio 95% Confidence interval P value
Intercept −2.06 [−3.00 to −1.12] <0.001
Age 0.01 [0.00 to 0.03] 0.016
Male sex 0.62 [0.44 to 0.80] <0.001
Vaccinated at least twice −0.54 [−0.72 to −0.36] <0.001
Current smoking −0.19 [−0.53 to 0.15] 0.274
Cardiovascular disease 0.35 [0.11 to 0.60] 0.004
Cerebrovascular disease 0.25 [0.04 to 0.46] 0.022
Chronic lung disease 0.88 [0.60 to 1.17] <0.001
Asthma 0.51 [0.14 to 0.89] 0.007
Liver disease 0.24 [−0.24 to 0.71] 0.325
Diabetes mellitus −0.11 [−0.30 to 0.08] 0.251
Obesity 0.76 [0.33 to 1.18] <0.001
Renal failure/dialysis 0.35 [−0.04 to 0.74] 0.081
Solid tumour −0.07 [−0.34 to 0.20] 0.610
Blood cancer 0.30 [−0.19 to 0.79] 0.225
Collagen disease 0.40 [−0.14 to 0.95] 0.148
Dementia −0.17 [−0.39 to 0.05] 0.122
Living in LTCF 0.29 [0.06 to 0.52] 0.012
Poor physical activity status 0.77 [0.55 to 0.98] <0.001
LTCF, long-term care facility.
Figures 2a–2c show the standardised mean difference before and after the matching procedure for dementia, admission from a long-term care facility and physical activity status, respectively. For all categorisations, neither group showed significant differences in each item included in the model. The details of the three datasets after matching are available in Tables S1–S3 in the supplementary file. Fig. 2. Balance of demographic characteristics of older COVID-19 inpatients before and after PS matching in relation to (a) with dementia or without dementia, (b) admission from a long-term care facility or from elsewhere and (c) poor or good physical activity status. LTCF, long-term care facility.
Table 3 shows the estimated ATT of each cohort for the risk of having severe disease. All three factors were significantly associated with disease severity. Dementia showed a negative relevance to the severity. Both admission from a long-term care facility and poor physical activity status were associated with severe illness, with the latter showing a larger ATT. Fisher's exact test determined similar results for admission from a long-term care facility and poor physical activity status (P = 0.014 and < 0.001, respectively), whereas dementia showed no significant difference (P = 0.435). Table 3. Average treatment effect on the treated for each matched cohort on supplementary oxygen requirement
Factor ATT 95% Confidence interval P value
Dementia −0.04 [−0.07 to −0.01] 0.004
Living in LTCF 0.09 [0.06 to 0.12] <0.001
Poor physical activity status 0.17 [0.14 to 0.19] <0.001
ATT, average treatment effect on the treated; LTCF, long-term care facility.
Table 4 shows the estimated ATT of each cohort for the risk of death. Similar to the estimated ATT for having severe disease, poor physical activity was positively associated with mortality, and dementia was negatively associated with it (P < 0.001 and = 0.004, respectively). Living in a long-term care facility showed no significant association with death. As for the results of Fisher's exact test, poor physical activity status showed significant difference in mortality (P < 0.001), whereas dementia and admission from a long-term care facility did not (P = 0.236 and 0.582, respectively). Table 4. Average treatment effect on the treated for each matched cohort on death
Factor ATT 95% Confidence interval P value
Dementia −0.03 [−0.04 to −0.01] 0.004
Living in LTCF 0.01 [0.00 to 0.03] 0.158
Poor physical activity status 0.07 [0.06 to 0.08] <0.001
ATT, average treatment effect on the treated; LTCF, long-term care facility.
Discussion
This study identified the risk factors for severe illness due to COVID-19 caused by the Omicron VOC in older adults. There has been little evidence relating to these factors in Japan until now, and our results show that the risk factors for severe illnesses due to the Omicron VOC are very similar to those of other variants (e.g. Alpha and Delta variants). As suggested previously, older age, male sex, cardiovascular disease, chronic lung disease and obesity are among the factors associated with severe COVID-19 [5, 9, 12, 17, 18]. In addition, these risk factors are similar to those specific to the elderly population [6]. These facts may suggest that the original pathology of SARS-CoV-2 infection is inflammation of the respiratory tract, regardless of the strain or variant of the causative organism.
At least two vaccine doses is strongly associated with non-severe illness for the Omicron VOC, as well as for other strains [13, 30–32]. This result supports the need to promote vaccination at the population level, even though there has been concern about the efficacy of the currently available COVID-19 vaccines against the Omicron VOC [13].
The results pertaining to dementia should be carefully interpreted. Although Fisher's exact test did not show significant differences in the risk of severe disease in the data after PS matching, logistic regression analysis did not identify dementia as one of the risk factors for severe illness. In addition, the ATT for dementia showed a negative relevance to its severity. These results are not in agreement with those of previous studies [22, 23, 33, 34], and dementia itself would not intuitively seem to have a positive effect on the severity of COVID-19. However, two reports from Japan stated that dementia was not a significant risk factor for severe illness due to COVID-19 [6, 35]. One possible reason is that dementia is easily confounded by other factors specific to the elderly population, such as poor physical activity, and so the true effect of dementia is difficult to determine by simple logistic regression analysis. Good physical activity is likely an important factor in preventing severe illnesses, and dementia itself does not impair physical activity directly. Identifying the reason for this discrepancy is a future challenge.
According to our results, both living in a long-term care facility and poor physical activity status were associated with severe COVID-19, but the ATT for poor physical activity status was the larger of the two. This may suggest that poor physical activity status has a greater relevance to the severity of COVID-19 than living in a long-term care facility; in other words, older adults who live in such facilities may also have different risk. Those who have a good physical activity status may have a lower risk of severe illness even if they live in a long-term care facility. This finding could be valuable when we consider how long-term care facilities manage COVID-19, particularly in super-aged societies like Japan. For instance, there is likely to be substantial diversity in activities of daily living among the residents of long-term care facilities, and physical activity status could be a potential determinant for the triage of hospitalisation requests from such facilities when healthcare resources are limited.
The similar results of ATT for mortality should also be noted. The negative association seen between dementia and mortality, and the positive association seen between poor physical activity and mortality, suggest that physical activity is important to prevent poor clinical outcomes. Furthermore, living in a long-term care facility did not show any significant difference in mortality. Given these results, the place of residence itself might be an indirect factor for prognosis, whereas physical activity may be more directly associated with it.
Several limitations of this study should be noted. First, this was a retrospective cohort study and not a randomised controlled trial. Although we adjusted for various factors using PS matching, not all factors were included in the model. Next, we excluded a large number of patients from the final analyses because if any two groups (i.e. presence/absence of dementia, living in a long-term care facility/elsewhere, good/poor physical activity status) had substantially different demographic characteristics, then numerous patients had to be removed to adjust the background of both groups. Although this would strengthen the internal validity of our results, the external validity and generalisability would be sacrificed to some extent. Furthermore, because our registry data did not include information directly assessing the activities of daily living of each patient (e.g. Barthel Index), we had to adopt a new indicator comprising several factors associated with physical activity. These factors – normal diet, independent walking, and ability to take care of oneself – were assessed by each physician in each facility participating in our registry, and subjectivity may have affected the result. Last, we defined severe disease as having required any supplementary oxygen therapy. Given that physicians sometimes use supplementary oxygen for mild cases, we cannot rule out that some mild cases were included in the severe group in this study, leading to potential bias of the results. However, our analyses of mortality showed similar results, so we believe it is reasonable to conclude that poor physical activity would be associated with a poor clinical outcome and dementia might be associated with a good clinical outcome.
Conclusions
Our results suggest that physical activity and living in a long-term care facility have a substantial association with severe illness caused by COVID-19 owing to the Omicron-19 variant, whereas dementia may be associated with non-severe illness. We should take these factors into consideration in the management of older adults with COVID-19.
Acknowledgements
The authors thank all of the participating facilities for their care of patients with COVID-19 and their cooperation with data entry into the registry. The data used for this research were provided by the REBIND (Repository of Data and Biospecimen of Infectious Disease) project, which was commissioned for the National Center for Global Health and Medicine by the Ministry of Health, Labour and Welfare of Japan.
Supplementary material
For supplementary material accompanying this paper visit https://doi.org/10.1017/S0950268822001686.
click here to view supplementary material
Author contributions
ST and NO conceived the study. TA curated the data. ST and TA analysed and interpreted the data. ST wrote the first draft of the manuscript. All authors critically reviewed the manuscript and approved the final version.
Financial support
This research was supported by the Health and Labour Sciences Research Grant, ‘Research on Emerging and Re-emerging Infectious Diseases and Immunisation’ (grant number 20HA2003) and JSPS KAKENHI (grant number 20K10546).
Conflict of interest
All authors have no conflicts of interest to be disclosed.
Ethical standards
Our study data were provided by Research Electronic Data Capture, a secure, Web-based data capture application hosted at the JCRAC Data Center of the National Center for Global Health and Medicine. The opt-out recruitment method was applied, and informed consents for individuals were waived, as approved by the National Center for Global Health and Medicine Ethics Review Board. Information about the entire research is available through the COVID-19 Registry Japan website (https://covid-registry.ncgm.go.jp/). This study was approved by the National Center for Global Health and Medicine Ethics Review Board (approval number: NCGM-G-003494-0).
Availability of data
The data supporting the findings of this study are not publicly available due to the privacy of research participants and sites but are available upon reasonable request. Data on an individual level are shared with limitations to participating healthcare facilities through application to the REBIND project.
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| 36325838 | PMC9744453 | NO-CC CODE | 2022-12-15 00:01:46 | no | Epidemiol Infect. 2021 Nov 3; 150:e189 | utf-8 | Epidemiol Infect | 2,021 | 10.1017/S0950268822001686 | oa_other |
==== Front
BJPsych Open
BJPsych Open
BJO
BJPsych Open
2056-4724
Cambridge University Press Cambridge, UK
36458508
10.1192/bjo.2022.615
S2056472422006159
Academic Psychiatry
Paper
Suicidal ideation among people with disabilities during the COVID-19 pandemic in Bangladesh: prevalence and associated factors
https://orcid.org/0000-0002-8454-6128
Roy Nitai
Amin Md. Bony
https://orcid.org/0000-0002-1728-8966
Mamun Mohammed A.
Hossain Ekhtear
Aktarujjaman Md.
Sarker Bibhuti
Department of Biochemistry and Food Analysis, Patuakhali Science and Technology University, Patuakhali, Bangladesh
Faculty of Nutrition and Food Science, Patuakhali Science and Technology University, Patuakhali, Bangladesh
CHINTA Research Bangladesh, Dhaka, Bangladesh; and Department of Public Health and Informatics, Jahangirnagar University, Dhaka, Bangladesh
Department of Biological Sciences and Chemistry, Southern University and A&M College, Baton Rouge, USA
Department of Economics, University of Manitoba, Winnipeg, Canada; and Department of Economics, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
Correspondence: Nitai Roy. Email: [email protected]
1 2023
02 12 2022
02 12 2022
9 1 e316 8 2022
23 10 2022
04 11 2022
© The Author(s) 2022
2022
The Author(s)
simple This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means subject to acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.
Background
Evidence from pandemic and pre-pandemic studies conducted globally indicates that people with disabilities (PWDs) have a higher risk for suicidality. However, none of these studies has assessed suicidality among PWDs in Bangladesh.
Aims
The purpose of this study was to determine the prevalence of and factors associated with suicidal ideation among PWDs during the COVID-19 pandemic in Bangladesh.
Method
Using a snowball sampling technique, a cross-sectional survey was conducted from February to April 2021 among PWDs from six districts in the northern region of Bangladesh. Information related to sociodemographic factors, clinical characteristics, behavioural factors and suicidal ideation was collected. Chi-squared test and logistic regression were used to describe the data and explain the relationship of factors associated with suicidal ideation.
Results
The prevalence of COVID-19-related past-year suicidal ideation was 23.9%. The factors associated with suicidal ideation included: age above 35 years, being female, acquiring a disability later in life, lack of sleep and current substance use. In addition, higher education appeared to be a protective factor against suicidal ideation.
Conclusions
This study highlighted that PWDs had an increased risk of suicide; that is, one-fourth of them had past-year suicidal ideation. This may have been because of COVID-19-related restrictions and stressors. Thus, the government and policy makers need to pay more attention to developing effective suicide assessment, treatment and management strategies, especially for at-risk groups, to minimise the impact of the COVID-19 outbreak.
Keywords
COVID-19
suicidal ideation
suicidality
people with disabilities
Bangladesh
==== Body
pmcThe COVID-19 pandemic has become a global threat to all aspects of life, hampering social stability, economic development and health security. A daunting effect on people's mental health and psychological state has been reported, owing to pandemic-related issues affecting aspects of mental health including fear, anger, sleep difficulties, boredom, hopelessness and frustration.1 These pandemic-related effects have appeared to reduce physical movement and activity, increase food and harmful junk food consumption, and increase mental health symptoms such as those of depression, anxiety, and post-traumatic stress disorder across various groups.2,3 Furthermore, the combination of these stressors with mental health effects may contribute to suicidal ideation.4,5
Suicidal behaviours among PWDs
Suicide is a major public health issue. As per the World Health Organization's recent estimate, there is an annual suicide rate of about 700 000 suicide worldwide, of which 77% of cases occur in low- and middle-income countries such as Bangladesh. Suicide rates are higher among vulnerable groups, including people with disabilities (PWDs), compared with the general population, as people in these groups experience discrimination such as being treated less favourably and not receiving the same facilities as others. This represents a pressing and complex public health issue.6,7 In a recent systematic review, suicidal ideation and death by suicide were reported to be associated with functional disability; the highest rate of suicide was reported in people with multiple sclerosis, followed by those with spinal cord injury and intellectual disability.6 Associations have also been found in people with other disabilities including autism spectrum disorders and Huntington disease.8,9
Suicidal behaviours in the context of the COVID-19 pandemic among PWDs
A recent study found that PWDs experienced increased symptoms of depression (56.6% v. 28.7%), substance use (38.8% v. 17.5%) and suicidal ideation (30.8% v. 8.3%) compared with people without disabilities during the COVID-19 pandemic.10 Two other studies from the UK and USA also found an increased prevalence of suicidal ideation among PWDs compared with those without disabilities during the COVID-19 pandemic (30.1% v. 6.9%, a twofold increase from pre-pandemic estimates, and 20.7% v. 4.1%, respectively).11,12 Despite such high rates of suicidal ideation among PWDs, relatively little research has examined the risk factors for suicidal ideation within and across populations.
On 15 March 2020, the first suicide case attributed to fear of COVID-19 in Bangladesh occurred.13 Later, a systematic review from Bangladesh identified the factors that lead to actual suicide completion and the prevalence of and risk factors associated with suicidal behaviors.5 The prevalence of suicidal ideation was reported to range from 5% to 19% across different cohorts, and the rate of suicidal ideation increased over time due to the COVID-19 pandemic.5 Minor- and PWD-related homicide–suicide has been reported in the context of the pandemic. For instance, a case study reported the alleged infanticide of a 6-month-old baby with the suicide of an Indian 30-year-old mother in Saudi Arabia due to fear of infection.14 In addition, a triadic suicide pact was reported in India, where a disabled son and his parents had been alleged to die by mutual suicide (note, there was no evidence of homicide).15 However, no actual suicide occurrence among PWDs during the COVID-19 pandemic has been reported to the authors’ best knowledge.
Study objectives
Bangladesh hosts a huge number of PWDs; 16 million or 10% of the country's population has some type of disability.16 A recent qualitative study conducted in Bangladesh among PWDs suggested that the COVID-19 pandemic created critical disruptions to the economy and decreased their food security, social security, and physical and mental health.17 As discussed above, people with mental issues are more prone to suicidality,4,5 and it is anticipated that PWDs might be at higher risk of suicidal behaviours. However, no other epidemiological study has been conducted in Bangladesh among PWDs considering suicidal behaviours during the COVID-19 pandemic. Thus, there is a need for research on suicidal ideation to clarify the associated factors in order to develop suicide prevention strategies. This study uses a cross-sectional survey to address these research gaps and examines the prevalence of COVID-19-related suicidal ideation and associated factors among Bangladeshi PWDs.
Method
Study area
This cross-sectional study was conducted from February to April 2021 in the districts of Kurigram, Lalmonirhat, Dinajpur, Nilphamari, Panchagarh and Gaibandha (under the Rangpur division located in the northern region of Bangladesh). These six districts were purposively selected. From these six districts, 15 Upazilas (the smallest administrative units of the local government) were randomly selected, and at least one Upazila was selected from each district to collect the data.
Study population and inclusion criteria
The target population was people with various disabilities (physical disability, hearing disability, visual disability, leprosy and multiple impairments). Disability types described previously18,19 were assessed. In brief, people with locomotor disability, amputation that causes loss or absence or inactivity of the whole or part of the hand or leg, paralysis or deformity of joints affecting the normal ability to move self or objects were considered to be physically disabled. People with serious difficulties seeing, even when wearing glasses, were considered to be visually impaired. Similarly, people with hearing difficulties, even if using a hearing aid, were included in the hearing disability category. People screened for leprosy and currently undergoing treatment were recruited as the leprosy group. Finally, people who suffered from more than one of the aforementioned disabilities were considered to have multiple impairments. PWDs aged ≥18 years were selected for this study. Of note, PWDs who were critically ill during the survey, unable to respond to the questionnaires, or had pre-existing depression, anxiety or sleep disorder were excluded from the study.
Ethical consideration
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. All procedures involving human subjects or patients were approved by the Patuakhali Science and Technology University's Human Research Ethics Committee (approval number: BFA: 10/01/2021:02). To participate in this study, written consent was required from either the participants or their caregivers. Participants were aware that this publication was intended while taking part in the study.
Sampling technique and data collection
The final required sample size was 423 with a 95% confidence interval, 10% non-response rate and an assumption of a 50% (owing to the lack of published literature) prevalence of suicidal ideation among the study subjects using the single proportion formula (n = z2pq / d2). A total of 410 PWDs were recruited. The snowball sampling method was applied to access the PWDs where team members identified additional participants based on the information given by the previous participants. Data were collected through face-to-face interviews by trained interviewers in participants’ homes using a pre-tested structured questionnaire, including sociodemographic information, clinical characteristics and behavioural characteristics. If any participants did not understand the consent process, caregivers were interviewed and answered our questions on behalf of the participants. Importantly, participants with hearing disability used hearing aids to improve their hearing and speech comprehension while participating in the survey.
Measures
Sociodemographic measures
Sociodemographic factors included age, locality (rural or urban), marital status (married, unmarried or divorced/widowed/separated), religion (Islam or Hinduism), educational level (uneducated, up to 5 standards, 6–10 standards, 10–12 standards, graduate or postgraduate or above), occupation (unemployed, business, cultivator, housewife, student or employed) and living situation (with parents, with partners, with friends/relatives or alone). Socioeconomic status was classified as follows: less than 15 000 Bangladeshi Taka (≈177 $), 15 000–30 000 Bangladeshi Taka (≈177–354 $) or more than 3000 Bangladeshi Taka (≈354 $).
Clinical and behavioural measures
Clinical and behavioural measures included type of impairment (multiple, physical, hearing, visual or leprosy), onset of impairment (from birth, from childhood or later in life), comorbidity (yes or no), testing positive for COVID-19 (yes or no), COVID-19 symptoms (yes or no) (COVID-19 symptoms at the time of the survey), current substance use (yes or no) and increased substance use because of COVID-19 (yes or no). Sleeping hours were divided into three categories: normal (7–9 h), less than normal (<7 h), or more than normal (>9 h).
Mental health measures
The Bangla version of the Depression, Anxiety, and Stress Scale (DASS-21) was used in this study.20 This scale is composed of 21 questions divided into three subscales, with seven items per subscale: depression, anxiety and stress, with scored using a four-point Likert scale ranging from 0 (‘never’) to 3 (‘always’). Predefined thresholds used for depression, anxiety and stress in the present study were normal (depression 0–9, anxiety 0–7 and stress 0–14), mild (depression 10–13, anxiety 8–9 and stress 15–18), moderate (depression 14–20, anxiety 10–14 and stress 19–25), severe (depression 21–27, anxiety 15–19 and stress 26–33) and extremely severe (depression ≥28, anxiety ≥20 and stress ≥34). The Cronbach's alpha values for depression, anxiety and stress were 0.70, 0.73 and 0.79, respectively (the overall Cronbach's alpha for DASS-21 was 0.86); these values were acceptable.
Fear of COVID-19 measures
The Bangla version of the fear of COVID-19 scale (FCV-19S)21 was used to measure the level of fear of COVID-19. This tool for assessment of fear of COVID-19 comprises seven items on a five-point Likert scale ranging from 1 (‘strongly disagree’) to 5 (‘strongly agree’) with scores ranging from 7 to 35. Scores of 0–21 are considered to indicate low COVID-19 fear, and scores of 22–35 are considered to indicate high COVID-19 fear.22 The Cronbach's alpha for fear was 0.84 in the present study, which was good.
COVID-19-related suicidal ideation measure
Suicidal ideation related to COVID-19 was determined by a single question with a binary response (‘yes’/‘no’) based on the previous study5 (i.e. ‘Do you think about committing suicide and are these thoughts persistent and related to COVID-19 issues?’). As the COVID-19 pandemic started on March 2020 in Bangladesh, and this study was conducted 1 year later, the suicidal ideation assessment timeframe was past-year.
Statistical analysis
Data were analysed using the SPSS version 26 (IBM Corp). Simple descriptive analyses (i.e. frequencies, percentages and means) were used to summarise the sociodemographic and clinical characteristics. Chi-squared tests and unadjusted and adjusted logistic regression models were developed to assess the associations of the main outcome (suicidal ideation) with independent variables. The multicollinearity of variables was also assessed before regression analysis. Variables with P < 0.25 in the unadjusted model were entered into the multivariable analysis. Model fitness was checked using the Hosmer–Lemeshow goodness of fit test (P = 0.701). Odds ratios and 95% confidence intervals were calculated for each variable included in the regression models with a P-value less than 0.05.
Results
Sociodemographic characteristics and suicidal ideation
Table 1 summarises the sociodemographic characteristics and their relationship with suicidal ideation. Of the total participants (N = 410; mean age = 30.73 ± 10.85 years), 67.3% were male, 44.5% were unmarried, 77.8% were rural, 58.0% were from lower economic status, 81.2% were Muslim, 24% were students and 44.1% were living with parents. About 23.9% of the participants reported experiencing COVID-19-related suicidal ideation (n = 98), defined as past-year suicidal ideation related to the COVID-19 pandemic and associated issues. Age, gender, marital status, education level and living situation were significantly associated with suicidal ideation. Regarding age groups, a 38.3% suicidal ideation rate was found among PWDs aged over 35 years, compared with 17.9% for those aged 18 to 35 years; this difference was statistically significant (χ2 = 19.42, P < 0.001). Females were more likely to report suicidal ideation compared with their male counterparts (38.8% v. 16.6%; χ2 = 24.31, P < 0.001). PWDs also reported higher suicidal ideation when their marital status was divorced/widowed/separated (χ2 = 142.07, P < 0.001), their education level was ‘uneducated’ (χ2 = 14.77, P = 0.011) or they lived alone (χ2 = 77.60, P < 0.001). Table 1 Distribution of sociodemographic characteristics and suicidal ideation of participants (N = 410)
Variable Categories Total Suicidal ideation χ2 P-value
No Yes
n % n % n %
Age Mean ± s.d. (30.73 ± 10.85)
Age group 18 to 35 years 290 70.7 238 82.0 52 17.9 19.42 <0.001
Above 35 years 120 29.3 74 61.6 46 38.3
Gender Male 276 67.3 230 83.3 46 16.6 24.31 <0.001
Female 134 32.7 82 61.2 52 38.8
Locality Rural 319 77.8 241 75.5 78 24.4 0.24 0.626
Urban 91 22.2 71 78.0 20 21.9
Marital status Unmarried 182 44.4 153 84.0 29 15.9 142.07 <0.001
Divorced/widowed/separated 47 11.5 3 6.38 44 93.6
Married 181 44.1 156 86.2 25 13.8
Socioeconomic status (BDT) Up to 15 000 238 58.0 173 72.7 65 27.3 4.49 0.106
15 000 to 30 000 129 31.5 102 79.0 27 20.9
More than 30 000 43 10.5 37 86.0 6 13.9
Religion Islam 333 81.2 256 76.8 77 23.1 0.59 0.442
Hindu 77 18.8 56 72.7 21 27.2
Education level Up to 5 standards 59 14.4 48 81.3 11 18.6 14.77 0.011
6 to 10 standards 86 21.0 71 82.5 15 17.4
10 to 12 standards 120 29.3 90 75.0 30 25.0
Graduate 30 7.3 26 86.6 4 13.3
Postgraduate or above 28 6.8 23 82.1 5 17.8
Uneducated 87 21.2 54 62.0 33 37.9
Occupation Unemployed 56 13.7 42 75.0 14 25.0 7.01 0.220
Business 97 23.7 77 79.3 20 20.6
Cultivator 63 15.4 51 80.9 12 19.0
Housewife 50 12.2 31 62.0 19 38.0
Student 98 23.9 76 77.5 22 22.4
Employed 46 11.2 35 76.1 11 23.9
Living situation With parents 181 44.1 140 77.3 41 22.6 77.60 <0.001
With partner 168 41.0 144 85.7 24 14.29
With friends/relatives 22 5.4 20 90.91 2 9.09
Alone 39 9.5 8 20.51 31 79.49
Clinical and behavioural characteristics and suicidal ideation
Table 2 presents various clinical and behavioural characteristics and their associations with suicidal ideation. About 57.3% of respondents had physical impairments, 53.9% had impairment from birth, 60.2% had comorbid illnesses, 62.0% slept less than normal, 2.4% tested positive for COVID-19, 6.8% had COVID-19 symptoms, 52.0% were currently using substances and 38.3% reported increased substance use because of COVID-19. Moreover, findings from this study revealed that the majority of the respondents, that is, 85.4%, 87.3% and 77.3%, experienced depression, anxiety and stress, respectively. Furthermore, fewer than half of the participants (40.5%) reported high fear during the COVID-19 pandemic. The onset of impairment, sleeping hours, testing positive for COVID-19, COVID-19 symptoms, current substance use, increased substance use because of COVID-19 and fear of COVID-19 were significantly associated with suicidal ideation. Table 2 Distribution of clinical and behavioural characteristics and suicidal ideation of participants (N = 410)
Variable Categories Total Suicidal ideation χ2 P-value
No Yes
n % n % n %
Type of impairments Multiple impairments 37 9.0 24 64.8 13 35.1 4.92 0.296
Hearing impairment 66 16.1 49 74.2 17 25.7
Visual impairment 44 10.7 31 70.4 13 29.5
Leprosy 28 6.8 23 82.1 5 17.8
Physical impairment 235 57.3 185 78.7 50 21.2
Time of impairment Later in life 86 21.0 53 61.6 33 38.3 12.95 0.002
Early childhood 103 25.1 80 77.6 23 22.3
From birth 221 53.9 179 81.0 42 19.0
Comorbid illness status Yes 247 60.2 185 74.9 62 25.1 0.49 0.484
No 163 39.8 127 77.9 36 22.0
Sleep status (h) Above normal (>9) 34 8.3 31 91.1 3 8.8 21.34 <0.001
Below normal (<7) 254 62.0 174 68.5 80 31.5
Normal (7–9) 122 29.8 107 87.7 15 12.3
Positive for COVID-19 Yes 10 2.4 2 20.0 8 80.0 17.73 <0.001
No 400 97.6 310 77.5 90 22.5
Current COVID-19 symptoms Yes 28 6.8 17 60.7 11 39.3 3.91 0.048
No 382 93.2 295 77.2 87 22.7
Current substance use Yes 213 52.0 139 65.2 74 34.7 28.64 <0.001
No 197 48.0 173 87.8 24 12.1
Drug use increment during the pandemic Yes 157 38.3 100 63.7 57 36.3 21.52 <0.001
No 253 61.7 212 83.8 41 16.2
Type of substance use Alcohol 88 21.5 54 61.4 34 38.6 52.71 <0.001
Tobacco/cigarettes 111 27.1 82 73.9 29 26.1
Marijuana 15 3.7 3 20.0 12 80.0
None 196 47.8 173 88.3 23 11.7
Depression Normal 41 10.0 34 82.9 7 17.1 5.18 0.269
Mild 19 4.6 14 73.7 5 26.3
Moderate 74 18.0 60 81.1 14 18.9
Severe 125 30.5 87 69.6 38 30.4
Extremely severe 151 36.8 117 77.5 34 22.5
Anxiety Normal 38 9.3 31 81.6 7 18.4 3.83 0.430
Mild 14 3.4 11 78.6 3 21.4
Moderate 61 14.9 51 83.6 10 16.4
Severe 52 12.7 40 76.9 12 23.1
Extremely severe 245 59.8 179 73.1 66 26.9
Stress Normal 72 17.6 58 80.6 14 19.4 2.56 0.633
Mild 21 5.1 16 76.2 5 23.8
Moderate 36 8.8 30 83.3 6 16.7
Severe 150 36.6 112 74.7 38 25.3
Extremely severe 131 32.0 96 73.3 35 26.7
Fear of COVID-19 Low fear 244 59.5 196 80.33 48 19.67 5.93 0.015
High fear 166 40.5 116 69.88 50 30.12
For depression, anxiety and stress, the use of a binary category (normal versus depressed/anxious/stressed) had non-significant relationships with suicidal ideation.
Among participants who reported becoming disabled later in life, a higher proportion (38.3%) experienced suicidal ideation compared with those who had impairment onset in early childhood and from birth (22.3% and 19.0%, respectively; χ2 = 12.95, P = 0.002). Those who reported sleeping for less than 7 h reported a higher suicidal ideation rate than those sleeping for normal or longer than normal lengths of time (χ2 = 21.34, P < 0.001). Those who tested positive for COVID-19 (80.0% v. 22.5%; χ2 = 17.73, P < 0.001) and had current COVID-19 symptoms (39.3% v. 22.7%; χ2 = 3.91, P = 0.048) were more likely to have suicidal ideation. In addition, PWDs who were substance users (χ2 = 28.64, P < 0.001) and reported an increment in substance use after the pandemic (χ2 = 21.52, P < 0.001) had higher suicidal ideation compared to those who did not meet these criteria. Finally, none of the mental disorders was significantly associated with suicidal ideation, but for fear of COVID the association was χ2 = 5.93 (P = 0.015). That is, 30.12% of PWDs who had high COVID-19 fear reported suicidal ideation, compared with 19.67% for those with low fear of COVID-19.
Risk factors of suicidal ideation
Multivariate logistic regression (Table 3) analyses were performed using sociodemographic, clinical and behavioural predictors to reveal the risk factors for suicidal ideation. The results showed that participants aged above 35 years were 2.65 times more likely to have suicidal ideation (adjusted odds ratio (AOR) = 2.65, 95% CI = 1.31–5.37) than those aged from 18 to 35 years. Regarding gender, females had a 5.14-times elevated suicidal ideation risk compared with male participants (AOR = 5.14, 95% CI = 2.28–11.56). Moreover, compared with participants who were uneducated, those having completed 6–10 standards (AOR = 0.28, 95% CI = 0.11–0.72), having graduated (AOR = 0.06, 95% CI = 0.01–0.31) and having postgraduate education (AOR = 0.15, 95% CI = 0.02–0.91) were less likely to have suicidal ideation. Table 3 Risk factors of suicidal ideation among PWDs
Variable Categories Unadjusted model Adjusted model (Nagelkerke's R2 = 0.396)
P-value COR [LL-UL] P-value AOR [LL-UL]
Age group Above 35 years <0.001 2.85 [1.77–4.57] 0.007 2.65 [1.31–5.37]
18 to 35 years Reference Reference
Gender Female <0.001 3.17 [1.98–5.07] <0.001 5.14 [2.28–11.56]
Male Reference Reference
Locality Rural 0.626 1.15 [0.66–2.01] NA NA
Urban Reference
Socio-economic status (BDT) Up to 15 000 0.070 2.32 [0.93–5.75] 0.062 2.83 [0.95–8.45]
15 000 to 30 000 0.318 1.63 [0.62–4.27] 0.403 1.62 [0.52–5.06]
More than 30 000 Reference Reference
Religion Islam 0.442 0.80 [0.46–1.41] NA NA
Hinduism Reference
Education level Up to 5 standards 0.014 0.37 [0.17–0.82] 0.053 0.36 [0.13–1.01]
6 to 10 standards 0.003 0.35 [0.17–0.70] 0.009 0.28 [0.11–0.72]
10 to 12 standards 0.047 0.55 [0.30–0.99] 0.126 0.48 [0.18–1.23]
Graduation 0.018 0.25 [0.08–0.79] 0.001 0.06 [0.01–0.31]
Post-graduation or above 0.056 0.36 [0.12–1.03] 0.039 0.15 [0.02–0.91]
Uneducated Reference Reference
Occupation Unemployed 0.899 1.06 [0.43–2.63] 0.801 0.82 [0.18–3.75]
Business 0.655 0.83 [0.36–1.91] 0.677 1.36 [0.32–5.86]
Cultivator 0.539 0.75 [0.30–1.89] 0.959 1.04 [0.22–4.88]
Housewife 0.140 1.95 [0.80–4.73] 0.447 0.55 [0.12–2.59]
Student 0.845 0.92 [0.40–2.11] 0.539 1.58 [0.37–6.73]
Employed Reference Reference
Types of impairments Multiple impairments 0.067 2.00 [0.95–4.22] 0.502 1.38 [0.54–3.54]
Hearing impairment 0.440 1.28 [0.68–2.42] 0.260 1.58 [0.71–3.48]
Visual impairment 0.231 1.55 [0.76–3.18] 0.763 1.16 [0.45–2.99]
Leprosy 0.675 0.80 [0.29–2.22] 0.269 0.47 [0.12–1.80]
Physical impairment Reference Reference
Time of impairment Later in life <0.001 2.65 [1.53–4.60] 0.018 2.35 [1.16–4.78]
Early childhood 0.487 1.23 [0.69–2.17] 0.686 1.16 [0.57–2.34]
From birth Reference Reference
Comorbid illness Yes 0.484 1.18 [0.74–1.89] NA NA
No Reference
Sleep status (hours) Above normal (>9) 0.577 0.69 [0.19–2.54] 0.793 0.82 [0.19–3.52]
Below normal (<7) <0.001 3.28 [1.80–5.99] 0.003 3.12 [1.49–6.52]
Normal (7–9) Reference Reference
Current COVID-19 symptoms Yes 0.053 2.19 [0.99–4.86] 0.369 1.67 [0.54–5.12]
No Reference Reference
Current substance use Yes <0.001 3.84 [2.30–6.40] 0.015 2.98 [1.23–7.21]
No Reference Reference
Drug use increment during the pandemic Yes <0.001 2.95 [1.85–4.70] 0.275 1.58 [0.69–3.60]
No Reference Reference
Depression Normal 0.452 0.71 [0.29–1.74] 0.940 0.95 [0.23–3.96]
Mild 0.711 1.23 [0.41–3.66] 0.891 0.89 [0.18–4.45]
Moderate 0.536 0.80 [0.40–1.61] 0.242 0.55 [0.20–1.50]
Severe 0.139 1.50 [0.88–2.58] 0.663 0.85 [0.41–1.76]
Extremely Severe Reference Reference
Anxiety Normal 0.268 0.61 [0.26–1.46] 0.500 1.55 [0.43–5.55]
Mild 0.651 0.74 [0.20–2.73] 0.914 1.10 [0.19–6.51]
Moderate 0.092 0.53 [0.26–1.11] 0.933 0.96 [0.35–2.59]
Severe 0.566 0.81 [0.40–1.65] 0.266 1.74 [0.66–4.64]
Extremely Severe Reference Reference
Stress Normal 0.248 0.66 [0.33–1.33] 0.334 1.84 [0.53–6.31]
Mild 0.779 0.86 [0.29–2.51] 0.549 1.57 [0.36–6.82]
Moderate 0.219 0.55 [0.21–1.43] 0.711 1.26 [0.37–4.26]
Severe 0.792 0.93 [0.55–1.59] 0.581 1.22 [0.60–2.49]
Extremely Severe Reference Reference
Fear of COVID-19 Low Fear 0.016 0.57 [0.36–0.90] 0.123 0.58 [0.29–1.16]
High Fear Reference Reference
AOR = Adjusted odds ratio, LL = Lower limit, UL = Upper limit, NA = Not applicable for multivariate analysis.
Table 3 also reports the clinical and behavioural predictors of SI obtained by multivariate analysis. Based on these findings, the odds of having suicidal ideation were 2.35 times higher among participants who developed a disability later in life than in those who had a disability from birth (AOR = 2.35, 95% CI = 1.16–4.78). Respondents who slept less than normal were 3.12 times more likely to have suicidal ideation than those who slept normally (AOR = 3.12, 95% CI = 6.50–7.52). Respondents currently using drugs had 2.98 times more suicidal ideation (AOR = 2.98, 95% CI = 1.23–7.21) compared with their counterparts.
Discussion
This study investigated for the first time the magnitude of and factors associated with suicidal ideation among PWDs in Bangladesh. About 23.9% past-year suicidal ideation related to the pandemic was reported during the COVID-19 pandemic, a very high prevalence rate. Factors significantly associated with suicidal ideation included age above 35 years, female gender, being uneducated, having developed disability later in life, reporting less sleep and current substance misuse. Unfortunately, to the best of the authors’ knowledge, no previous studies have been conducted among Bangladeshi PWDs to explore suicidality. Hence, this study's findings were compared with those of earlier studies involving diverse cohorts, methods and cultures conducted inside and outside Bangladesh during or before the COVID-19 pandemic.
A recent pre-pandemic systematic review including studies of PWDs concluded that the prevalence of suicidal ideation was 10.2% to 12.7% (past month) and 1.4% to 27.7% (past year).23 During the pandemic, in the USA (April to May 2020) and UK (February to March 2021), prevalences of 30.6% and 20.7% for suicidal ideation, respectively, were found among PWDs.10,12 Notably, this study found the prevalence of past-year suicidal ideation related to the COVID-19 pandemic to be 23.9%. In the recent systematic review of COVID-19-related studies, the suicidal ideation rate ranged from 5% to 19% across different Bangladeshi populations; thus, this study's suicidal ideation prevalence rate appears very high.5 However, the present study covered a longer timescale than the previous Bangladeshi studies, and the cohort appears to be mentally vulnerable. Therefore, we conclude that a large proportion of PWDs are at risk of suicidality, requiring emergency mental health support to prevent suicide during the post-COVID-19 pandemic period.
Suicidal ideation was higher in this study among older PWDs (i.e. a 2.65-times higher risk of suicidal ideation among participants aged more than 35 years participants compared with those aged less than 35 years), consistent with previous studies.23 During the COVID-19 pandemic, this finding was also in line with those of another study conducted among disabled adults,10 although two other studies did not find such an association.11,12 The higher rate of suicidal ideation in middle-aged and older adults could be explained by the fact these individuals are less likely to express suicidal ideation before their death, have greater determination and are less likely to be rescued owing to physical frailty; this could reduce the prevention of suicide as well as limiting opportunities for intervening with those who have suicidal behaviour. However, only two age categories were considered in this study, and the relationship of age with suicidal ideation might therefore have been overestimated. Thus, the relationship between age and suicidal ideation among PWDs is still unclear, especially regarding suicidal thoughts and suicide attempts; this requires further elucidation.
Gender plays an important part in suicide and suicidality. As estimated by the World Health Organization, higher rates of deaths by suicide occur among males, for instance, 13.7 deaths per 100 000 population compared with 7.5 for females.24 However, suicidal behaviours appear to be prevalent among female,25 and the prevalence of suicidal ideation as a way to cope with stress or emotions is higher among females than among males. For example, a US study among PWDs conducted during the COVID-19 pandemic focusing on different aspects of psychological health found that 37.4% of the male participants had seriously considered suicide, compared with 22.6% of the females.11 However, more studies are recommended to investigate which gender is at higher risk of suicide and suicidality, to better understand gender-based suicide risk and prevention.
Consistent with this study's findings, Rahman et al and Meltzer et al found lower educational attainment to be a potential risk factor for suicidal ideation among PWDs,26,27 although the effect of lack of education still remains controversial.28 Individuals with lower educational levels may be at a higher risk of suicide owing to early-life factors both decreasing educational opportunities and increasing mental health difficulties. Another notable finding of this study was that participants who had been disabled from birth were less likely to report suicidal ideation. This could be explained by the fact that individuals disabled from birth might develop coping mechanisms from an early age, find the support system that they need, and increase their acceptance after many years of struggling to cope with life, although further studies are needed to reach more robust conclusions.
Consistent with the findings of the present study, it has been well established that there is a strong relationship between suicidal ideation and sleeping problems.5,11 In the systematic review of Bangladeshi studies, a wide range of psychopathological factors including depression, anxiety, stress, sleep problems, history of suicidal behaviour and family history of suicide were found to increase the risk of suicidality during the COVID-19 pandemic.5 Notably, this study found no significant difference in suicidal ideation rates based on whether the PWDs experienced depression, anxiety and stress, similar to the findings of other studies,29,30 suggesting that depression, anxiety and stress might not strongly contribute to the increased rate of suicidal ideation among PWDs. This is a very unusual finding in the context of the pandemic or otherwise; thus, the psychopathological factors in suicidality among PWDs should be further investigated.
To better understand the indirect consequences of the COVID-19 pandemic, variables directly related to the COVID-19 pandemic were included in this study; we found that PWDs who had tested positive for COVID-19 had more thoughts of suicidal ideation, as documented earlier. The pandemic-related variables that were estimated to increase the risk of suicide in Bangladesh included lower knowledge about COVID-19, practicing fewer preventive behaviours related to COVID-19, having elevated levels of fear of COVID-19, residing in COVID-19-prone areas, experiencing economic problems and experiencing COVID-19-related deaths of family members or relatives.15 As aforementioned, the first case of COVID-19-related suicide in Bangladesh was attributed to fear of COVID-19.13 Later, an Indian study reported that COVID-19 fear was the factor with the greatest effect on suicide, accounting for 21 deaths out of 69.31 Consistent with other pandemic studies, the present study identified fear of COVID-19 as a prominent stressor for suicidal ideation, possibly owing to the increasing number of infections, uncertainty and phobia.13,15 The suicidality-related factors identified in this study and elsewhere should be considered when planning further studies or any preventive actions.
Substance misuse and associated disorders have increased after the pandemic. For instance, a US longitudinal study found a 13–36% increase in problems related to alcohol or illicit substance use across three groups, adults without children, parents, and adolescents, after the inception of the pandemic.32 In addition, a hospital registry analysis reported a 5.90% rate of substance use disorders among Ugandan adolescents, which showed a non-significant increase to 9.80% after the pandemic.33 In this study, 38% of PWDs noted an increase in their drug use, and drug use in general appeared as a risk factor for suicidality. Consistent with previous studies,10–12 these findings demonstrate a higher prevalence of substance use as well as a higher risk of suicidal ideation to cope with stress and emotions during the COVID-19 pandemic.
The present study had some limitations that are worth noting. This study was cross-sectional; therefore, the data cannot be used to infer causality. In addition, this study did not assess changes in disability status and suicide-related outcomes over time owing to its cross-sectional nature. Thus, further studies are warranted to determine how disability is associated with suicide-related outcomes over time. Besides, suicidal ideation was measured using a single-item question with a binary response (i.e. yes or no). Future studies are needed to understand the continuum between suicidal ideation and suicidal planning before attempting suicide completion using a longitudinal study design. Moreover, this study did not include a number of other important factors related to suicidal ideation, including history of suicidality among friends and family, social support, loneliness and self-esteem.34 Further studies with larger sample sizes and including people with other forms of disabilities could shed more light on this important public health issue.
In this study, PWDs tended to have a number of sociodemographic, clinical and behavioural factors associated with suicidal ideation. The findings provide essential baseline information on suicidal ideation among PWDs during the COVID-19 pandemic, which could direct preventive programmes or further studies inside and/or outside Bangladesh. About 23.9% of the suicidal ideation was reported within 1 year of the pandemic, which appears to be a very high prevalence rate; this could be attributed to the massive lockdown measures and curfew situations. Thus, care of this vulnerable population should be focused on accommodating and targeting their specific needs while planning for any lockdown situation (previous studies strongly recommend adopting cohort-specific plans and preventive strategies35–38). In addition, health education and awareness-related programmes in communities to increase knowledge about COVID-19 could help to reduce the incidence of COVID-19-related suicide. Finally, the public health system should consider long-term screening and treatment interventions to help prevent suicide-related issues during the COVID-19 pandemic.
Acknowledgements
We thank all the research assistants and participants for their support of this study.
Data availability
The data supporting this study's findings are available from the corresponding author upon reasonable request.
Author contributions
N.R.: conceptualisation, visualisation, methodology, software, data curation, formal analysis, writing – original draft, writing – reviewing and editing, supervision. M.B.A.: visualisation, methodology, software, data curation, formal analysis, writing – original draft, writing – reviewing and editing. M.A.M.: visualisation, writing – reviewing and editing. E.H.: visualisation, writing – reviewing and editing. M.A.: methodology, writing – reviewing and editing. B.S.: visualisation, writing – reviewing and editing. N.R. and M.A.M. addressed the reviewers' comments and revised the manuscript critically. All authors read and approved the final version of the manuscript.
Funding
The present study did not receive any financial support. The authors involved in this research communication do not have any relationships with other people or organisations that could inappropriately influence (bias) the findings.
Declaration of interest
None.
==== Refs
References
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| 36458508 | PMC9744454 | NO-CC CODE | 2022-12-15 00:01:46 | no | BJPsych Open. 2022 Dec 2; 9(1):e3 | utf-8 | BJPsych Open | 2,022 | 10.1192/bjo.2022.615 | oa_other |
==== Front
Disaster Med Public Health Prep
Disaster Med Public Health Prep
DMP
Disaster Medicine and Public Health Preparedness
1935-7893
1938-744X
Cambridge University Press New York, USA
36245103
S1935789322002348
10.1017/dmp.2022.234
Original Research
Characterizing Emergency Supply Kit Possession in the United States During the COVID-19 Pandemic: 2020–2021
Schnall Amy Helene DrPH 1
Kieszak Stephanie MA, MPH 1
Hanchey Arianna MPH 1
Heiman Harry MD, MPH 2
Bayleyegn Tesfaye MD, MPH 1
Daniel Johnni PhD 1
Stauber Christine PhD 2
1 Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA
2 National Center for Environmental Health, Georgia State University, Atlanta, GA, USA
Corresponding author: Amy Helene Schnall, Email: [email protected]
17 10 2022
17 10 2022
115
25 7 2022
20 8 2022
© The Author(s) 2022
2022
The Author(s)
simple This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means subject to acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.
Objective:
In the immediate aftermath of a disaster, household members may experience lack of support services and isolation from one another. To address this, a common recommendation is to promote preparedness through the preparation of an emergency supply kit (ESK). The goal was to characterize ESK possession on a national level to help the Centers for Disease Control and Prevention (CDC) guide next steps to better prepare for and respond to disasters and emergencies at the community level.
Methods:
The authors analyzed data collected through Porter Novelli’s ConsumerStyles surveys in fall 2020 (n = 3625) and spring 2021 (n = 6455).
Results:
ESK ownership is lacking. Overall, while most respondents believed that an ESK would help their chance of survival, only a third have one. Age, gender, education level, and region of the country were significant predictors of kit ownership in a multivariate model. In addition, there was a significant association between level of preparedness and ESK ownership.
Conclusions:
These data are an essential starting point in characterizing ESK ownership and can be used to help tailor public messaging, inform work with partners to increase ESK ownership, and guide future research.
Keywords:
disaster
disproportionately affected groups
emergency supply kit (ESK)
national survey
preparedness
Abbreviations:
CDC Centers for Disease Control and Prevention
ESK Emergency Supply Kit
FEMA Federal Emergency Management Agency
NHS National Household Survey
PN Porter Novelli
==== Body
pmcDisasters, such as hurricanes, floods, winter storms, and human-induced incidents (eg, chemical spills, terrorism), devastate US communities every year, leading to increased morbidity and mortality among the population. 1–5 The year 2020 was no exception with a record-breaking 30 named storms during the Atlantic hurricane season, wildfires burning more than 8.8 million acres, and heavy rain leading to flooding in several areas of the country; all on top of the global coronavirus disease (COVID-19) pandemic. 6–11 Unfortunately, disasters do not impact society equitably with certain population groups facing greater risk before, during, and after disasters, including, but not limited to, access to resources and supports as well as exposure to disasters themselves. 1,12,13 For example, low-income communities and communities of color may have access to fewer resources, higher social vulnerability, and less access to health care. 14,15 They also are more likely to live in areas prone to natural disasters. 14,15 Once a disaster strikes, these pre-existing gaps are often exacerbated. Therefore, it is essential that preparedness policies, plans, and practices account for social, economic, and health inequities.
Millions of dollars are allocated each year for US hospital preparedness, and yet a large portion of disaster-related morbidity and mortality occurs before individuals ever have the opportunity to be transported to a hospital. 16 Further, much of the disaster-related morbidity and mortality that occur are indirectly related to the disaster (eg, they are associated with living in damaged or destroyed infrastructure). 17–19 Therefore, household preparedness is essential to a successful response and can help mitigate loss of life, injuries, and illnesses immediately after a disaster’s impact. During a disaster, household members may be on their own for a period of time because of the ongoing response efforts, size of the affected area, loss of communication, impassible roads, and safety purposes that lead to shelter-in-place. 20 Therefore, a common recommendation is to promote household preparedness through the preparation of an emergency supply kit (ESK). 21–23 An ESK is a collection of basic items (eg, water and food, radio, flashlight) that a household may need in a disaster that are stored together in a manner that can be easily accessed, such as in large boxes, bins, or bags. Having an ESK can aid in short-term survival by providing essential items for use during a disaster or emergency, thus limiting the need to rely on emergency services or leave a safe structure into a hazardous environment to secure necessary items.
While an ESK is essential for everybody, it is even more essential for those who cannot (or will not) evacuate from their home. This often includes those in low-income or minority communities, persons with disabilities, and/or those with chronic medical conditions who may lack mobility (eg, no transportation, rely on others to be physically mobile) and be less able to evacuate on short notice. 24–26 Yet, as ESKs can be costly and require additional storage space within the home, the same households that may be unable or unwilling to leave, may also face barriers in assembling and storing an ESK. A review of published literature on the use of ESKs following a disaster found that data tend to focus on general ESK ownership, including prevalence, factors associated with ownership, and interventions to increase ownership. 27–46 Data often focus on specific populations, making it difficult to generalize across studies because of the variation in population groups and questions researched. In general, ESK ownership varies based on the population assessed (eg, geographic location, demographics), with estimates ranging from as low as 22% to upward of 81%. 36,47 The most comprehensive data are from the Federal Emergency Management Agency’s (FEMA) National Household Survey (NHS), which surveys approximately 5000 adults yearly to track progress in personal disaster preparedness. 48 In 2021, 45% of respondents reported they have gathered supplies, comparable to the 81% and 80% reported in 2020 and 2019, respectively. 34–36 While people often express optimism about having ample supplies to endure 3 days without electricity or running water, studies suggest that even with regional variation, less than half of households actually assemble dedicated ESKs. 34,44 Factors such as previous disaster experience, education in the field of disaster response or emergency management, and health status of individuals as well as demographic factors and social determinants of health such as education, marital status, race, ethnicity, and gender all have potential impacts on the likelihood of owning an ESK. 37,46
The ongoing COVID-19 pandemic has had a major impact on many aspects of life, directly and indirectly, and may have affected the way households prepare for emergencies such as how supplies are gathered and the items to include in ESKs (eg, masks, hand sanitizer). 34 Because of this, many of the preparedness estimates before 2020 may no longer be accurate. In addition, with more households potentially staying at home during a disaster to avoid potential COVID-19 exposure, ESKs are even more essential. At the time of our survey implementation, there were limited current (ie, 2020–2021) national data on ESK ownership publicly available. Therefore, our goal was to characterize ESK possession on a national level to help guide next steps to better prepare for and respond to disasters and emergencies—specifically, describing the proportion and distribution of ESK ownership, exploring any regional differences, and examining how factors such as social determinants of health, previous experience, and beliefs may impact preparedness and ESK ownership.
Methods
The Centers for Disease Control and Prevention (CDC) added 10 questions to the existing Porter Novelli’s (PN) ConsumerStyles surveys in fall 2020 and spring 2021. PN ConsumerStyles is a cross-sectional market survey of a random sample of non-institutionalized adults (age 18 years or older) from Ipsos’ KnowledgePanel®. 46 In 2020, FallStyles was sent to 4548 panelists between September 24 and October 10. In 2021, SpringStyles was sent to 10 919 panelists between March 23 and April 13. For both surveys, reminders were sent to non-responders on days 3, 7, and 13 and those who completed the survey received 5000 cash-equivalent reward points (worth approximately US $5) and were eligible for a sweepstakes. While sampled from the same KnowledgePanel® pool, the 2020 FallStyles and 2021 SpringStyles are 2 separate samples; there is no way of knowing if any respondents participated in both surveys.
While the specific questions related to ESKs remained the same in both surveys, there were changes to some demographic variables between fall 2020 and spring 2021 (eg, income, household type). All modifications were accounted for by creating matching variables between 2020 FallStyles and 2021 SpringStyles, except for employment which could not be aligned and, therefore, could not be directly compared. Both surveys are weighted on several demographic and household factors. 49,50
Descriptive analyses examined distributions of demographic characteristics, preparedness levels (ie, having 1 or more of the 5 FEMA recommended plans 26 ), previous disaster experience and beliefs, and ESK possession and items. Missing data were minimal in both surveys for all variables (< 5%). Chi-square tests investigated the associations between ESK ownership and demographics, disaster experience and perceptions of preparedness, and beliefs. Because FallStyles and SpringStyles data were similar in terms of descriptive statistics and significant associations, we ran a multivariable logistic regression on the most recent SpringStyles data to help explain the importance of key variables (eg, race, ethnicity, income, education) in terms of their relationship with overall ESK ownership, in the presence of others. The authors used a backward stepwise elimination procedure, beginning with all demographic variables in the model and eliminating those that did not statistically predict (P < 0.05) the dependent variable (ESK ownership) 1 by 1. Only the final model is presented in the text. All data presented within this report, including the tables, are weighted. Data are presented with fall 2020 first followed by spring 2021 unless otherwise noted. However, data are presented as 1 value if they were the same for the 2 surveys. If the 2 data points had less than 1% difference, they are reported as 1 value with an approximate (∼) sign.
Results
A total of 3625 (79.7%) completed the 2020 FallStyles survey and 6455 (59.1%) adults completed the 2021 SpringStyles. Overall, the fall and spring weighted demographics were comparable (Table 1). Slightly more than half of respondents (51.6%) were female and educational attainment was distributed across categories. Roughly 63% self-identified as white with ∼11% black, ∼16% Hispanic, and less than 2% multiracial. Most live in single-family homes (73.1%, 71.7%), with ∼15% in apartment homes, ∼8% in townhomes or duplexes, and ∼4% in mobile homes, RVs, boats, or vans. The majority (73.7%, 72.5%) own their homes with a quarter (24.4%, 25.6%) renting and 1.9% living in their home without payment. The South had the most representation with ∼38%, followed by the West (24%), Midwest (∼21%), and Northeast (∼17%), with the majority living in metro areas (86.6%) compared to non-metro (13.4%). Less than 15% live alone.
Table 1. Weighted demographics of respondents, United States: 2020–2021
Fall 2020 (N = 3625) Spring 2021 (N = 6455)
Frequency Percent Frequency Percent
Age
18-34 years 1035.4 28.6 1819.9 28.2
35-54 years 1200.3 33.1 2146.4 33.3
55-74 years 1138.2 31.4 2046.1 31.7
75+ years 251.1 6.9 442.7 6.9
Sex
Male 1756.1 48.4 3121.6 48.4
Female 1868.9 51.6 3333.4 51.6
Education
Less than high school 365.2 10.1 688.0 10.7
High school 1022.7 28.2 1768.8 27.4
Some college 1010.5 27.9 1948.4 30.2
Bachelor’s or higher 1226.6 33.8 2049.8 31.8
Race/ethnicity
White, non-Hispanic 2316.1 63.9 4099.9 63.5
Black, non-Hispanic 414.4 11.4 747.2 11.6
Hispanic 582.2 16.1 1049.2 16.3
Mixed race 52.9 1.5 119.4 1.9
Other 259.4 7.2 439.4 6.8
Housing structure
Single family home 2650.1 73.1 4626.0 71.7
Townhome/duplex 300.4 8.3 575.9 8.9
Apartment 529.9 14.6 990.1 15.3
Mobile home, boat, RV, van 144.6 4.0 263.1 4.1
Ownership status
Owns 2671.5 73.7 4681.1 72.5
Rents 883.3 24.4 1654.6 25.6
Occupy w/o payment 70.3 1.9 119.3 1.9
Region
South 1369.4 37.8 2447.6 37.9
West 869.1 24.0 1547.2 24.0
Midwest 748.5 20.7 1344.3 20.8
Northeast 638.0 17.6 1115.9 17.3
Urbanicity
Metropolitan 3137.6 86.6 5592.9 86.6
Non-metropolitan 487.4 13.4 862.1 13.4
Household size
Lives alone 533.1 14.7 911.5 14.1
Lives with others 3091.9 85.3 5543.5 85.9
Marital status
Married/with partner 2306.4 63.6 3665.4 56.8
Single 1318.6 36.4 2789.6 43.2
Children in household
Household has children 1155.0 31.9 2136.3 33.1
No children in home 2470.0 68.1 4318.7 66.9
Household income
< $25 000 485.4 13.4 796.9 12.4
$25 000 < $50 000 646.0 17.8 1128.2 17.5
$50 000 < $75 000 602.8 16.6 1119.2 17.3
$75 000 < $100 000 508.0 14.0 908.8 14.1
$100 000 < $150 000 639.9 17.7 1207.7 18.7
$150 000 or more 742.9 20.5 1294.2 20.1
Employment status*
Employed 2324.0 64.1 2805.2 43.5
Unemployed/retired 1118.7 30.9 2522.1 39.1
Other 182.4 5.0 1127.8 17.5
* Fall 2020 “Employed” includes all currently employed persons, and “Other” includes those who are temporarily out of work; Spring 2021 “Employed” is employed full-time only, and “Other” are those who are employed part-time. Therefore, these are separate categories and should not be compared.
Most respondents (69.0%, 63.5%) have experienced a disaster, with severe weather with power outages being the most common (55.1%, 50.3%), followed by a tropical storm or hurricane (29.2%, 23.4%) (Table 2). A tornado; earthquake, mudslide, or landslide; or flood was experienced by roughly 15% for each disaster type. Several (16.4%, 19%) responded that they, or somebody in their household, worked, volunteered, or trained in disaster response or recovery. Overall, ∼27% of respondents stated they had an “easy to get to” ESK as part of the preparedness plans and items. When given the definition of an ESK in a separate question, approximately a third (33.8%, 36.3%) reported having one. This difference in response could be because of the definition provided or the lack of “easy to get to” in the question. Of those who had an ESK based on the latter question (ie, with the definition provided), almost all (95.4%, 93.6%) reported having a flashlight with batteries, ∼85% reported medical supplies, ∼80% reported having water, almost 70% had food, and roughly 60% had a radio. Household cleaning supplies were present in approximately a third (32.6%, 29.3%) of ESKs.
Table 2. Weighted preparedness levels and disaster experience, United States, 2020–2021
Fall 2020 (N = 3625) Spring 2021 (N = 6455)
Frequency Percent Frequency Percent
Experienced previous disaster
Yes 2491.5 69.0 4089.5 63.5
No 1119.4 31.0 2346.1 36.5
Type of disaster experienced
Severe weather with power outages 1988.4 55.1 3235.2 50.3
Tropical storm or hurricane 1054.1 29.2 1504.1 23.4
Tornado 567.4 15.7 888.6 13.8
Earthquake, mudslide, or landslide 559.1 15.5 913.9 14.2
Flood 513.9 14.2 785.8 12.2
Wildfire 205.1 5.7 347.5 5.4
Employment in disaster response/recovery
Yes 593.3 16.4 1220.5 19.0
No 3018.6 83.6 5212.0 81.0
Type of response/recovery employment
Volunteered for disaster response 212.2 5.9 481.9 7.5
Work in disaster response or recovery 160.0 4.4 293.2 4.6
Taken CERT training 159.9 4.4 353.0 5.5
Work in emergency management 110.1 3.1 203.7 3.2
Volunteer with American Red Cross 102.3 2.8 180.0 2.8
Other 143.1 4.0 285.8 4.4
Has the following preparedness plans/items
Stored copies of important documents 1247.6 34.6 2080.5 32.4
Easy to get to ESK 989.6 27.4 1744.3 27.2
Designated meeting place outside the home 672.2 18.6 1237.7 19.3
Multiple evacuation routes away from home 640.1 17.7 816.7 12.7
Emergency communication plan 485.0 13.4 987.0 15.4
Meeting place outside the neighborhood 342.5 9.5 463.4 7.2
Preparedness level
No plans 1845.2 51.1 3366.2 52.4
Some plans 1659.0 46.0 2898.5 45.2
All 5 FEMA-recommended plans 106.3 2.9 155.0 2.4
ESK
Has an ESK 1160.1 33.8 2201.3 36.3
Does not have an ESK 2276.0 66.2 3864.1 63.7
ESK items
Flashlight with batteries 1106.3 95.4 2053.9 93.6
Medical supplies 981.4 84.6 1872.9 85.4
Water 926.6 79.9 1803.9 82.2
Food 803.2 69.2 1503.6 68.5
Radio 709.4 61.2 1291.8 58.9
Household cleaning supplies 378.1 32.6 643.6 29.3
Other 84.3 7.3 210.3 9.6
When asked whether an ESK would help their chance of surviving a disaster, three-quarters (78.1%, 73.0%) agreed while few (∼4%) disagreed (Figure 1). The cost of an ESK does not seem to be a barrier for almost half (49.6%, 47.8%), but slightly more than 20% agreed that an ESK costs a lot of money. When asked whether the risk of their household being affected by an infectious disease was greater than that of a disaster, slightly more agreed in the fall (44.3%) than the spring (41.4%). Based on chi-square tests, there is a significant association between ESK ownership and age, race/ethnicity, region, and household income for both surveys (Table 3). In addition, ESK ownership is associated with housing structure, household size, and ownership status in FallStyles and education in SpringStyles. Preparedness level, disaster experience, and beliefs are also associated with ESK ownership (Table 4). All preparedness plan items are significantly associated with increased ESK ownership. Of those who do not have any preparedness plans, 82.0% and 78.1% also do not have an ESK. Of those who have all 5 preparedness plans, 89.6% and 94.7% have an ESK. Experience through work, volunteering, or training in disaster response or recovery is also associated with ESK ownership. Roughly half of those who indicated they or a household member had experience in the response and recovery field had an ESK (53.8%, 50.8%).
Figure 1. Weighted beliefs about disasters and emergency supply kits (ESKs), United States, 2020 -2021.
Table 3. Emergency supply kit (ESK) ownership by demographic characteristics (weighted) United States, 2020–2021
Fall 2020 Spring 2021
Has kit
(N = 1160) No kit
(N = 2276) Total
(N = 3436) P-value Has kit
(N = 2201) No kit
(N = 3864) Total
(N = 6065) P-value
Age
18-34 years 287.3 (30.2) 663.2 (69.8) 950.5 (27.7) 0.0067 554.1 (34.0) 1073.6 (66.0) 1627.8 (26.8) 0.0068
35-54 years 423.8 (37.1) 718.3 (62.9) 1142.1 (33.2) 768.6 (37.6) 1277.7 (62.4) 2046.3 (33.7)
55-74 years 375.8 (34.1) 727.5 (65.9) 1103.3 (32.1) 748.1 (37.9) 1223.9 (62.1) 1972.0 (32.5)
75+ years 73.2 (30.5) 166.9 (69.5) 240.1 (7.0) 130.4 (31.1) 288.9 (68.9) 419.3 (6.9)
Sex
Male 582.0 (34.8) 1090.7 (65.2) 1672.8 (48.7) 0.2130 1101.3 (37.7) 1821.7 (62.3) 2923.0 (48.2) 0.0308
Female 578.1 (32.8) 1185.2 (67.2) 1763.3 (51.3) 1100.1 (35.0) 2042.4 (65.0) 3142.4 (51.8)
Education
Less than high school 105.8 (32.2) 222.7 (67.8) 328.5 (9.6) 0.1043 212.0 (35.3) 387.8 (64.7) 599.8 (9.9) 0.0019
High school 295.8 (30.9) 661.4 (69.1) 957.1 (27.9) 544.4 (33.2) 1094.0 (66.8) 1638.4 (27.0)
Some college 334.9 (34.9) 624.6 (65.1) 959.6 (27.9) 731.1 (39.5) 1122.1 (60.6) 1853.2 (30.6)
Bachelor’s or higher 423.6 (35.6) 767.3 (64.4) 1190.8 (34.7) 713.8 (36.2) 1260.3 (63.8) 1974.0 (32.6)
Race/ethnicity
White, non-Hispanic 692.2 (31.1) 1533.3 (68.9) 2225.5 (64.8) < 0.0001 1361.8 (34.9) 2540.6 (65.1) 3902.5 (64.3) 0.0155
Black, non-Hispanic 143.5 (37.3) 241.0 (62.7) 384.5 (11.2) 269.8 (40.2) 401.5 (59.8) 671.3 (11.1)
Hispanic 197.7 (37.7) 326.7 (62.3) 524.4 (15.3) 364.2 (37.1) 616.4 (62.9) 980.7 (16.2)
Mixed race 13.7 (26.8) 37.4 (73.2) 51.1 (1.5) 48.4 (44.0) 61.6 (56.0) 110.1 (1.8)
Other 113.0 (45.1) 137.5 (54.9) 250.4 (7.3) 157.1 (39.2) 243.9 (60.8) 980.7 (16.2)
Housing structure
Single family home 875.6 (34.8) 1637.9 (65.2) 2513.5 (73.2) 0.0008 1631.7 (37.2) 2760.0 (62.9) 4391.6 (72.4) 0.1463
Townhome/duplex 105.1 (37.2) 117.7 (62.8) 282.8 (8.2) 177.2 (33.2) 357.0 (66.8) 534.2 (8.8)
Apartment 130.9 (26.0) 372.9 (74.0) 503.8 (14.7) 311.2 (34.4) 594.4 (65.6) 905.6 (14.9)
Mobile home, boat, RV, etc. 48.5 (35.7) 87.5 (64.3) 136.0 (4.0) 81.2 (34.7) 152.7 (65.3) 233.9 (3.9)
Ownership status
Owns 906.8 (35.5) 1644.8 (64.5) 2551.6 (74.3) 0.0007 1632.2 (36.7) 2816.7 (63.3) 4448.9 (73.4) 0.5707
Rents 232.2 (28.3) 587.9 (71.7) 820.1 (23.9) 533.3 (35.2) 981.5 (64.8) 1514.7 (25.0)
Occupy w/o payment 21.0 (32.7) 43.3 (67.3) 64.3 (1.9) 35.9 (35.3) 65.9 (64.8) 101.8 (1.7)
Region
South 497.5 (38.3) 800.2 (61.7) 1297.7 (37.8) < 0.0001 938.4 (40.8) 1360.6 (59.2) 2298.9 (37.9) < 0.0001
West 312.3 (38.1) 508.4 (62.0) 820.7 (23.9) 601.5 (41.8) 837.3 (58.2) 1438.8 (23.7)
Midwest 183.0 (26.0) 520.9 (74.0) 703.8 (20.5) 354.4 (27.7) 924.5 (72.3) 1279.0 (21.1)
Northeast 167.3 (27.3) 446.4 (72.7) 613.8 (17.9) 307.0 (29.3) 741.7 (70.7) 1048.7 (17.3)
Urbanicity
Metropolitan 146.3 (32.2) 307.7 (67.8) 453.9 (13.2) 0.4559 1925.3 (36.7) 3327.3 (63.4) 5252.6 (86.6) 0.1374
Non-metropolitan 1013.8 (34.0) 1968.3 (66.0) 2982.1 (86.8) 276.0 (34.0) 536.7 (66.0) 812.8 (13.4)
Household size
Lives alone 147.3 (29.6) 350.9 (70.4) 498.2 (14.5) 0.0321 329.2 (39.1) 513.8 (61.0) 843.1 (13.9) 0.0727
Lives with others 1012.8 (34.5) 1925.0 (65.5) 2937.8 (85.5) 1872.1 (35.9) 3350.2 (64.2) 5222.3 (86.1)
Marital status
Married/with partner 757.9 (34.4) 1446.9 (65.6) 2204.8 (64.2) 0.3094 1311.3 (37.3) 2207.5 (62.7) 3518.8 (58.0) 0.0641
Single 402.2 (32.7) 829.0 (67.3) 1231.2 (35.8) 890.0 (35.0) 1656.6 (65.1) 2546.6 (42.0)
Children in household
Household has children 382.3 (35.3) 702.2 (64.8) 1084.5 (31.6) 0.2107 744.8 (37.5) 1241.4 (62.5) 1986.2 (32.8) 0.1732
No children in home 777.8 (33.1) 1573.7 (66.9) 2351.5 (68.4) 1456.5 (35.7) 2622.6 (64.3) 4079.1 (67.3)
Household income
< $25 000 150.7 (34.4) 287.5 (65.6) 438.3 (12.8) < 0.0084 253.2 (36.1) 448.0 (63.9) 701.3 (11.6) 0.0314
$25 000 < $50 000 172.5 (28.4) 435.7 (71.6) 608.1 (17.7) 368.2 (35.0) 685.2 (65.1) 1053.5 (17.4)
$50 000 < $75 000 191.4 (33.7) 376.6 (66.3) 567.9 (16.5) 376.1 (35.6) 681.0 (64.4) 1057.2 (17.4)
$75 000 < $100 000 159.3 (33.1) 321.8 (66.9) 481.1 (14.0) 282.7 (32.7) 582.4 (67.3) 865.1 (14.3)
$100 000 < $150 000 209.9 (33.6) 414.3 (66.4) 624.1 (18.2) 451.8 (39.6) 689.6 (60.4) 1141.5 (18.8)
$150 000 or more 276.3 (38.6) 440.1 (61.4) 716.5 (20.9) 469.2 (37.6) 777.8 (62.4) 1247.0 (20.6)
Employment status *
Employed 798.0 (34.5) 1458.1 (65.5) 2226.1 (64.8) 0.4588 952.9 (35.5) 1729.2 (64.5) 2682.1 (44.2) 0.1788
Unemployed/retired 338.7 (32.3) 709.2 (67.7) 1047.9 (30.5) 847.5 (36.1) 1501.4 (63.9) 2349.0 (38.7)
Other 53.4 (33.0) 108.6 (67.0) 162.0 (4.7) 400.9 (38.8) 633.4 (61.2) 1034.3 (17.1)
* Fall 2020 “Employed” includes all currently employed persons, and “Other” includes those who are temporarily out of work; Spring 2021 “Employed” is employed full-time only, and “Other” are those who are employed part-time. Therefore, these are separate categories and should not be compared.
Table 4. Emergency supply kit (ESK) ownership by preparedness, disaster experience, and beliefs (weighted) – United States, 2020–2021
Fall 2020 Spring 2021
Has kit
(N = 1160) No kit
(N = 2276) Total
(N = 3436) P-value Has kit
(N = 2201) No kit
(N = 3864) Total
(N = 6065) P-value
Has the following preparedness plans/items
Copies of important docs 608.0 (50.5) 596.4 (49.5) 1204.4 (35.2) < 0.0001 1049.0 (52.0) 966.9 (48.0) 2015.9 (33.4) < 0.0001
Easy to get to ESK 755.4 (79.4) 196.1 (20.6) 951.5 (27.8) < 0.0001 1396.9 (82.4) 298.7 (17.6) 1695.5 (28.1) < 0.0001
Meeting place outside home 381.8 (58.4) 271.5 (41.6) 653.3 (19.1) < 0.0001 714.7 59.5) 487.4 (40.6) 1202.1 (19.9) < 0.0001
Multiple evacuation routes 379.2 (61.9) 233.8 (38.1) 613.0 (17.9) < 0.0001 529.9 (66.9) 262.5 (33.1) 792.4 (13.1) < 0.0001
Emergency comms plan 342.6 (73.2) 125.4 (26.8) 468.0 (13.7) < 0.0001 695.7 (72.9) 258.4 (27.1) 954.0 (15.8) < 0.0001
Meeting place outside of the neighborhood 242.4 (73.3) 88.2 (26.7) 330.6 (9.7) < 0.0001 328.6 (73.7) 117.2 (26.3) 445.8 (7.4) < 0.0001
None of the above 191.4 (12.3) 1370.5 (87.8) 1561.9 (45.6) < 0.0001 343.3 (12.8) 2332.1 (87.2) 2675.4 (44.4) < 0.0001
Preparedness level
No plans 311.9 (18.0) 1416.8 (82.0) 1728.7 (50.5) < 0.0001 677.5 (21.9) 2415.8 (78.1) 3093.3 (51.3) < 0.0001
Some plans 755.1 (47.4) 838.9 (52.6) 1594.1 (46.6) 1366.1 (49.1) 1418.9 (51.0) 2785.0 (46.2)
All plans 91.2 (89.6) 10.6 (10.4) 101.9 (3.0) 145.8 (94.7) 8.1 (5.3) 153.9 (2.6)
Experienced previous disaster
Yes 863.3 (36.0) 1534.5 (64.0) 2397.8 (70.0) < 0.0001 1562.6 (40.0) 2346.7 (60.0) 3909.3 (64.6) < 0.0001
No 290.9 (28.3) 736.0 (71.7) 1027.0 (30.0) 636.9 (29.8) 1501.3 (70.2) 2138.2 (35.4)
Type of disaster experienced
Sever weather w/outages 678.0 (35.4) 1238.2 (64.6) 1916.3 (56.0) 0.0191 1231.5 (39.5) 1885.6 (60.5) 3117.1 (51.5) < 0.0001
Hurricane/storm 422.4 (41.7) 590.4 (58.3) 1012.8 (29.6) < 0.0001 649.5 (44.8) 801.3 (55.2) 1450.8 (24.0) < 0.0001
Tornado 224.7 (41.3) 319.3 (58.7) 544.0 (15.9) < 0.0001 384.7 (45.4) 463.2 (54.6) 847.9 (14.0) < 0.0001
Earthquake/landslide 226.9 (41.7) 317.7 (58.3) 544.6 (15.9) < 0.0001 392.1 (45.6) 467.1 (54.4) 859.2 (14.2) < 0.0001
Flood 233.3 (47.9) 253.8 (52.1) 487.1 (14.2) < 0.0001 330.1 (44.5) 411.2 (55.5) 741.3 (12.3) < 0.0001
Wildfire 89.8 (44.6) 111.5 (55.4) 201.2 (5.9) 0.0007 167.6 (50.7) 163.2 (49.3) 330.8 (5.5) < 0.0001
Employment/volunteer in disaster response/recovery
Yes 307.7 (53.8) 264.4 (46.2) 572.1 (16.7) < 0.0001 594.4 (50.8) 576.4 (49.2) 1170.8 (19.4) < 0.0001
No 844.8 (29.6) 2006.0 (70.4) 2850.8 (83.3) 1599.2 (32.8) 3275.9 (67.2) 4875.1 (80.6)
Would evacuate if told to do so
Yes 681.5 (34.4) 1299.6 (65.6) 1981.1 (57.8) 0.3797 1346.0 (37.7) 2227.3 (62.3) 3573.2 (59.1) 0.0089
No 476.6 (33.0) 969.4 (67.0) 1446.1 (42.2) 850.9 (34.4) 1624.2 (66.6) 2475.1 (40.9)
Confident and knows how to prepare for a disaster
Agree 849.6 (43.3) 1110.5 (56.7) 1960.1 (57.2) < 0.0001 1616.0 (45.8) 1909.3 (54.2) 3525.3 (58.2) < 0.0001
Neutral 219.6 (24.8) 666.0 (75.2) 885.6 (25.8) 434.2 (27.2) 1164.7 (72.8) 1598.9 (26.4)
Disagree 85.4 (14.7) 496.9 (85.3) 582.3 (17.0) 149.2 (16.0) 785.1 (84.0) 934.3 (15.4)
ESK will improve chance of surviving a disaster
Agree 991.5 (36.5) 1723.9 (63.5) 2715.4 (79.2) < 0.0001 1871.0 (41.6) 2627.4 (58.4) 4498.3 (74.3) < 0.0001
Neutral 120.1 (21.2) 446.1 (78.8) 566.2 (16.5) 282.6 (21.7) 1017.5 (78.3) 1300.1 (21.5)
Disagree 44.8 (30.4) 102.6 (69.6) 147.4 (4.3) 47.8 (18.6) 209.7 (81.5) 257.5 (4.3)
ESK costs a lot of money
Agree 257.3 (32.4) 536.4 (67.6) 793.7 (23.2) 0.0083 552.4 (41.8) 770.7 (58.3) 1323.1 (21.8) < 0.0001
Neutral 270.8 (30.3) 622.2 (69.7) 893.1 (26.1) 512.5 (29.2) 1245.4 (70.8) 1757.9 (29.0)
Disagree 628.7 (36.1) 1113.4 (63.9) 1742.1 (50.8) 1136.4 (38.1) 1844.1 (61.9) 2980.4 (49.2)
Risk of my household being affected by an infectious disease is greater than that of a disaster
Agree 521.1 (33.6) 1029.5 (66.4) 1550.6 (45.3) 0.5403 876.0 (34.3) 1679.7 (65.7) 2555.7 (42.2) < 0.0001
Neutral 423.7 (33.1) 857.1 (66.9) 1280.8 (37.4) 814.0 (35.7) 1468.3 (64.3) 2282.3 (37.7)
Disagree 212.1 (35.7) 382.9 (64.4) 595.1 (17.4) 510.9 (42.0) 705.1 (58.0) 1216.0 (20.1)
As far as beliefs, being confident in knowing how to prepare for a disaster and agreeing that ESKs will improve chance of survival are significantly associated with having an ESK; over 40% of those who agree they are confident have a kit (43.3%, 45.8%) and a higher percentage of those who agree a kit will improve the chance of surviving a disaster own a kit versus those who disagree (36.5% vs 30.4%; 41.6% vs 18.6%). Additionally, the belief that ESKs cost a lot of money is associated with kit ownership; those who are neutral have lower reported kit ownership than those who either agree or disagree with the statement. However, there is some discrepancy between FallStyles and SpringStyles with regards to the perception that the risk of an infectious disease is greater than that of a disaster. While there is no significant association in the fall data (P = 0.5403), there is a significant association in SpringStyles with 42.0% of those who disagree that infectious disease is a greater risk to their household than a disaster reporting kit ownership.
With regard to believing an ESK will improve their chance of survival (Table 5), education level, race/ethnicity, urbanicity, and household income all have significant associations in both surveys. Also, several variables are associated with believing that ESKs are expensive (Table 6). For example, women were more likely than men to agree that an ESK is expensive. In addition, of those with a household income of less than $25,000, ∼29% agree supply kits are expensive compared to 19.7% and 14.9% of those with a household income of more than $150,000 annually, and ∼28% households with kids agree kits are expensive compared to 20.8% and 18.9% of homes without kids.
Table 5. Respondent believes an emergency supply kit (ESK) improves chance of survival (weighted) – United States, 2020–2021
Fall 2020 Spring 2021
Agree
(N = 3682) Neutral
(N = 1769) Disagree
(N = 992) Total
(N = 6443) P-value Agree
(N = 3682) Neutral
(N = 1769) Disagree
(N = 992) Total
(N = 6443) P-value
Age
18-34 years 830.3 (80.6) 160.4 (15.6) 39.9 (3.9) 1030.7 (28.5) 0.0021 1337.6 (73.7) 417.8 (23.0) 60.6 (3.3) 1816.1 (28.2) 0.4266
35-54 years 928.2 (77.5) 233.7 (19.5) 36.6 (3.1) 1198.5 (33.1) 1543.1 (72.1) 496.1 (23.2) 102.3 (4.8) 2141.5 (33.3)
55-74 years 877.5 (77.2) 191.8 (16.9) 67.7 (6.0) 1137.0 (31.4) 1498.7 (73.4) 458.3 (22.4) 86.0 (4.2) 2043.0 (31.7)
75+ years 187.5 (74.9) 47.1 (18.8) 15.8 (6.3) 250.4 (6.9) 320.6 (72.8) 98.8 (22.4) 21.1 (4.8) 440.5 (6.8)
Sex
Male 1342.3 (76.5) 323.5 (18.4) 88.9 (5.1) 1754.8 (48.5) 0.0508 2231.3 (71.6) 746.8 (24.0) 139.2 (4.5) 3117.3 (48.4) 0.0503
Female 1481.3 (79.6) 309.5 (16.6) 71.1 (3.8) 1861.9 (51.5) 2468.8 (74.3) 724.3 (21.8) 130.8 (3.9) 3323.9 (51.6)
Education
Less than high school 261.3 (71.6) 78.8 (21.6) 25.1 (6.9) 365.2 (10.1) < 0.0001 434.7 (63.2) 214.6 (31.2) 38.8 (5.6) 688.0 (10.7) < 0.0001
High school 764.0 (74.9) 218.1 (21.4) 38.6 (3.8) 1020.7 (28.2) 1258.8 (71.6) 431.8 (24.6) 66.8 (3.8) 1757.5 (27.3)
Some college 788.7 (78.2) 169.5 (16.8) 50.3 (5.0) 1008.5 (27.9) 1468.4 (75.4) 401.7 (20.6) 77.3 (4.0) 1947.4 (30.2)
Bachelor’s or higher 1009.6 (82.6) 166.6 (13.6) 46.0 (3.8) 1222.2 (33.8) 1538.2 (75.1) 423.0 (20.7) 87.0 (4.3) 2048.2 (31.8)
Race/ethnicity
White, non-Hispanic 1759.8 (76.2) 442.1 (19.1) 107.6 (4.7) 2309.5 (63.9) 0.0254 2942.3 (72.0) 969.1 (23.7) 176.9 (4.3) 4088.2 (63.5) 0.0241
Black, non-Hispanic 343.1 (82.8) 58.2 (14.0) 13.1 (3.2) 414.4 (11.5) 534.8 (71.8) 172.5 (23.2) 37.6 (5.1) 745.0 (11.6)
Hispanic 468.3 (80.6) 90.1 (15.5) 22.3 (3.9) 580.8 (16.1) 814.2 (77.6) 202.3 (19.3) 32.7 (3.1) 1049.2 (16.3)
Mixed race 41.1 (78.3) 9.5 (18.1) 1.9 (3.7) 52.5 (1.5) 93.8 (78.5) 22.1 (18.5) 3.5 (3.0) 119.4 (1.9)
Other 211.2 (81.4) 33.1 (12.8) 15.0 (5.8) 259.4 (7.2) 315.1 (71.7) 105.1 (23.9) 19.2 (4.4) 439.4 (6.9)
Housing structure
Single family home 2068.1 (78.3) 463.0 (17.5) 110.9 (4.2) 2642.1 (73.1) 0.1163 3393.1 (73.5) 1027.5 (22.3) 195.8 (4.2) 4616.4 (71.7) 0.0883
Townhome/duplex 233.9 (77.8) 43.7 (14.5) 22.8 (7.6) 300.4 (8.3) 398.2 (69.3) 152.4 (26.5) 24.3 (4.2) 574.8 (8.9)
Apartment 407.0 (76.9) 101.4 (19.2) 21.1 (4.0) 529.5 (14.6) 728.3 (73.6) 217.8 (22.0) 43.0 (4.4) 989.0 (15.4)
Mobile home, RV, etc. 114.6 (79.3) 24.9 (17.2) 5.1 (3.5) 144.6 (4.0) 180.5 (69.2) 73.5 (28.2) 6.9 (2.6) 260.8 (4.1)
Ownership status
Owns 2098.2 (78.8) 446.6 (16.8) 118.7 (4.5) 2663.5 (73.7) 0.3173 3436.2 (73.6) 1040.4 (22.3) 192.7 (4.1) 4669.2 (72.5) 0.4441
Rents 675.0 (76.5) 169.8 (19.2) 38.1 (4.3) 882.9 (24.4) 1181.7 (71.5) 399.4 (24.2) 72.5 (4.4) 1653.6 (25.7)
Occupy w/o payment 50.4 (71.8) 16.6 (23.7) 3.2 (4.5) 70.3 (1.9) 82.1 (69.4) 31.3 (26.5) 4.8 (4.1) 118.3 (1.8)
Region
South 1058.3 (77.5) 250.8 (18.4) 56.7 (4.2) 1365.8 (37.8) 0.4379 1826.0 (74.7) 516.6 (21.1) 102.0 (4.2) 2444.6 (38.0) 0.0002
West 684.3 (78.8) 140.5 (16.2) 43.9 (5.1) 868.7 (24.0) 1168.5 (75.6) 317.4 (20.5) 60.3 (3.9) 1546.1 (24.0)
Midwest 572.7 (76.6) 143.4 (19.2) 31.7 (4.2) 747.8 (20.7) 916.4 (68.4) 362.8 (27.1) 60.7 (4.5) 1339.9 (20.8)
Northeast 508.4 (80.1) 98.3 (15.5) 27.6 (4.4) 634.3 (17.5) 789.2 (71.1) 274.3 (24.7) 47.0 (4.2) 1110.6 (17.2)
Urbanicity
Metropolitan 2471.2 (78.9) 523.8 (16.7) 137.5 (4.4) 3132.5 (86.6) 0.0059 4111.8 (73.7) 1250.1 (22.4) 220.8 (4.0) 5582.7 (86.7) 0.0025
Non-metropolitan 352.4 (72.8) 109.3 (22.6) 22.5 (4.6) 484.1 (13.4) 588.2 (68.5) 221.0 (25.7) 49.2 (5.7) 858.4 (13.3)
Household size
Lives alone 416.7 (78.2) 101.7 (19.1) 14.2 (2.7) 532.7 (14.7) 0.0727 633.7 (69.9) 213.7 (23.6) 59.0 (6.5) 906.3 (14.1) 0.0005
Lives with others 2406.9 (78.1) 531.3 (17.2) 145.7 (4.7) 3083.9 (85.3) 4066.4 (73.5) 1257.4 (22.7) 211.0 (3.8) 5534.8 (85.9)
Marital status
Married 1607.6 (77.2) 368.1 (17.7) 105.9 (5.1) 2081.6 (57.6) 0.0664 2675.4 (73.1) 839.0 (22.9) 145.4 (4.0) 3659.8 (56.9) 0.6029
Not married 1216.0 (79.2) 264.9 (17.3) 54.1 (.5) 1535.0 (42.4) 2024.7 (72.8) 632.1 (22.7) 124.6 (4.5) 2781.4 (43.2)
Children in household
Household has children 905.6 (78.5) 203.8 (17.7) 43.6 (3.8) 1153.0 (31.9) 0.4394 1584.1 (74.3) 458.0 (21.5) 89.8 (4.2) 2131.8 (33.1) 0.1875
No children in home 1918.0 (77.9) 429.2 (17.4) 116.4 (4.7) 2463.6 (68.1) 3116.0 (72.3) 1031.1 (23.5) 180.2 (4.2) 4309.3 (66.9)
Household income
< $25 000 336.6 (69.8) 112.1 (23.2) 33.5 (6.9) 482.2 (13.3) < 0.0001 547.6 (68.8) 224.6 (28.2) 23.5 (3.0) 795.8 (12.4) 0.0004
$25 000 < $50 000 486.0 (75.2) 135.0 (20.9) 24.9 (3.9) 646.0 (17.9) 798.9 (71.2) 269.9 (24.0) 54.0 (4.8) 1122.8 (17.4)
$50 000 < $75 000 477.0 (79.3) 98.5 (16.4) 25.7 (4.3) 601.2 (16.6) 808.7 (72.4) 263.1 (23.6) 45.6 (4.1) 1117.4 (17.4)
$75 000 < $100 000 399.0 (78.7) 75.1 (14.8) 32.7 (6.5) 506.8 (14.0) 666.5 (73.4) 193.8 (21.3) 48.1 (5.3) 908.4 (14.1)
$100 000 < $150 000 511.1 (80.2) 106.9 (16.8) 19.5 (3.1) 637.5 (17.6) 913.2 (75.7) 256.1 (21.2) 37.5 (3.1) 1206.7 (18.7)
$150 000 or more 613.9 (82.6) 105.4 (14.2) 23.6 (3.2) 742.9 (20.5) 965.1 (74.8) 263.6 (20.4) 61.3 (4.8) 1290.0 (20.0)
Employment status *
Employed 1830.3 (78.9) 397.6 (17.2) 90.6 (3.9) 2318.5 (64.1) 0.0127 2016.2 (72.0) 653.5 (23.3) 130.6 (4.7) 2800.3 (43.5) 0.1703
Unemployed/retired 859.1 (77.0) 192.0 (17.2) 64.7 (5.8) 1115.7 (30.9) 1845.8 (73.3) 566.1 (22.5) 105.2 (4.2) 2517.1 (39.1)
Other 134.3 (73.6) 43.4 (23.8) 4.7 (2.6) 182.4 (5.0) 838.1 (74.6) 251.5 (22.4) 34.1 (3.0) 1123.7 (17.5)
* Fall 2020 “Employed” includes all currently employed persons, and “Other” includes those who are temporarily out of work; Spring 2021 “Employed” is employed full-time only, and “Other” are those who are employed part-time. Therefore, these are separate categories and should not be compared.
Table 6. Respondent believes emergency supply kits are expensive – United States, 2020 - 2021
Fall 2020 Spring 2021
Agree
(N=3682) Neutral
(N=1769) Disagree
(N=992) Total
(N=6443) p-value Agree
(N=3682) Neutral
(N=1769) Disagree
(N=992) Total
(N=6443) p-value
Age
18-34 years 332.8 (32.3) 218.9 (21.2) 478.9 (46.5) 1030.7 (28.5) <.0001 515.0 (28.4) 516.3 (28.4) 784.8 (43.2) 1816.1 (28.2) <.0001
35-54 years 290.5 (24.2) 340.7 (28.4) 567.3 (47.3) 1198.5 (33.1) 531.4 (24.8) 612.5 (28.6) 1000.9 (46.7) 2144.8 (33.3)
55-74 years 190.1 (16.7) 334.7 (29.4) 612.1 (53.8) 1136.9 (31.4) 302.3 (14.8) 657.3 (32.2) 1083.6 (53.0) 2043.1 (31.7)
75+ years 30.0 (12.0) 85.8 (34.3) 134.6 (53.8) 250.4 (6.9) 57.6 (13.0) 175.7 (39.7) 209.4 (47.3) 442.7 (6.9)
Sex
Male 361.8 (20.6) 505.1 (28.8) 887.8 (50.6) 1754.8 (48.5) 0.0006 605.3 (19.4) 1003.7 (32.2) 1509.3 (48.4) 3118.3 (48.4) <.0001
Female 481.6 (25.9) 475.0 (25.5) 905.2 (48.6) 1861.8 (51.5) 801.0 (24.1) 958.0 (28.8) 1569.3 (47.2) 3328.4 (51.6)
Education
Less than high school 85.9 (23.5) 110.7 (30.3) 168.6 (46.2) 365.2 (10.1) <.0001 160.1 (23.3) 261.7 (38.0) 266.2 (38.7) 688.0 (10.7) <.0001
High school 280.2 (27.5) 306.0 (30.0) 433.2 (42.5) 1019.4 (28.2) 422.4 (24.0) 601.7 (34.1) 728.8 (41.9) 1762.9 (27.4)
Some college 236.4 (23.4) 283.2 (28.1) 489.2 (48.5) 1008.9 (27.9) 459.8 (23.6) 592.5 (30.4) 895.2 (46.0) 1947.5 (30.2)
Bachelor’s or higher 240.9 (19.7) 280.1 (22.9) 702.0 (57.4) 1223.0 (33.8) 364.1 (17.8) 505.8 (24.7) 1178.4 (57.5) 2048.2 (31.8)
Race/Ethnicity
White, Non-Hispanic 497.5 (21.5) 660.8 (28.6) 1152.4 (49.9) 2310.7 (63.9) 0.0069 863.7 (21.1) 1207.6 (29.5) 2020.3 (49.4) 4091.5 (63.5) 0.0001
Black, Non-Hispanic 105.4 (25.4) 118.8 (28.7) 190.2 (45.9) 414.4 (11.5) 143.5 (19.2) 241.8 (32.4) 361.9 (48.4) 747.2 (11.6)
Hispanic 154.0 (26.6) 134.4 (23.2) 291.1 (50.2) 579.5 (16.0) 274.7 (26.2) 340.9 (32.5) 433.5 (41.3) 1049.2 (16.3)
Mixed Race 12.8 (24.4) 9.6 (18.3) 30.1 (57.3) 52.5 (1.5) 34.2 (28.6) 31.1 (26.0) 54.1 (45.4) 119.4 (1.9)
Other 73.6 (28.4) 56.5 (21.8) 129.3 (49.9) 259.4 (7.2) 90.3 (20.6) 140.3 (31.9) 208.8 (47.5) 439.4 (6.8)
Housing Structure
Single family home 590.8 (22.4) 703.1 (26.6) 1348.1 (51.0) 2642.0 (73.1) 0.0237 946.3 (20.5) 1407.3 (30.5) 2265.1 (49.0) 4618.6 (71.6) <.0001
Townhome/Duplex 78.2 (26.0) 81.3 (27.1) 140.9 (46.9) 300.4 (8.3) 118.3 (20.5) 181.1 (31.5) 276.5 (48.0) 575.9 (8.9)
Apartment 128.7 (24.3) 150.4 (28.4) 250.4 (47.3) 529.5 (14.6) 252.2 (25.5) 290.5 (29.3) 447.4 (45.2) 990.1 (15.4)
Mobile home, RV, etc. 45.7 (31.6) 45.2 (31.3) 53.7 (37.1) 144.6 (4.0) 89.6 (34.2) 82.9 (31.6) 89.7 (34.2) 262.1 (4.1)
Ownership Status
Owns 574.3 (21.6) 716.9 (26.9) 1372.2 (51.5) 2663.4 (73.7) <.0001 900.1 (19.3) 1434.4 (30.7) 2339.3 (50.1) 4673.7 (72.5) <.0001
Rents 256.8 (29.1) 249.1 (28.2) 376.9 (42.7) 882.9 (24.4) 469.3 (28.4) 480.9 (29.1) 704.4 (42.6) 1654.6 (25.7)
Occupy w/o payment 12.4 (17.6) 14.0 (19.9) 43.9 (62.5) 70.3 (1.9) 37.0 (31.3) 46.4 (39.2) 34.9 (29.5) 118.3 (1.8)
Region
South 286.6 (21.0) 355.5 (26.0) 723.1 (53.0) 1365.2 (37.8) <.0001 519.7 (21.2) 726.3 (29.7) 1200.8 (49.1) 2446.8 (38.0) <.0001
West 246.5 (28.4) 247.6 (28.5) 375.0 (43.2) 869.1 (24.0) 442.3 (28.6) 459.6 (29.7) 644.4 (41.7) 1546.2 (24.0)
Midwest 183.1 (24.5) 203.4 (27.2) 361.3 (48.3) 747.8 (20.7) 272.3 (20.3) 410.3 (30.6) 660.5 (49.2) 1343.1 (20.8)
Northeast 127.2 (20.1) 173.5 (27.3) 333.7 (52.6) 634.3 (17.5) 172.1 (15.5) 365.6 (32.9) 572.9 (51.6) 1110.6 (17.2)
Urbanicity
Metro 732.3 (23.4) 825.5 (26.4) 1574.7 (50.3) 3132.4 (86.6) 0.0288 1199.9 (21.5) 1690.5 (30.3) 2694.5 (48.3) 5584.9 (86.6) 0.1030
Non-Metro 111.2 (23.0) 154.6 (31.9) 218.4 (45.1) 484.1 (13.4) 206.4 (24.0) 271.2 (31.5) 384.1 (44.6) 861.7 (13.4)
Household Size
Lives alone 120.7 (22.6) 157.8 (29.6) 254.6 (47.8) 533.1 (14.7) 0.3688 174.9 (19.2) 266.4 (29.3) 468.2 (51.5) 909.5 (14.1) 0.0339
Lives with others 722.7 (23.4) 822.2 (26.7) 1538.5 (49.9) 3083.4 (85.3) 1231.4 (22.2) 1695.3 (30.6) 2610.4 (47.1) 5537.1 (85.9)
Marital Status
Married 431.7 (20.7) 569.7 (27.4) 1080.1 (51.9) 2081.5 (57.6) <.0001 754.4 (20.6) 1098.4 (30.0) 1809.3 (49.4) 3662.1 (56.8) 0.0039
Not married 411.7 (26.8) 410.3 (26.7) 713.0 (46.5) 1535.0 (42.4) 652.0 (23.4) 863.3 (31.0) 1269.3 (45.6) 2784.6 (43.2)
Children in home
Household has kids 331.2 (28.8) 285.2 (24.8) 535.4 (46.5) 1151.7 (31.9) <.0001 592.5 (27.8) 591.0 (27.7) 948.3 (44.5) 2131.8 (33.1) <.0001
No kids in home 512.2 (20.8) 694.9 (28.2) 1257.7 (51.0) 2464.8 (68.2) 813.8 (18.9) 1370.7 (31.8) 2130.3 (49.4) 4314.8 (66.9)
Household Income
<$25,000 134.1 (27.8) 152.6 (31.6) 195.5 (40.6) 482.2 (13.3) <.0001 231.5 (29.1) 253.3 (31.8) 312.1 (39.2) 796.9 (12.4) <.0001
$25,000 < $50,000 177.4 (27.5) 203.4 (31.5) 265.2 (41.1) 646.0 (17.9) 284.4 (25.3) 384.8 (34.2) 457.0 (40.6) 1126.2 (17.5)
$50,000 < $75,000 130.0 (21.6) 187.0 (31.1) 284.2 (47.3) 601.2 (16.6) 267.8 (24.0) 368.3 (32.9) 482.3 (43.1) 1118.4 (17.4)
$75,000 < $100,000 119.3 (23.5) 120.2 (23.7) 268.6 (52.9) 508.0 (14.1) 190.6 (21.0) 304.5 (33.5) 413.3 (45.5) 908.4 (14.1)
$100,000 < $150,000 136.5 (21.5) 152.2 (23.9) 347.5 (54.6) 636.2 (17.6) 239.3 (19.8) 341.7 (28.3) 625.8 (51.9) 1206.7 (18.7)
$150,000 or more 146.2 (19.7) 164.7 (22.2) 432.0 (58.2) 742.9 (20.5) 192.7 (14.9) 309.2 (24.0) 788.1 (61.1) 1290.0 (20.0)
Employment Status*
Employed 560.1 (24.2) 621.7 (26.8) 1135.9 (49.0) 2317.7 (64.1) 0.0950 577.7 (20.6) 867.4 (30.9) 1358.5 (48.5) 2803.6 (43.5) 0.0050
Unemployed/Retired 231.5 (20.7) 310.4 (27.8) 574.5 (51.5) 1116.5 (30.9) 581.1 (23.1) 791.9 (31.4) 1146.4 (45.5) 2519.3 (39.1)
Other 51.9 (28.5) 47.9 (26.3) 82.6 (45.3) 182.4 (5.0) 247.5 (22.0) 302.5 (26.9) 573.7 (51.1) 1123.7 (17.4)
* Fall 2020 “Employed” includes all currently employed persons and “Other” includes those who are temporarily out of work; Spring 2021 “Employed” is employed full time only and “Other” are those who are employed part-time. Therefore, these are separate categories and should not be compared.
Adults ages 35–54 years and 55–74 years have a 32.0% and 37.8% increased odds, respectively, of having an ESK compared to older adults ages 75 years and more (data not shown). In addition, there is a 10.9% decreased odds that women will have a kit (compared to men). As mentioned, region plays an important role, with those in the Midwest and Northeast being close to half (44.6% and 40.4%, respectively) as likely to have a kit as those in the South. The South and the West were comparable.
Those who are fully prepared (ie, have all 5 FEMA recommended plans), are ∼64 times more likely to have an ESK (data not shown). But, having any plans increases the likelihood of also having an ESK (OR = 3.4). When analyzed individually, the preparedness plan with the highest odds ratio was an emergency communication plan (OR = 6.5). When it comes to disaster experience, experiencing a previous disaster increases the odds of having an ESK by 57% (OR = 1.6). Among individual disasters included in the questionnaire, experiencing wildfires had the highest odds for ESK ownership (OR = 1.9). Working, volunteering, or having training (eg, Community Emergency Response Team [CERT]) increases the likelihood of having a kit more than twofold (OR = 2.1).
Those who are confident (ie, agree with the statement) that they know how to prepare for a disaster have almost 4.5 times the odds of having a kit as those who disagree and almost 3 times the odds of being prepared (OR = 2.9) (data not shown). Furthermore, those who believe that an ESK will improve their chance of surviving a disaster are also more than 3 times as likely to have a kit as those who disagree with that sentiment (OR = 3.1). They are also 86.0% more likely to be prepared overall (OR = 1.9). When it comes to beliefs about the cost of ESKs, those who agree they cost a lot of money are more likely to have a kit than those who disagree (OR = 1.2), but those who are neutral are 33.2% less likely to have a kit (OR = 0.7). Finally, those who believe the risk of their household being affected by an infectious disease is greater than that of a disaster are 28.0% less likely to have an ESK (OR = 0.7) and 15.5% (0.8) less likely to be prepared.
Limitations
These data are not without limitations. ConsumerStyles surveys are cross-sectional and limited to only those within the panel. Therefore, while we have 2 surveys, they are only 2 snapshots in time and do not represent a longitudinal analysis. Also, even though KnowledgePanel® works to ensure representativeness of the respondents on several key aspects, there are some potential differences in areas that have traditionally mattered in disaster preparedness and response, such as household structure, home ownership, and persons within the home (eg, marital status, living with others, having kids). However, none of these determinants were found to be significant in our modeling. Further, the panel only represents those within the 50 US states and does not include panel members from the territories. The US territories are prone to disasters and should be included in all disaster research. However, as previous data have shown, the island territories may have different preparedness needs as, for example, the traditional 3-day supply of food and water may not be enough for such harder-to-reach geographies. 31 As far as the survey questions, the demographic categories changed between fall 2020 and spring 2021, making it impossible to compare employment and limiting the analysis of household type by combining mobile homes with boats, RVs, and vans. Finally, because all questions were closed-ended, any reasoning for certain responses (eg, “other”) had to be inferred. While this research is integral in acquiring knowledge of current possession of ESKs, it does not address the gap in knowledge regarding actual use and effectiveness of ESKs during a disaster. Therefore, a needed step is to explore in detail the actual effectiveness of ESKs with more granular data. This would require an immediate post-impact survey assessing whether households had an ESK, what they did (and did not) use within the kit, what items were missing or needed that required them to leave the home or call for emergency services, and related questions.
Discussion
This analysis reflects nationally representative samples characterizing ESK possession in the United States during the COVID-19 pandemic. Overall, the fall and spring samples are comparable and show that ESK ownership remains lacking across the country. While most respondents believed that an ESK would help their chance of survival, only a third have one. Of note, for those respondents only reporting 1 preparedness plan or item, an ESK was the second most popular (after copies of important documents). This shows that, while ownership is low, ESKs are still one of the top preparedness items among households. Similarly, there is a strong increase in the likelihood of having an ESK when having 1 or more emergency preparedness plans.
Results highlighted that there seems to be some confusion about what comprises an ESK. Two questions were asked within the survey (as part of the preparedness plans and separately) and answers varied by roughly 10%. Of those who reported not having an ESK when asked directly, roughly 8% reported having an “easy to get to emergency supply kit” in the previous question. While the wording differed (one specifying “easy to get to” and the other providing a definition), the varied responses are concerning and indicate a need for communication efforts to clearly define ESKs to the general population. Despite this confusion, of those who reported having an ESK, the most common item was a flashlight with batteries, followed by medical supplies, water, food, and a radio; all of which are recommended on both FEMA and CDC websites. However, because the question did not define medical supplies (eg, it included a 7-day supply of prescription medication) or the amount of food and water (ie, a 3-day supply), it is unclear whether the ESK would be adequate for the household during an emergency response.
Therefore, it is vital to provide clear guidance on the essential components of a household ESK. While there are suggested items on FEMA, CDC, American Red Cross, and several other agency (both local and federal) websites, there is little consistency among these lists, and several include over 20 items, which can cost hundreds of dollars depending on the size of the family. 51 In fact, an environmental scan synthesizing recommendations identified 36 common items (defined as listed on at least a third of lists) among the 196 ESK lists around the United States. 51 While no single item was listed on all 196 lists, the most common item was a flashlight (83%), followed by a radio (82%), batteries (81%), and medications (80%). While ESKs should have some items tailored to regional or local needs (eg, sunscreen, mylar thermal blankets), there should be a core set of common items recommended on all lists (eg, food, water). In addition, creative solutions must be implemented to ensure that cost is not a barrier to preparedness. This could include campaigns that encourage purchasing 1 item each month to reduce cost burden, making homemade kit items, providing discounts for prebuilt kits in major retailers, or providing kits at no cost to low-income households.
The identified gaps in ESKs are not equitable across the nation, with several social and demographic factors associated with kit ownership including age, gender, education level, and region of the country. These data are comparable to the recently released FEMA NHS, which collected data in the first half (February through May) of 2021 and found that 45% had “assembled or updated supplies,” with lower percentages among groups at higher risk (eg, non-primarily English-speaking households, socioeconomically disadvantaged, minority populations). 34 Interestingly, race, income, housing structure type, and home ownership status were not significant within the multivariable models of our data. This could potentially be because these factors are overlapping with the other components (eg, education level) or are modifiers of the relationship, which has been found in other research. 52,53 This is also consistent with our understanding of race as a social construct disproportionately associated with social, economic, and environmental disadvantages because of systemic and structural racism. 54 While income may not be a barrier to having an ESK, the fact that roughly a quarter cited that ESKs cost a lot of money suggests that this is a potential barrier that needs to be addressed. Those who think it costs a lot report higher kit ownership than those who disagree or are neutral so their perception could be based on their experience in purchasing items. Further analysis into this relationship between cost (or perception of cost) and possession of an ESK is warranted.
Of particular concern are older adults (those 75 years or more) who were less likely than other age groups to have a kit. Older adults tend to have more chronic conditions, mobility issues, or other factors that may impact their health and safety during a disaster. Men are more likely than women to have an ESK as well as be confident in preparing for a disaster. In addition, those who completed at least some college were more likely to have a kit than those with just a high school education. There are several promotional efforts that could be done to help mitigate the potential financial barrier and address the demographic disparities (eg, older adults, women) such as campaigns that suggest gathering supplies over time to reduce the financial burden, marketing pre-made kits at discounted prices in common retailers, and using preparedness funds to help provide kits to those in need. 40,46 This could help ensure that those who are both most in need and least likely to have a kit have a basic level of preparedness.
Despite their importance, social determinants were not the only factors that mattered in terms of ESK ownership. As expected, being prepared in 1 area increased the likelihood of having an ESK. In fact, those who had all 5 recommended FEMA plans were almost 64 times more likely to have an ESK. Even having some plans increased the odds of having a kit by almost 3.5 times. This positive impact on having an ESK by having 1 or more emergency preparedness plans can be leveraged to further increase awareness and education around preparedness planning and encourage the creation of such plans by households. In addition, those who felt confident in preparing for a disaster had over 4 times the odds of having an ESK and had almost 3 times the odds of being prepared. Also, those who believed that ESKs would improve their chance of surviving a disaster were 3 times more likely to have a kit. This is important in terms of people’s mindset and is consistent with previous research on preparedness and several theories on behavior modifications. 55–57
Believing that a disaster is not the greatest threat to the household also has an impact. Those who believe the risk of an infectious disease is greater than that of a disaster were less likely to have a kit than those who disagreed with the statement. This is important to help inform and target communication efforts to households. For example, if someone is confident in their preparedness for a disaster or does not believe that a disaster will affect their home, they may not listen to standard approaches to messaging. In addition, the personal experiences of respondents played a key role in both attitudes and behaviors. Most respondents had experienced some type of disaster. This factored into their preparedness with those experiencing any type of disaster reporting higher levels of kit ownership than those who had not. While respondents in these surveys experienced mostly natural disasters, such as flooding and wildfires, ESK recommendations should not be limited to such incidents. ESKs are beneficial to any disaster or emergency that may necessitate staying within the home for a period of time or that limits access to resources (eg, road blockages, supply chain issues). The COVID pandemic served to reinforce this point and the continued need for such an all-hazards approach to preparedness.
The impact of respondent disaster experience was amplified when it came to experience working or volunteering in disaster response or recovery. Those who had such experiences had more than 100% increased odds of having a kit and almost 200% increased odds of being prepared. Those who have experienced wildfires were the most likely to have an ESK. This is important since wildfires can occur without warning and in unpredictable ways, causing necessary evacuations to happen quickly. The disaster-type associations could be linked to regional associations as geographic region significantly impacts ESK ownership. Respondents in the South and West were more likely to report having ESKs. Texas and California are the 2 most disaster-prone states in the United States with 102 and 100 federal major disaster declarations since 1950, respectively. 57 However, while the South had the most disaster declarations in that time frame (n = 989), the Midwest had the second most disaster declarations with 576, and New York state (in the Northeast) ranked fourth. Therefore, while true that Southern states have the most experience and therefore could be more prepared based on such experience, disasters can (and do) happen in all regions.
Conclusion
Overall, these data show that, as a nation, there is much work to be done in terms of ESK ownership. While these data are important to provide a national picture to federal agencies, the significant regional differences also highlight the fact that all disasters are local. Therefore, efforts must continue to be made at the local level to both inform and address ESK ownership. For example, the need for tailored strategies focused on groups that have been marginalized and under-resourced communities who are both at high risk for disasters and have low levels of emergency kit ownership. These include focused communication strategies to address barriers, including those related to costs, as well as efforts to provide ESKs. These data are an essential starting point in characterizing ESK ownership and can be used to help tailor public messaging, work with partners to increase ESK ownership, and guide future research.
Author contributions
Conceptualization, Schnall, Hanchey, Bayleyegn, and Daniel; Methodology, Schnall, Hanchey, Daniel, and Stauber; Formal Analysis, Schnall, Kieszak, Heiman, Hanchey, and Stauber; Writing – Original Draft Preparation, Schnall; Writing – Review & Editing, Schnall, Kieszak, Hanchey, Heiman, Bayleyegn, Daniel, and Stauber; Supervision, Daniel, Bayleyegn, Heiman, and Stauber; Funding Acquisition, Schnall and Daniel.
Conflict(s) of interest
None.
The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry.
Ethical standards
These data were considered not human subjects research by the CDC’s National Center for Environmental Health (NCEH) Office of Science on August 14, 2020; therefore, it was exempt from the human subjects institutional review board review.
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| 36245103 | PMC9744458 | NO-CC CODE | 2022-12-15 00:01:47 | no | Disaster Med Public Health Prep.;:1-15 | utf-8 | Disaster Med Public Health Prep | 2,022 | 10.1017/dmp.2022.234 | oa_other |
==== Front
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J Invest Dermatol
J Invest Dermatol
The Journal of investigative dermatology
0022-202X
1523-1747
23344460
10.1038/jid.2013.32
nihpa437467
Article
Stat3 targeted therapies overcome the acquired resistance to vemurafenib in melanomas
Liu Fang 1236
Cao Juxiang 12
Wu Jinxiang 1
Sullivan Kayleigh 1
Shen James 1
Ryu Byungwoo 1
Xu Zhixiang 4
Wei Wenyi 5
Cui Rutao 16
1 Department of Dermatology, Boston University School of Medicine, 609 Albany St, Boston, MA 02478
3 Department of Dermatology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100043, China
4 Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham School of Medicine, 17th Ave S, Birmingham, AL 35233
5 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02115
2 Contributed equally to this work.
6 Correspondence to Fang Liu: [email protected] or Rutao Cui: [email protected]
24 1 2013
8 2013
23 1 2013
12 12 2022
133 8 20412049
http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
Vemurafenib (PLX4032), a selective inhibitor of Braf, has been FDA-approved for the treatment of unresectable or metastatic melanoma in patients with BrafV600E mutations. Many patients treated with vemurafenib initially display dramatic improvement, with decreases in both risk of death and tumor progression. Acquired resistance, however, rapidly arises in previously sensitive cells. We attempt to overcome this resistance by targeting the Stat3-PAX3 signaling pathway, which is upregulated, due to FGF2 secretion or increased kinase activity, with the BrafV600E mutation. We found that activation of Stat3 or overexpression of PAX3 induced resistance to vemurafenib in melanoma cells. Additionally, PAX3 or Stat3 silencing inhibited the growth of melanoma cells with acquired resistance to vemurafenib. Furthermore, treatment with the Stat3 inhibitor, WP1066, resulted in growth inhibition in both vemurafenib-sensitive and -resistant melanoma cells. Significantly, vemurafenib stimulation induced FGF2 secretion from keratinocytes and fibroblasts, which might uncover, at least in part, the mechanisms underlying targeting Stat3-PAX3 signaling to overcome the acquired resistance to vemurafenib. Our results suggest that Stat3-targeted therapy is a new therapeutic strategy to overcome the acquired resistance to vemurafenib in the treatment of melanoma.
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pmcIntroduction
Braf is a serine–threonine specific protein kinase and an isoform of Raf. Raf proteins (Raf-1, Araf and Braf) are intermediates in the Ras and MAPK signaling pathways and affect cell proliferation (Fecher et al., 2007). Braf mutations are the most prevalent somatic genetic events in human cutaneous melanoma, occurring in 40% to 60% of metastatic melanoma (Chin et al., 2006). Most Braf melanoma mutations are within the kinase domain, with a single substitution (V600E), accounting for 80% of the Braf melanoma mutations (Brose et al., 2002; Davies et al., 2002; Pollock and Meltzer, 2002). The mutant BrafV600E protein possesses 10.7-fold increased kinase activity, compared to wild-type Braf (Davies et al., 2002).
Currently, selective inhibitors of Braf, such as vemurafenib (Bollag et al.; Chapman et al., 2011; Flaherty et al., 2010) and GSK2118436 (Flaherty and McArthur, 2010), have demonstrated remarkable clinical activity in patients with melanoma, and vemurafenib has recently been FDA-approved for the treatment of patients with unresectable or metastatic melanoma with BrafV600E mutations (Chapman et al., 2011). Vemurafenib was associated with a 63% relative reduction in the risk of death and a 74% reduction in the risk of tumor progression in patients with previously untreated, unresectable stage IIIC or stage IV melanoma with BrafV600E mutations (Chapman et al., 2011). Although the initial response to these drugs is profound, it is temporary. Drug resistance frequently appears after only 6 to 9 months of therapy (Poulikakos and Rosen, 2011). This type of “acquired resistance” develops after the melanomas were originally sensitive to vemurafenib. Acquired resistance has emerged as the major hurdle, preventing vemurafenib from having a truly transformative impact on patients with unresectable or metastatic melanoma with BrafV600E mutations.
One potential solution to overcome the acquired resistance of vemurafenib in patients with melanoma is to develop combination-targeted therapies. One possible approach is targeting a frequently altered pathway together with one of the essential pathways in normal pigment cells. This strategy could simplify patient selection, because the status of only one molecularly altered pathway is required for choosing the most appropriate therapy. In addition, this therapy strategy would reduce the potential toxicities, as lower drug doses could be utilized to target the essential pathway. One prospective candidate of the essential pathway in melanocytes is the paired box homeotic gene 3 (PAX3) signaling cascade.
PAX3 is essential for maintaining melanocytic progenitor cells (Blake and Ziman, 2005; Scholl et al., 2001; Steingrimsson et al., 2005). A chromosomal deletion, a splice-site mutation and an amino acid substitution within PAX3 cause Splotch-retarded, Splotch and Splotch-delayedgenetic mouse mutants, respectively (Tassabehji et al., 1994). Splotch-delayed homozygous mice survive to birth, compared to Splotch mutant mice which die at E13 due to neural tube defects (Moase and Trasler, 1992). Heterozygous Splotch-delayed (Splotch/+) mice display pigmentation abnormalities characterized by abdominal white patches due to defective neural crest-derived melanocyte development (Epstein et al., 1993). PAX3 mutations result in humans to produce type I and type III Waardenburg syndromes (Read and Newton, 1997; Tassabehji et al., 1992), conditions characterized by melanocyte deficiencies in the skin and inner ear.
Our previous work has demonstrated that Stat3 binds to the PAX3 upstream regulatory regions to transactivate the PAX3 promoter, resulting in constitutive PAX3 expression in melanocytes in vivo and increased melanocyte numbers (Dong et al., 2012). Although no small molecules are currently available to directly target PAX3 transcription factor, Stat3-targeted therapies are being evaluated in clinical trials for several types of tumors (Darnell, 2005).We therefore investigated whether Stat3 inhibition could be used to overcome the acquired resistance to vemurafenib in melanoma.
Results
Stat3-PAX3 signaling is activated by BrafV600E or N-RASQ61K in melanoma cells
In the case of vemurafenib resistance, certain N-RAS mutations have been implicated (Nazarian et al., 2010). Thus, a plethora of additional agents are needed to continue therapy. To characterize the connection of vemurafenib resistance and Stat3-PAX3 signaling in melanocytes, we introduced N-RASQ61K or BrafV600E mutations into genetically modified human melanocytes (hTERT/CDK4(R24C)/p53DD melanocytes) (Garraway et al., 2005) and measured phospho-Stat3 protein as well as PAX3 mRNA and protein levels at 48 hr after introduction of N-RASQ61K or BrafV600E. We observed a nearly 5-fold induction of PAX3 mRNA, accompanied by a marked induction of phospho-Stat3 and PAX3 protein expression after the infection with N-RASQ61K virus or BrafV600E virus (Figure 1). These results suggest that activation of Stat3 and upregulation of-PAX3 are downstream targets of mutant N-RASQ61K or BrafV600E in melanoma cells.
Vemurafenib resistance in melanoma cell lines
To identify whether Stat3-PAX3 targeted therapy is an effective strategy to overcome the acquired resistance to vemurafenib, we generated vemurafenib-resistant A375 (A375R) and UACC62 (UACC62R) melanoma cells. A375 and UACC62 melanoma cells both harbor the BrafV600E mutation, and both are sensitive to vemurafenib treatment (Supplementary Figure 1). Drug-resistant A375 and UACC62 cells were generated through treatment with increasing concentrations of vemurafenib (Nazarian et al., 2010; Villanueva et al., 2010) (Supplementary Figure 1). The IC50's of parental A375 and UACC62 were 70nM and 90nM, respectively. As expected, we found that the vemurafenib-resistant cells required higher doses of vemurafenib for partial growth inhibition; the IC50's of A375R and UACC62R were 4.4μM and 5.1μM, respectively (Supplementary Figure 1B & C). Cell cycle analysis demonstrated that treatment with 90nM of vemurafenib induced G0/G1 cell cycle arrest after 24 hr in parental cells, but this level of vemurafenib did not effect in the vemurafenib-resistant cells (Supplementary Figure 1C).
Vemurafenib treatment represses Stat3-PAX3 signaling in vemurafenib-sensitive melanoma cells
The activation of Stat3-PAX3 signaling is induced upon infection with Ad-RASQ61K or Ad-BrafV600E adenoviral vectors (Figure 1). Next, we examined the effect of vemurafenib on Stat3-PAX3 signaling in vemurafenib-sensitive and -resistant melanoma cells. The expression of phospho-Stat3 and PAX3 was detected in vemurafenib-stimulated parental and resistant A375 and UACC62 melanoma cells (Figure 2). We found that the activation of Stat3 and the protein expression of PAX3 were both repressed in vemurafenib sensitive (parental) A375 and UACC62 melanoma cells, but higher vemurafenib concentration were required in resistant A375 and UACC62 melanoma cells. Specifically, vemurafenib at 1μM inhibited the expression of phospho-Stat3 in sensitive cells, but not in resistant cells (Figure 2). These results suggest that inhibition of Stat3 signaling represents a potential therapeutic strategy to overcome the acquired resistance to vemurafenib in melanoma cells.
PAX3 or Stat3 overexpression inhibits the sensitivity of melanoma cells to vemurafenib
To further characterize the connection of vemurafenib resistance and Stat3-PAX3 signaling in melanoma cells, we introduced pcDNA-3.1-Stat3-CA (Ginsberg et al., 2007) or PECE-PAX3 plasmids into A375 and UACC62 parental cells and then measured the response of these cells to vemurafenib. Introduction of pcDNA-3.1-Stat3-CA results in overexpression of constitutively active Stat3 due to cysteine residues at A661 and N663 of Stat3 (Dai et al., 2011; Ginsberg et al., 2007). The IC50's of A375 sensitive cells with Stat3 or phospho-PAX3 overexpression were 2.3μM and 3.7μM, respectively. The IC50's of UACC62 sensitive cells with phospho-Stat3 or PAX3 overexpression were 3.6μM and 4.7μM, respectively (Figure 3C). These results indicate that A375 and UACC62 cells were resistant to vemurafenib treatment after phospho-Stat3 or PAX3 introduction.
PAX3 or Stat3 silencing inhibits the growth of resistant melanoma cells
To examine whether inhibition of Stat3-PAX3 signaling could be a therapeutic strategy to overcome the acquired resistance to vemurafenib in melanoma cells, Stat3 or PAX3 expression was silenced in A375 and UACC62 vemurafenib-resistant cells (Figure 4A & B). We found that knockdown of PAX3 and Stat3 expression significantly inhibited melanoma cell growth (Figure 4C). Taken together, the phospho-Stat3 and PAX3 expression studies and the Stat3 and PAX3 silencing experiments both indicate that Stat3-PAX3 signaling represents a target for overcoming acquired vemurafenib resistance in melanoma cells.
Vemurafenib treatment induces FGF2 secretion from melanoma cells and stromal cells
A recent report demonstrates that tumor drug resistance is caused, at least in part, by factors secreted by the tumor micro-environment (Straussman et al., 2012). Secreted fibroblast growth factor (FGF2) signaling plays an important role in the activation of Stat3-PAX3 signaling in melanocytes (Dong et al., 2012). To examine whether FGF2 secretion is induced by vemurafenib treatment in melanoma cells, FGF2 levels were monitored in growth media from cultured parental and vemurafenib-resistant melanoma cells. Cells were grown for 48 hr at 80% confluence in serum-free media and FGF2 was assayed in growth media, using an enzyme-linked immunosorbent assay (ELISA) FGF2 kit (F4210-19, US Biologic Marblehead, MA)). We found that secreted FGF2 levels were higher in vemurafenib-resistant melanoma cells compared to vemurafenib-sensitive (parental) cells (Figure 5A). In addition, both primary keratinocytes and fibroblasts were treated with different doses of vemurafenib. Culture media was collected and FGF2 levels were determined by ELISA (Figure 5B). We found that FGF2 secretion was induced by vemurafenib treatment in a dose dependent manner. FGF2 has well–documented proliferative activities and transduces signals via FGF receptors (Jaye et al., 1992). Multiple studies have shown that FGF2 treatment can induce proliferation of melanocytes in vitro (Halaban et al., 1988; Imokawa et al., 1992) as well as in pigmented lesions in grafts (Berking et al., 2001). Our previous work demonstrated that secreted FGF2 from keratinocytes activates Stat3 in melanocytes. Mechanistically, Stat3 binds to PAX3 upstream regulatory sequences resulting in constitutive PAX3 expression and increased numbers of melanocytes (Dong et al., 2012). In this study, we found higher levels of secreted FGF2 in vemurafenib-resistant melanoma cells compared to vemurafenib-sensitive melanoma cells. In addition, vemurafenib stimulation induced FGF2 secretion from both keratinocytes and fibroblasts. We postulate that Stat3-PAX3-mediated vemurafenib resistance involves FGF2 secreted by the tumor micro- environment (Figure 5C).
Stat3 targeted therapy overcomes the acquired resistance to vemurafenib in melanomas
We have demonstrated that silencing Stat3-PAX3 signaling inhibits the growth of vemurafenib-resistant cells (Figure 4). This suggests that Stat3-PAX3 targeted treatment could be a new therapeutic strategy to overcome the acquired resistance to vemurafenib. To date, small molecules that target the PAX3 transcription factor are not available. In contrast, Stat3-targeted therapies are well established (Levy and Inghirami, 2006) and, in fact, several small molecules targeting Stat3 are currently being evaluated for head and neck tumors in Phase I/II clinical trials (clinicaltrials.gov), including the reagent WP1066 (Verstovsek et al., 2008). To examine whether Stat3-targeting reagents can overcome melanoma acquired resistance to vemurafenib, we tested the effect of WP1066 on vemurafenib sensitivity of melanoma. We found that WP1066 blocked Stat3 signal activation by inhibiting the phosphorylation of Stat3 and repressing of PAX3 protein expression in both parental and vemurafenib-resistant melanoma cells (A375 and UACC62; Figure 6A). Consistent with this, Stat3-PAX3 inhibition by WP1066 resulted in growth inhibition (Figure 6B) in parental and resistant A375 and UACC62 melanoma cells. The IC50's of parental A375 and UACC62 cells were 2.5μM and 3.4μM, respectively. The IC50's of resistant A375 and UACC62 cells were 2.5μM and 3.5μM, respectively, which are similar to the IC50's of parental A375 and UACC62 cells. We next evaluated the growth inhibitory potential of combining vemurafenib and WP1066 in vemurafenib-resistant cells. As shown in Figure 6C, cell growth was more significantly inhibited by combining WP1066 (2μM) and vemurafenib (200nM) treatments together, compared to either agent on its own. Thus, combination therapy with WP1066 and vemurafenib can overcome the acquired resistance to vemurafenib.
We also investigated the effects of Stat3 inhibition on cell growth in three other vemurafenib-resistant cells: M249R, M263R and M308R (Nazarian et al., 2010). Naturally occurring vemurafenib resistance arose in both M263R and M308R cells and a specific N-RAS mutation gave rise to vemurafenib resistance in M249R cells (Nazarian et al., 2010). To confirm that inhibition of Stat3 is a new therapeutic strategy to overcome the acquired resistance to vemurafenib in melanoma cells, we first silenced the expression of Stat3 in M263R and M249R cells (Figure 6D). The IC50's of vemurafenib in M263R resistant cells with stable shStat3 was 46nM and the IC50 of vemurafenib in M249R cells with stable shStat3 was 58nM (Figure 6E). These results indicate that PAX3 or Stat3 silencing inhibits the growth of M263R and M249R cells. We also found that WP1066 treatment resulted in growth inhibition in M263R, M249R and M308R cells (Figure 6B). The vemurafenib IC50's in M249R, M263R and M308R cells were 2.3μM, 2.3μM and 3.9μM, respectively. These results are consistent with the effects of WP1066 on parental and vemurafenib-resistant A375 and UACC62 melanoma cells and suggest that inhibition of Stat3-PAX3 signaling by WP1066 is an effective therapeutic strategy to overcome acquired resistance to vemurafenib.
To identify whether PAX3 repression is required in WP1066-induced growth inhibition in resistant melanoma cells, we introduced PECE-PAX3 plasmids into A375 and UACC62 resistant cells and then evaluated the growth inhibitory potential of combining vemurafenib and WP1066. As shown in Figure 6 F & G, cell growth was inhibited by combining WP1066 (2 μ M) and vemurafenib (200nM) treatment together in A375 and UACC62 resistant melanoma cells, but higher vemurafenib concentration were required (500nm) in resistant A375 and UACC62 melanoma cells with PAX3 overexpression.
Discussion
Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011. Unfortunately, de novo and acquired resistance to vemurafenib are common (Chapman et al., 2011). Therefore, it is important to understand vemurafenib resistance mechanisms and identify potential therapeutic strategies that could overcome this resistance. In the case of vemurafenib resistance, PDGFRβ up-regulation, N-RAS mutation (Nazarian et al., 2010) and increased MAP3K8/COT activity (Johannessen et al., 2010; Wagle et al., 2011) have all been implicated.
Drug combination therapies involving 1) Braf inhibitors and MEK inhibitors (Basse et al., 2010; Bollag et al., 2010; Joseph et al., 2010; Paraiso et al., 2010; Villanueva et al., 2010), 2) PI3K/AKT/mTOR inhibitors (Dankort et al., 2009; Shi et al., 2011; Villanueva et al., 2010) and 3) different immunotheraptic reagents (Hodi et al., 2010; Tsao et al., 2004) have all been studied in vitro. However, these combination therapies would theoretically only be effective in specific group of patients. In our present study, we demonstrate that vemurafenib treatment represses Stat3-PAX3 signaling in vemurafenib-sensitive melanoma cells, but higher vemurafenib concentration are required in vemurafenib-resistant melanoma cells. In addition, we show that inhibition of Stat3-PAX3 signaling inhibits cellular growth in melanoma cells with the acquired resistance to vemurafenib.
PAX3 is essential for maintaining melanocytic progenitor cells (Blake and Ziman, 2005; Schollet al., 2001; Steingrimsson et al., 2005) and PAX3 overexpression is also frequently detected in melanomas (Abrahams et al., 2008; Barr et al., 1999; Carreira et al., 1998; Plummer et al., 2008; Rodriguez et al., 2008; Scholl et al., 2001; Vachtenheim and Novotna, 1999). Approximately 30-70% of primary melanoma specimens and 77% of cultured primary melanoma cells displayed PAX3 overexpression (Barr et al., 1999; Plummer et al., 2008; Scholl et al., 2001; Yang et al., 2008). However, the role of PAX3 in acquired resistance to vemurafenib in melanoma is not known. Here, we demonstrate that PAX3 silencing inhibits growth in melanomas with acquired resistance to vemurafenib.
The Jak2-Stat3 pathway is emerging as a target of interest for melanoma (Kortylewski et al., 2005; Krasilnikov et al., 2003; Smalley and Herlyn, 2005). In malignant cells, Stat3 functions in regulating cell proliferation, angiogenesis and inhibition of apoptosis (Amin et al., 2004; Catlett-Falcone et al., 1999; Zushi et al., 1998). Importantly, activation of Stat3 signaling is a negative prognostic factor in human cutaneous melanoma (Lee et al., 2012; Wang et al., 2007). In addition, the anti-tumor effects of tyrosine isomers were mediated in part by both inhibition of the MAP/ERK pathway and inactivation of Stat3 signaling (Ruggiero et al., 2012). Here we confirm previous reports and demonstrate that vemurafenib treatment repressed the activation of Stat3 in melanoma cells. We also show that inhibition of Stat3 signaling inhibits cellular growth in melanoma cells with acquired resistance to vemurafenib. A previous report demonstrated that tyrosine phosphorylation of Stat3/5 and of Jak2 was induced upon treatment of LU1205 melanoma cells with the MEK inhibitor PD98059 (Krasilnikov et al., 2003). To further identify the connection between MEK and Stat3 in melanoma cells, we silenced MEK1/2 expression in B16-F10 cells and found that tyrosine phosphorylation of Stat3 was repressed upon MEK1/2 silencing in B16-F10 cells (Supplementary Figure 2). One possibility is that the PD98059-mediated induction and activation of Stat3 signaling in LU1205 melanoma cells is a cell and time-point specific.
WP1066 is a cell-permeable, AG 490 tyrphostin analog that effectively inhibits the Jak2-Stat3 pathway (Hussain et al., 2007) and subsequently inhibits the growth of malignant glioma cells (Hussain et al., 2007), acute myelogenous leukemia cells (Ferrajoli et al., 2007) and melanoma cells (Kong et al., 2008). Previous reports have demonstrated that WP1066 inhibits melanoma cell growth and melanoma metastasis (Kong et al., 2008), and enhances T-cell cytotoxicity against melanoma by inhibiting regulatory T cells (Kong et al., 2009). A recent report shows that WP1066 enhanced the antitumor activity of cyclophosphamide (CTX) in a xenograft melanoma mouse models (Hatiboglu et al., 2012). In this study, we demonstrate that WP1066 reduced cell proliferation, and induced apoptosis and cell cycle arrest in melanoma cells both with and without the acquired resistance to vemurafenib. The IC50's of WP1066 for cancer cells, including the melanoma cells used here, range from 1.5-5μmols (Kong et al., 2008; Kong et al., 2009). Although WP1066 is currently being evaluated for head and neck tumors and lymphoma in Phase I/II clinical trials (clinicaltrials.gov), these high IC50 values would limit its potential in a clinical setting. Therefore, new, more-sensitive small molecules that target Stat3 need to be developed and evaluated. However, these intriguing findings should encourage the identification of other Stat3-targeting reagents that could be useful in addressing the acquired resistance to vemurafenib in melanoma.
Material and Methods
Cell lines and reagents
Primary keratinocytes and human foreskin fibroblasts were isolated from normal discarded foreskins as described (Dunham et al., 1996; Horikawa et al., 1996). Human primary keratinocytes were cultured in keratinocyte serum-free medium (SFM) (Invitrogen Corporation, USA). A375 and UACC62 melanoma cells were generously provided by Dr. David Fisher (MGH, Harvard Medical School). M249R, M263R and M308R were generously provided by Dr. Roger S. Lo and Dr. Antoni Ribas (UCLA) (Nazarian et al., 2010). All cells were cultured in DMEM medium plus 10% FBS. Immortal human melanocytes (hTERT/p53DD/CDK4(R24C)) (Garraway et al., 2005) were cultured in glutamine containing Ham's F12 media supplemented with 7% FBS, 0.1mM IBMX, 50ng/mL TPA, 1 μ M Na3VO4 and 1 μ M dbcAMP. Vemurafenib (PLX4032) was purchased from Selleckchem (Houston, TX). WP1066 was purchased from Santa Cruz (Santa Cruz, CA). pRetro-shStat3, pRetro-shPAX, pRetro-shMEK1 and pRetro-shMEK2 silencing vectors, were purchased from Cellogenetics (Ijamsville, MD). Plasmids pcDNA-3.1-Stat3-CA was generously provided by Dr. James E. Darnell (The Rockefeller University, New York) (Ginsberg et al., 2007). PECE-PAX3 plasmids were generously provided by Dr. Michel Goossens. Lipofectamine™ 2000 (Invitrogen, Inc) was used in transfection. FGF2 ELISA kits were purchased from Invitrogen.
MTT Assay of Cell Numbers
Ten thousand cells per well were plated in a 96-well plate. Vemurafenib (PLX4032) or WP1066 was added to the growth media after overnight culture and MTT solution was added 72 hrs later. Optical density was read at 550 nm, and background was subtracted at 690 nm.
Flow cytometry
Cells were fixed in ice-cold 70% ethanol before DNA staining with 50μg/ml propidium iodide (Sigma Aldrich) in PBS containing 0.1 mg/ml RNase (Amersham). DNA content was analyzed by flow cytometry (Becton Dickinson FACSCalibur).
Total RNA isolation, protein isolation, Real-Time RT-PCR, Western Blotting and Enzyme Immunoassay
Total RNA was isolated from melanocytes using TRIzol reagent (Invitrogen). cDNA was synthesized with the SuperScript first strand system (Invitrogen) using 2 μg of total RNA as template and oligo(dT) as primer. Total protein was extracted by in DOC buffer (Pierces protein assay kit).
For quantitative RT-PCR, total RNA was converted into cDNA using the SuperScript™ III reverse transcriptase kit (Invitrogen). cDNA expression was measured using the QuantiTect Probe RT-PCR kit (Qiagen, Valencia, CA) and the ICycler detector (BioRad, Hercules, CA). Gene-specific primers are as described (Dong et al., 2012).
Western blotting was performed using the following antibodies: anti-PAX3 (The Developmental Studies Hybridoma Bank at the University of Iowa); anti-p-Stat3 (Tyr705) (Cell Signaling); anti-p-Stat33 (Ser727) (Cell Signaling); anti-Stat3 (9D8, Thermo Scientific); anti-p-ERK1/2 (Cell Signaling); and anti-tubulin (Sigma). Enzyme immunoassay was performed using FGF2 ELISA kit (F4210-19, US Biologic Marblehead, MA).
Statistical Analysis
Experiments were independently carried out at least three times and one representative data set out of the three independent experiments was presented where appropriate. The results were evaluated for statistical significance by student t-test or two-sample t-test. Error bars were marked as the standard deviation (SD) of the mean. p-values less than 0.05 were regarded as significant.
Supplementary Material
01
Acknowledgments
The PAX3 monoclonal antibody developed by Dr. Charles P. Ordahl was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biology, Iowa City, IA 52242. This work was supported by National Institutes of Health (7RO1CA137098 for RC), American Cancer Society (RSG-09-022-01-CNE), and The Harry J. Lloyd Charitable Trust (RC). RC is an American Cancer Society Research Scholar. No potential conflicts of interest exist.
Figure 1 Introduction of BrafV600E or N-RASQ61K activates Stat3-PAX3 signaling in melanocytes
Genetically engineered human melanocytes (hTERT/p53DD/CDK4(R24C)) were infected with Ad-N-RASQ61K, Ad-BrafV600E or Ad-GFP. RNA and protein were collected at 24 hr after infections. (A) The mRNA expression of PAX3 was measured by quantitative RT-PCR and normalized to GAPDH. Results are expressed as the mean of the experiment done in triplicate ± SEM. Induction is calculated relative to PAX3 levels in vehicle-treated cells. (B) Protein expressions of Stat3, phospho-Stat3 and PAX3 were analyzed by western blot along with tubulin, which served as a loading control.
Figure 2 Stat3 is activated in melanoma cells with acquired resistance to vemurafenib
Sensitive and resistant A375 and UACC62 melanoma cells were stimulated by different doses of vemurafenib as indicated. Total protein was collected 6 hr after stimulation. Protein expressions of phospho--ERK1/2, Stat3, phospho-Stat3 and PAX3 were analyzed by western blot along with tubulin, which served as a loading control.
Figure 3 Overexpression of PAX3 or Stat3 inhibits the response of melanoma cells to vemurafenib
A375 and UACC62 parental cells with pcDNA-3.1-Stat3-CA plasmids or PECE-PAX3 plasmids introduction were stimulated with different doses of vemurafenib as indicated. Total protein was collected 6 hr after stimulation. Protein expressions of Stat3 and PAX3 were analyzed by western blot along with tubulin, which served as a loading control. (A) A375 cells and (B) UACC62 cells. (C) Melanoma cell growth was assessed by MTT assays. Relative growth (RG) was calculated as the ratio of treated to untreated cells at each dose for each replicate.
Figure 4 Resistant melanoma cellular growth was inhibited after silencing PAX3 or Stat3 and vemurafenib treatment
A375 and UACC62 resistant cells stably expressing control shRNA (shScr), shStat3 or shPAX3 were stimulated with different doses of vemurafenib as indicated. Total protein was collected 6 hr after stimulation. Protein expressions of Stat3 and PAX3 were analyzed by western blot along with tubulin, which served as a loading control. (A) A375R cells and (B) UACC62R cells. (C) Melanoma cells were infected with shPAX3, shStat3 or control virus and after 48 hrs, cells were subjected to MTT assays to evaluate the relative cell numbers. Relative growth (RG) was calculated as the ratio of treated to untreated cells at each dose for each replicate.
Figure 5 Vemurafenib induces FGF2 secretion
(A) Levels of FGF2 were measured in resistant melanoma cells. FGF2 levels in growth media of cultured parental and resistant melanoma cells, growing at 80% confluence in serum-free medium were examined by ELISA. FGF2 is induced by vemurafenib treatment in vitro. (B) Human primary keratinocytes and human primary fibroblast were stimulated by different doses of vemurafenib as indicated. FGF2 levels were measured by ELISA in culture media 24 hr after stimulation. Results are expressed as the mean of the experiment done in triplicate ± SEM. Induction is calculated relative to FGF2 levels in vehicle-treated cell media. (C) Schematic diagram of the FGF2-Stat3-PAX3 signaling pathway.
Figure 6 Inhibition of Stat3 overcomes the acquired resistance to vemurafenib in resistant melanoma cells
(A) M263R and M249R melanoma cells stably expressing control shRNA (shScr), shStat3 or shPAX3 were stimulated different doses of vemurafenib as indicated. (C) Sensitive and resistant A375 and UACC62 melanoma cells were stimulated with 5.0μm WP1066. Total protein was collected at 6 hr after stimulation. Protein expression of Stat3 and phospho-Stat3 were analyzed by western blot along with tubulin, which served as a loading control. A375R and UACC62R melanoma cells were stimulated with different doses of vemurafenib (B), WP1066 (D) or both (E) as indicated. Melanoma cell growth was assessed by MTT assays. Relative growth (RG) was calculated as the ratio of treated to untreated cells at each dose for each replicate (*p< 0.01; **p<0.05). A375 and UACC62 resistant cells with PECE-PAX3 plasmids were stimulated with vemurafenib and/or WP1066 as indicated. (F) Total protein was collected 6 hr after stimulation. Protein expression of phospho-Stat3 and PAX3 were analyzed by western blot along with tubulin, which served as a loading control. (G) Cells were subjected to MTT assays to evaluate the relative cell numbers. Relative growth (RG) was calculated as the ratio of treated to untreated cells at each dose for each replicate (*p< 0.01).
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Editorial
COVID-19’S IMPACTS ON HOUSING MARKETS: INTRODUCTION
Schwartz Amy Ellen a
Wachter Susan b⁎
a Robert F. Wagner Graduate School of Public Service, New York University, New York, NY, USA
b Penn Institute for Urban Research, The University of Pennsylvania, Philadelphia, PA, USA
⁎ Corresponding author.
13 12 2022
13 12 2022
101911© 2022 Elsevier Inc. All rights reserved.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
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pmcThis special issue features papers on the short- and long-term impacts of the COVID-19 pandemic on housing markets. Beyond short-run effects associated with an economic downturn and contagion fears, policy interventions have had additional impacts, as have technology shifts associated with the pandemic. The papers in this volume describe these effects, using innovative data techniques to describe real time and longer run outcomes. One effect of the pandemic is an increase in the demand for housing associated first with the public health measures of the pandemic such as social distancing and quarantining, and then with the widespread adoption of work from home technology, spurred by the pandemic. This may be a lasting effect as some expansion in remote work is likely to persist, even as the pandemic passes, leaving transformed housing markets and changed residential location decisions. The unprecedented rises in housing prices and rents, due to work from home technology, along with fiscal and monetary policy interventions during the pandemic, have contributed to affordability declines reaching a 30-year low.
The immediate negative effect of the pandemic on economic output, as well as fears of ongoing declines, decreased housing demand. “Behavioral changes in the housing market before and after the Covid-19 lockdown,” by Andre Anundsen, Erling Røed Larsen, Leif Anders Thorsrud, and Bjørnar Kivedal, draws on daily transaction and hourly bidding data from Norway to identify how housing markets reacted to news of the pandemic, from the onset in the beginning of March 2020 to the March 12 lockdown, and the reopening on April 20, 2020. The authors find that prices fell immediately and that nearly half of the fall in prices occurred prior to the lockdown, an effect which was entirely reversed upon reopening. The article demonstrates the correlation between daily fluctuations in public sentiment and otherwise unexplained daily house price changes.
As the pandemic spread, so did fears of contagion which spurred demands for social distancing and moves to less dense living arrangements, often in outlying areas. The demand for increased living space may have been well founded, as showed by Ingrid Ellen, Sherry Glied and Renata Howland in “Demons of Density: Do Higher-Density Environments Put People at Greater Risk of Contagious Disease?”. Using a broad cross-section of Medicaid claims data, this article provides evidence that household size, and therefore crowding, correlates to increased hospitalization rates from COVID-19, while population density bears no such correlation. The evidence on this critical question for public health is that density in itself did not contribute to disease, but crowding did. Importantly, the authors also show that those experiencing housing instability and living in institutional settings experienced more severe disease.
Major housing market effects were associated with the pandemic. “Stuck at Home: Housing Demand During the COVID-19 Pandemic,” by James Graham, William Gamber, and Anirudh Yadav, shows how the pandemic resulted in a joint increase in the amount of time households spent at home as well as in their share of expenditures for at-home consumption. Drawing on data from across the United States, the authors demonstrate that these time and expenditure shifts were the result of the increased share of demand for goods consumed at home as well as for the home itself. Faster acceleration in housing prices is observed in those counties where households spent more time at home. A key finding is that nearly half of the increase in house prices in 2020 can be attributed to the stay-at-home demand phenomenon, while lower mortgage rates caused a one-third rise and government stimulus explained a proportionally smaller amount. The authors also show that while the increased demand largely stemmed from young households and first-time homebuyers, this same segment was crowded out from the market by the resulting increase in housing prices.
Such effects on housing prices were not unique to the U.S. market. Drawing on daily data on UK housing price listings, Baptiste Meunier, Jean-Charles Bricongne, and Sylvain Pouget analyze the supply-side mechanics of the housing market during the pandemic. In “Web Scraping Housing Prices in Real-time the Covid-19 Crisis in the UK,” the authors assess seller sentiment from fluctuating listing prices, match these data to transaction prices, and show how such web-scraped data can be used to nowcast housing prices. During the lockdown, sellers’ listing prices remained high relative to transaction prices, causing an initial freezing of the market due to the “wait-and-see” behavior of sellers, but the margin dropped quickly after lockdown ended and prices rose. They also show that post-lockdown listing prices declined in London but increased in outlying regions, effects which are consistent with longer run incentives to relocate to less expensive markets as demand rose with increased working from home.
While the aggregate data show a rise in house prices after the short period of economic downturn, economic distress continued to depress rents. “Landlords’ Rental Businesses Before and After the COVID-19 Pandemic: Evidence from National Cross-Site Survey,” by Elijah de la Campa and Vincent Reina, investigates how rents and landlord behavior changed during the pandemic. The paper uses a survey of several thousand rental property owners in US cities to determine the impact of the pandemic on landlords’ rent collection and business behavior. They show that yearly rent collection was down significantly throughout 2020 relative to 2019 and that an increasing number of owners had a large share of their portfolio behind on rent. Further, landlords granted payment extensions and forgave rent payments to a greater extent during the pandemic than previously, but also exercised disinvestment practices and greater rates of eviction, missed mortgage payments, and property sales. These changes disproportionately affected communities of color and pose an ongoing threat post-pandemic. The impact of Covid-19 on rental markets resulted in the adoption of several ameliorative policies including national eviction moratoria and the Emergency Rental Assistance Program, but these only partially mitigated the underlying stresses (Goodman et al. 2023).
Major policy interventions to assist the homeownership market, including federal government policies to aid the homeownership market, had immediate positive effects. These policies included a forbearance program, as well as monetary and fiscal expansion., which contributed to the substantial rise in housing prices. Using data from the forbearance program, “Single Borrower VS Co-Borrowers in the Pandemic: Evidence from Mortgage Forbearance and Performance,” by Laurie Goodman and Jun Zhu, analyzes how single and co-borrowers reacted to the forbearance program. They find that single borrowers were more likely than co-borrowers to opt for forbearance. As a result, forbearance provided greater assistance to single borrowers in overcoming delinquency status than co-borrowers. These findings add to the literature on the efficacy of quickly implemented policies to assist the owner-occupied market (Gerardi et al. 2022).
Migration to take advantage of work from home (WFH) technology and the lower cost of living arbitrage is a long run outcome of Covid-19. “Intercity Impacts of Work-from-Home with Both Remote and Non-Remote Workers,” by Jan Brueckner and S. Sayantani, shows the likely effects on the demand for housing. WFH enables employees to relocate to reduce commuting costs, making suburban residential locations more attractive, increasing population and housing prices in outlying areas {Brueckner, Kahn and Lin (2022). When cities differ in productivity, a shift to WFH causes some workers to relocate from high-productivity cities to low-productivity cities with cheaper housing while maintaining their jobs in the origin city. When cities differ instead in amenities, this leads to the opposite relocation pattern, with some workers relocating from low-amenity to high-amenity cities despite their expensive housing, while keeping their original jobs. Brueckner and Sayantani (2023) generalizes this two-city one-worker model by incorporating non-remote workers who must live in the city in which they work. In each scenario, the population relocation of non-remote workers is in the opposite direction to that of remote workers, mitigating overall outcomes. The paper also reviews recent empirical findings which provide evidence showing housing prices are rising faster in suburbs and remote locations then in center cities (Gupta et al., 2021; Bloom and Ramani, 2021; and Althoff et al., 2021).
While these papers report early findings during and in the aftermath of the pandemic, they and others in the burgeoning literature imply longer run effects as well. WFH, along with continued development of supportive new technology will persist (Morris et al. 2021, Bloom et al. 2021, Wachter 2022). While WFH expands the geographical range of location, the increase in the demand for housing associated with greater space needs and the inter- and intra-city demand increases raised housing prices. Hence, the significant rise in house prices and affordability pressures are not simply a bubble reversible with monetary policy tightening (Kmetz et al. 2022, Graham et al. 2023, Acolin and Wachter 2022).
Uncited References
(Meunier et al., 2023, Anundsen et al., 2023, de la Campa and Reina, 2023, Ellen et al., 2023), Brueckner, 2020)
==== Refs
References
Acolin A Wachter S. Homeownership for the Long Run Journal of Comparative Urban Law and Policy 5 1 2022 274 296
Althoff The Geography of Remote Work. NBER Working Papers National Bureau of Economic Research 2022
Anundsen A Behavioral changes in the housing market before and after the Covid-19 lockdown Journal of Housing Economics 2023 THIS VOLUME insert volume #; insert page #
Bloom N COVID-19 Shifted Patent Applications toward Technologies that Support Working from Home 111 2021 Becker Friedman Institute University of Chicago 263 266
Brueckner J Sayantani S. Intercity Impacts of Work-from-Home with Both Remote and Non-Remote Workers Journal of Housing Economics 2023 THIS VOLUME insert volume #; insert page #
Brueckner J A new spatial hedonic equilibrium in the emerging work-from-home economy? American Economic Journal: Applied Economics, forthcoming 2020
de la Campa E Reina R Landlords’ Rental Businesses Before and After the COVID-19 Pandemic: Evidence from National Cross-Site Survey Journal of Housing Economics 2023 THIS VOLUME insert volume #; insert page #
Ellen Demons of Density: Do Higher-Density Environments Put People at Greater Risk of Contagious Disease? Journal of Housing Economics 2023 THIS VOLUME insert volume #; insert page #
Gerardi K Lessons Learned from Housing Policy during COVID-19 Edelberg W Recession Remedies. Brookings; 2022 2022 163 213
Goodman L Zhu J. Single Borrower VS Co-Borrowers in the Pandemic: Evidence from Mortgage Forbearance and Performance Journal of Housing Economics 2023 THIS VOLUME insert volume #; insert page #
Graham J Stuck at Home: Housing Demand During the COVID-19 Pandemic Journal of Housing Economics 2023 THIS VOLUME insert volume #; insert page #
Gupta Flattening the Curve: Pandemic-Induced Revaluation of Urban Real Estate Journal of Financial Economics 146 2 2022 594 636
Kmetz A Remote Work and Housing Demand Federal Reserve Bank of San Francisco Economic Letter 2022
Meunier B Web Scraping Housing Prices in Real-time the Covid-19 Crisis in the UK Journal of Housing Economics 2023 THIS VOLUME insert volume #; insert page #
Morris D The Work-from-Home Technology Boon and its Consequences. NBER Working Papers National Bureau of Economic Research 2021
Ramani A Bloom N. The Donut Effect of COVID-19 on Cities. NBER Working Papers National Bureau of Economic Research 2021
Wachter S. How Remote Work is Affecting Real Estate Markets World Financial Review 2022
| 0 | PMC9744473 | NO-CC CODE | 2022-12-15 00:01:48 | no | J Hous Econ. 2022 Dec 13;:101911 | utf-8 | J Hous Econ | 2,022 | 10.1016/j.jhe.2022.101911 | oa_other |
==== Front
Int J Infect Dis
Int J Infect Dis
International Journal of Infectious Diseases
1201-9712
1878-3511
Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
S1201-9712(22)00648-8
10.1016/j.ijid.2022.12.011
Article
Hospital at Home treatment with Remdesivir for patients with COVID-19: Real life experience
Pereta Irene 1
Moracho Alma 2
López Néstor 2
Ibáñez Begoña 1
Salas Cristina 3
Moreno Laura 1
Castells Eva 1
Barta Ariadna 3
Cubedo Marta 4
Coloma Emmanuel 157
Cardozo Celia 157
García-Pouton Nicole 157
Ugarte Ainoa 127
Rivero Andrea 6
Bodro Marta 157
Rico Verónica 157
García Laura 1
Altés Jordi 1
Seijas Nuria 1
Nicolás David 127⁎
1 Hospital at Home Unit, Medical and Nurse Direction, Hospital Clínic Barcelona, Barcelona, Spain
2 Internal Medicine Service, Hospital Clínic Barcelona, Barcelona, Spain
3 Nurse Direction, Hospital Clínic Barcelona, Barcelona, Spain
4 Genetics, Microbiology and Statistics Department, Statistics Section, Biology Faculty, Universitat de Barcelona
5 Infectious Diseases Service, Hospital Clínic Barcelona, Barcelona, Spain
6 Haematology Service, Hospital Clínic Barcelona, Barcelona, Spain
7 University of Barcelona, Barcelona, Spain
⁎ Corresponding author: Hospital Clinic, Villarroel 170, 08036, Barcelona., Phone number: +34-932272030//+34610560336.
13 12 2022
13 12 2022
23 2 2022
6 12 2022
7 12 2022
© 2022 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Background
: Access and appropriateness of therapeutics for COVID-19 vary due to access or regulatory barriers, severity of disease, and for some therapies, stage of the pandemic and circulating variants. Remdesivir has shown benefits in clinical recovery and is the treatment of choice for selected patients, both hospitalized and non-hospitalized, in main international guidelines. The use of Remdesivir in alternatives to conventional hospitalization such as Hospital at Home units remain incompletely explored. In this work, we aim to describe the real-life experience of outpatient remdesivir infusion for COVID-19 in a Hospital at Home unit.
Methods
: We selected all the consecutive patients receiving remdesivir from a prospective cohort of 507 COVID-19 patients admitted at a Hospital at Home unit. Admission criteria included COVID-19 with FiO2 requirement under 0.35 and respiratory rate under 22 rpm. Patients were daily assessed in-person by a nurse and a physician.
Results
: Two-hundred thirty-six patients admitted in HaH received remdesivir, from whom 172 were treated at home. Only 2% presented any adverse event related to the infusion, all of them mild. HaH saved 1416 day-beds, with only 5% of the patients requiring transfer back to hospital.
Conclusions
: Remdesivir infusion in Hospital at Home units seems to be a safe and efficient alternative to conventional hospitalization for treating non-severe COVID-19 patients.
Keywords
COVID-19
Remdesivir
outpatient
Hospital at Home
management
outcomes
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pmcBackground
The COVID-19 pandemic has posed a serious challenge to health systems around the world. Alternatives to conventional hospitalization have been proposed in order to avoid hospital collapse and prioritize those requiring higher intensity of care [1]. Strategies aiming to minimize conventional hospital admission include out-hospital management in repurposed Hospital at Home (HaH) units [2, 3] or in ad hoc monitoring programs[4], with a great heterogeneity in the admission criteria for the different programs in different settings, some of them oriented to early detection of complications in mild COVID-19 patients[4, 5] while others aim to fully substitute hospital admission in non-severe COVID-19 patients[6]. These last strategies, aiming to provide an acute, hospital-level care at home, should therefore ensure a clinical quality and safety standard, comparable to conventional hospitalization, including the administration of gold-standard treatments for COVID-19.
Since the onset of the pandemic, several pharmacological treatments have been assayed with unequal results. Remdesivir, is an intravenous antiviral that has shown benefits in reducing the length of stay in patients with low flow oxygen requirements[7], while a recent multicentric observational cohort study has shown a reduction in mortality at 14 and 28 days in patients receiving remdesivir[8]. Early this year, a randomized clinical trial showed that the use of early remdesivir treatment (in the first 7 days since symptoms onset) in symptomatic non-hospitalized patients with at least one risk factor for severe COVID-19 development resulted in 87% lower risk of hospitalization or death versus placebo[9]. Given this evidence, remdesivir is used worldwide as standard of care treatment for COVID-19 patients requiring hospital admission and in some selected non-hospitalized patients in order to prevent disease progression[10].
In the present work we aim to describe real-life experience in the use of remdesivir in the out-hospital setting, specifically in a HaH Unit, for non-severe COVID-19 patients.
Methodology
Hospital Clinic of Barcelona is a 750-bed public, tertiary teaching hospital which serves 560,000 people in the metropolitan area of Barcelona. The Hospital Clinic's HaH Unit started providing hospital-level, specialized, health care at patients’ homes in 1996. Nowadays has a maximum capacity of 60 patients, with approximately 1,800 patients treated per year. Since March 2020, the Hospital Clínic HaH Unit has been adapted for also managing and treating COVID-19 patients at home as well as non-COVID19 patients. Criteria for COVID-19 patients transfer to HaH included: Home conditions allowing patient isolation from cohabitants; respiratory rate <22 rpm and oxygen saturation >95% with FiO2 <0.35[6]. Intervention during HaH admission included daily medical and nurse visit, around the clock call centre, usual tests at home (blood tests, cultures, EKG and ultrasound) and oral and intravenous treatment. An emergent circuit for transfer back to hospital was organized, for further test (e.g. chest X-ray), emergent assessment at the Emergency Department or planned conventional hospitalization if required. For the purpose of this study, we included every COVID-19 patient admitted in HaH from July 2020 to June 2022.
National and local pharmacological treatment protocols were followed. Since May 2020 remdesivir was included as standard of care for patients. Following national protocols, the indication for remdesivir was initially for patients with ≤7 days since symptoms onset, pneumonia and with respiratory failure (air room saturation <93% or PaO2/FiO2 <300 mmHg><300 mmHg. Since September 2020, the indication was widened to patients with ≤8 days of symptoms. In January 2022 because of new published evidence[9], remdesivir was also indicated in patients at high risk of progression with ≤7 days of symptoms as a 3-day course of treatment[11]. Remdesivir dosage was 200 mg daily the first day followed by 100 mg daily 2-4 more days. Remdesivir at home was infused by a registered nurse through a peripheral venous catheter over 45 minutes.
Statistical analysis: Summary statistics of quantitative characteristics were presented with median and interquartile range (IQR) and compared between groups with Student's t-test. Qualitative variables were described with absolute frequency and percentage and compared between groups with Chi-squared exact test. Descriptive analysis was performed using SPSS for Windows, version 23.0 (SPSS Inc. Chicago. Illinois. USA). All tests were two-tailed with confidence level set at 95%.
Results
During the two-year period of the study, a total of 3192 patients were admitted in the HaH Unit of Hospital Clínic Barcelona. From them, 15.9% (n=507) patients were diagnosed with COVID-19, which represents a 10.7% of the total of COVID-19 patients admitted in the Hospital Clinic in the same period.
From the total of COVID-19 patients admitted in the HaH Unit, 69.9% (n=354) were patients previously admitted in the Hospital Clínic COVID-19 ward and transferred at some point to the HaH unit. 23.1% (n=117) of the patients were admitted to the HaH unit from the Emergency Department and 7.1% (n=36) were admitted directly to the HaH unit from their homes after General Practitioner (GP) or specialist referral (Figure 1 ).Figure 1 Alluvial graphic showing patient allocation at each step of the process.
Figure 1
A total of 46.7% (n=236) of the HaH COVID-19 patients received remdesivir at any point of the disease course, composing our present study cohort. From this cohort, 27.2% (n= 64) received the full treatment at hospital before HaH admission (Hospital-based treatment group), 22.2% (n=52) receiving the full course of remdesivir at home (Home-based treatment group), and 50.6% (n=120) starting the treatment at hospital and finishing at least one dose at home (mixed treatment group). In this last group, median time from hospital admission to HaH transfer was 3 days (IQR 2-3), and patients received a median of 2 (IQR 1-3) doses of remdesivir prior to HaH transfer, while patients receiving full treatment at hospital ward were transferred to HaH at a median of 7 days (IQR 4-11) after hospital admission (p<0,001) (Table 1 ).Table 1 Clinical characteristics and outcomes of patients receiving full remdesivir treatment at home versus at hospital versus mixed home-hospital treatment.
Table 1 Global (n=236) Hospital-based treatment group (n=64) Home-based treatment group (n=52) Mixed treatment group (n=120) P
Age years old, median (IQR) 63 (51.5-72) 59 (51-70) 66.5 (51-74.5) 64 (51.3-74) 0.260
Male sex, n (%) 153 (64.6) 47 (73.4) 28 (53.8) 77 (64.2) 0.028
Active smoker, n (%) 25 (10.1) 5 (7.8) 4 (7.7) 16 (13.3) 0.488
Past smoker, n (%) 60 (25.3) 13 (20.3) 15 (28.8) 31 (25.8) 0.556
Hypertension, n (%) 108 (45.6) 26 (40.6) 34 (65.4) 48 (40) 0.006
Immunosuppression, n (%) 114 (48.1) 2 (3.1) 32 (65.4) 33 (27.5) <0.001
Charlson index score, median (IQR) 2 (1-4) 1 (1-3) 3 (2-4.75) 2 (1-4) 0.012
ICU prior to HaH transfer, n (%) 27 (11.4) 25 (39) - 2 (1.7) <0.001
Days from symptoms onset to admission, median (IQR) 5 (3-7) 5.5 (3-7)* 3 (1-4)* 6 (3-8)*
Days from symptoms onset to remdesivir initiation, median (IQR) 5 (3-8) 6 (4-8)* 3 (2-5)* 6 (4-8)*
Remdesivir side-effect, n (%) 5 (2.1) 1 (1.6) 2 (3.9) 2 (1.7) 0.612
Remdesivir discontinuation, n (%) 1 (0.4) 1 (0.8) 0 (0) 0 (0) 0.078
Length of global stay, median (IQR) 10 (7-13) 14 (10.3-18.75)* 6 (5-10)* 9 (7-11)
Length of in-hospital stay, median (IQR) 3 (1-6) 7 (5-11)* 0 (0-1)* 3 (2-3)*
Length of HaH stay, median (IQR) 6 (5-8) 6 (4.3-8) 6 (4.3-7.8) 6 (5-8)
Oxygen supplementation requirements, n (%) 150 (63.8) 60 (93.8) 16 (30.7) 75 (63) <0.001
X-ray performed, n (%) 203 (86) 64 (100) 29 (55.7) 110 (91.7) <0.001
Pneumonia total cohort, n (%) 165 (69.9) 61 (95.3) 17 (32.7) 87 (72.5) <0.001
Pneumonia among those with chest x-ray, n (%) 165 (81.3) 61 (95.3) 17 (58.6) 87 (79.1) 0.023
Transfer back to hospital from HaH, n (%) 10 (4.3) 4 (6.3) 1 (1.9) 5 (4.2) 0.008
ICU admission after HaH transfer 4 (1.7) 2 (3.1) 0 (0) 2 (1.7) 0.060
Death during admission, n (%) 1 (0.4) 1 (1.6) 0 (0) 0 (0) 0.261
30-day readmission, n (%) 20 (8.5) 5 (7.9) 5 (9.6) 10 (8.3) 0.945
30-day death, n (%) 1 (0.4) 0 (0) 0 (0) 1 (0.8) 0.618
⁎ p<0.05 when comparing HaH-based group with the other two groups separately.
Regarding baseline characteristics for the 236 remdesivir patients, globally 64.1% (n=152) were men, with a median age of 63 years old (IQR 51.5-72). 45.6% (n=108) had a history of hypertension, while 10.5% (n=25) were active smokers and 25.3% (n=60) past smokers. Median Charlson index score was 2 (IQR 1-4), with a 10.8% presenting a Charlson index score over 6 points. 28.3% (n=67) were immunocompromised, mainly drug related (Table 1).
When comparing the clinical characteristics among the three groups (hospital-based treatment, HaH-based treatment, and mixed treatment) we observe that patient's gender in the HaH-based treatment group is more balanced (54% of men versus 73% and 64% in the hospital-based and mixed groups, p=0.028), with a higher Charlson index score (3 vs 1 and 2, p<0.001 and p=0.181 respectively), and with a higher proportion of immunocompromised patients (65.4% in the Home-based vs 3.1% in the Hospital-based and 27.5% in the mixed group respectively, p<0.001).
Patients in the HaH-based treatment were admitted earlier in the course of the disease, with a median time from symptoms onset to admission of 3 days (IQR 1-4) versus 5.5 days in the Hospital-based group (p=0.006) and 6 days in the mixed group (p=0.005). Also, treatment with remdesivir was started earlier, with a median days from symptoms onset to treatment of 3 days (IQR 2-5), while in the hospital-based group the treatment was delayed until 5.5 (3-7) days (p<0.001), and until 6 (4-8) days in the mixed group (p<0.001).
Radiological confirmed pneumonia was present in 70% (n=165) of the cases. 95% (n=61) of the Hospital-based treatment patients and 73% (n=87) of the mixed-group patients had a pneumonia in the x-ray while only 33% (n=17) of the fully HaH-based treatment patients presented a pneumonia confirmed by x-ray, although it should be considered that only 56% (n=29) of the HaH-based treatment patients had an x-ray taken. Regarding oxygen supplementation, 94% (n=60) of the Hospital-based patients required oxygen supplementation at any point (including HaH), while only a 31% (n=16) of the HaH-based patients required oxygen at home. 39% (n=25) of the Hospital-based patients and only 1.7% (n=2) of the mixed groups required ICU admission prior to HaH transfer.
Remdesivir infusion was, in general, well tolerated. Only 2% (n=5) patients were reported to present a possible adverse event during or after the infusion, without differences between groups. Side-effects were mild (one of them reported feeling light-headed, one presented sweating and cough, one presented with emesis and the other two presented hypotension solved with postural measures). In one of the Hospital-based patients remdesivir was discontinued due recurrent vomiting. As this is not a placebo-controlled trial, side-effect causality cannot be distinguished between remdesivir versus the underlying COVID-19, as any potential excess of any event observed above that expected cannot be determined without a control.
As for the outcomes, 4% (n=10) of the patients required transfer back to the hospital ward after HaH admission, of which 4 patients were from the Hospital-based group (representing a 6% of the group), 5 patients were in the mixed group (4%) and only 1 patient (1.9%) from the Home-based group (p=0.008). From the 10 patients transferred back to hospital, 4 (1.7%) required ICU admission. Only 1 patient (0.4%) died during admission, belonging to the Hospital-based group. Global median length of stay (combining hospital and HaH) was 10 days (IQR 7-13), being 6 days (IQR 5-10) in the HaH-based group vs 14 days (10-19) in the Hospital-based (p<0.001) and 9 days (IQR 7-11) in the mixed group (p=0.082). HaH admission length was comparable for the three groups, 6 days (IQR 4-8) in the HaH-based group versus 6 days (IQR 4-8) in the Hospital-based (p=0.205) and 6 days (5-8) in the mixed-treatment group (p=0.865).
Readmission at 30 days post-discharge was necessary in 20 patients (8.5%), with similar rates among groups (7.9% in the Hospital-based, 8.3% in the mixed group and 9.6% in the Home-based group. One patient in the mixed group (0.8%) died in the 30 days post-discharge.
Discussion
Remdesivir efficacy and use in treating hospitalized COVID-19 patients is supported by some strong evidence showing potential benefit in shortening the hospital stay and reducing all-cause mortality, particularly when started promptly, in hospitalized patients requiring conventional oxygen supplementation with or without corticosteroids and its use is recommended by the principal international guidelines[10, 12]. In non-hospitalized patients, treatment with remdesivir is indicated only in those patients at risk for disease progression. For those without limiting drug-drug interactions, oral treatment with ritonavir-boosted nirmatrelvir is also considered an equally valid alternative in the subsetting of patients not requiring hospitalization, with data showing similar efficacy to that of remdesivir[14]. Bebtelovimab, a SARS-CoV-2 RBD-specific antibody, has shown in vitro action against all circulating variants, but pre-print evidence [15] has not yet been peer-reviewed, and therefore is reserved as a second line in non-hospitalized patients[16]. Finally, molnupinavir is an oral antiviral mutagen with activity against SARS-CoV-2, but with a lower clinical efficacy in preventing adverse events in clinical trials compared to remdesivir or ritonavir-boosted nirmatrelvir[17]. Because of remdesivir requiring IV infusion 3 to 5 days, both in hospitalized and non-hospitalized patients, it is necessary to promote the standardization of alternatives to conventional hospitalization, assuring safety and clinical quality in the outpatient setting, such as Hospital at Home units.
The deployment of alternatives to conventional hospitalization to manage COVID-19 has flourished during the past two years, including the adaptation of HaH units to also manage COVID-19 patients as one of the most popular due to the pre-existence of those units, and their experience in other acute, severe conditions. These units should therefore be able to provide comparable standard of care and treatments as in conventional hospitalization, including intravenous treatments such as remdesivir.
In this work we present a cohort of 236 patients receiving remdesivir admitted in a Hospital at Home unit. These patients are divided into three groups according to the allocation in the moment of remdesivir administration (Hospital-based treatment, Home-based treatment, and mixed treatment for those receiving at least one dose at hospital and/or at least one dose at home).
Patients receiving remdesivir in our cohort were middle-aged with low comorbidities, being noticeable that the Charlson index score and the proportion of immunocompromised patients in the Home-based group is higher than the other two groups (median Charlson of 3 versus 1 and 2, and 65% of immunocompromised versus 27% and 3% respectively). This fact is explained by the launch of an early-treatment strategy in immunocompromised patients directly from their homes from January 2022 forward (data published elsewhere[11]). This fact also might partially explain the lower medians in days from symptoms onset to admission and to remdesivir treatment in the Home-based group, showing that a well-planned HaH program can be even more agile than a brick-and-mortar hospital in treating COVID-19 patients, particularly when oversaturated during COVID-19 waves.
Patients in the Hospital-based group presented a more severe COVID-19 initially, with a higher proportion of bilateral pneumonia, oxygen requirements and ICU admission rate. Furthermore, patients in the mixed treatment group were more similar in clinical characteristics to the Home-based group, and transfer to HaH was 3 days sooner as median than the Hospital-based group. This may indicate that some of the patients in the mixed group might had benefit from a direct admission to HaH from the ED or GP, highlighting the importance of a good communication between the different levels of attention and of establishing clear protocols on HaH admission criteria.
Only 5 patients, representing 2% of the cohort, were reported to present any possible adverse event during or after remdesivir infusion, all of them being mild except one patient in whom remdesivir was interrupted. This real-life data complements the safety information reported in the PINETREE trial, in which 16.5% of the patients received remdesivir at least one dose at home. In PINETREE, a 3.4% excess of adverse events were attributed to remdesivir (25/283, 8.8% in placebo compared to 34/279, 12.2 % on remdesivir)[9]. Together, this supports the safe use of remdesivir in the outpatient setting, although the limitations of the present study, without placebo comparator, precludes determination of whether side-effects were truly related to remdesivir treatment versus underlying COVID-19. Regarding outcomes, only 4.3% of the patients required transfer back to hospital, which can be considered a fairly low percentage if compared to other cohorts. In the Permanent Kaiser Southern California preliminary report, with 13055 patients monitored at home, a 10% rate of readmissions is reported, although in this program patients were self-monitored, and the objective was to detect early complications rather than provide a full hospital admission substitution[4]. In other similar programs in our country, transfer back to hospital rates are between 6% and 22%[3, 18] Only one patient in our cohort died during the admission, after hospital transfer back from HaH. Finally, it is notable that patients in the Hospital-based treatment group and in the mixed treatment group experienced a median 6 day reduction in their overall hospital stay, which were spent in HaH instead of occupying a hospital bed, entailing a saving of approximately 1416 bed-days in hospital.
This work has some limitations. First, we report observational data, and therefore extrapolation and reproducibility might be limited. Secondly, heterogeneity in COVID-19 patients along the different waves may complicate the extension of the results to other centres. Despite these shortcomings, this report is among the first to analyse the real-life experience of infusing remdesivir in the home setting, in the context of a pre-established, experienced Hospital at Home program. This proof of concept might be of interest especially to decision-makers, emphasizing the potential decentralization of COVID-19 care from hospitals. Also, these results may encourage the expansion of HaH programs, aiming to improve efficiency and patients’ comfort, while reducing hospital overload during COVID-19 peaks, as well as costs and nosocomial infections.
In conclusion, our work shows that it is feasible to infuse remdesivir at home, with the same quality and safety standards as in the hospital setting. Hospital at Home units might be of significant importance in coping with high incidence peaks of the pandemic, by decongesting hospitals and facilitating the allocation of more severe patients in a conventional hospital bed. Our work shows that HaH units can safely provide the international guideline consensus standard of care to COVID-19 patients in a patient-centred environment such as home. COVID-19 patients fulfilling criteria for HaH admission (home conditions allowing patient isolation; respiratory rate <22 rpm and oxygen saturation >95% with FiO2 <0.35) should be therefore treated at home. In the future, the expansion in the use of oral antivirals may ease the early treatment of high-risk patients, although HaH units may still play a role in supplying the treatment and monitoring the evolution of patients.
Declarations
Ethics approval and consent to participate
The Ethical Board of the Hospital Clínic evaluated and approved the collection of data (HCB.2020.0443). A waiver for informed consent was granted due to the state of pandemic emergency.
Consent for publication
Not applicable.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare that they have no competing interests
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Data have been generated as part of the routine work of the Hospital Clínic's Hospital at Home Unit.
Authors' contributions
DN and IP conceived the study and led the protocol design. DN wrote the first draft of the manuscript. AM, CS and NL lead the protocol implementation. BI, LM, EC, AB, and EC contributed to study design and/or implementation. MC, CC, AR, AU, NG conducted the data analysis. MB, VR, JA, NS and DN had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors read and approved the final manuscript.
Acknowledgments
Not applicable.
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[8] Mozaffari E, Chandak A, Zhang Z, et al. Remdesivir treatment in hospitalized patients with COVID-19: a comparative analysis of in-hospital all-cause mortality in a large multi-center observational cohort. Clin Infect Dis. Epub ahead of print 1 October 2021. DOI: 10.1093/cid/ciab875.
[9] Gottlieb RL, Vaca CE, Paredes R, et al. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med 2022; 386: 305–315.
[10] National Institutes of Health. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines., https://www.covid19treatmentguidelines.nih.gov/ (2019, accessed 19 August 2022).
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[16] Iketani S, Liu L, Guo Y, et al. Antibody evasion properties of SARS-CoV-2 Omicron sublineages. Nature 2022; 604: 553–556.
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[18] Llorens P, Moreno-Pérez O, Espinosa B, et al. An integrated emergency department/hospital at home model in mild COVID-19 pneumonia: feasibility and outcomes after discharge from the emergency department. Intern Emerg Med 2021; 16: 1673.
Appendix Supplementary materials
Image, application 1
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ijid.2022.12.011.
| 36521589 | PMC9744477 | NO-CC CODE | 2022-12-15 00:01:48 | no | Int J Infect Dis. 2022 Dec 13; doi: 10.1016/j.ijid.2022.12.011 | utf-8 | Int J Infect Dis | 2,022 | 10.1016/j.ijid.2022.12.011 | oa_other |
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Biotechnol Rep (Amst)
Biotechnol Rep (Amst)
Biotechnology Reports
2215-017X
The Author(s). Published by Elsevier B.V.
S2215-017X(22)00076-5
10.1016/j.btre.2022.e00779
e00779
Research Article
Immunogenicity and Efficacy of Recombinant Subunit SARS-CoV-2 Vaccine Candidate in the Syrian Hamster Model
Shanmugaraj Balamurugan 1
Khorattanakulchai Narach 23
Paungpin Weena 4
Akkhawattanangkul Yada 4
Manopwisedjaroen Suwimon 5
Thitithanyanont Arunee 5
Phoolcharoen Waranyoo 23⁎
1 Baiya Phytopharm Co., Ltd, Bangkok, 10330, Thailand
2 Center of Excellence in Plant-produced Pharmaceuticals, Chulalongkorn University, Bangkok, 10330, Thailand
3 Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
4 Faculty of Veterinary Science, Mahidol University, Nakhon Pathom 73170, Thailand
5 Department of Microbiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
⁎ Correspondence: Tel: 662-218-8359; Fax: 662-218-8357
13 12 2022
13 12 2022
e0077916 10 2022
27 11 2022
11 12 2022
© 2022 The Author(s). Published by Elsevier B.V.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
SARS-CoV-2 causes devastating impact on the human population and has become a major public health concern. The frequent emergence of SARS-CoV-2 variants of concern urges the development of safe and efficacious vaccine against SARS-CoV-2 variants. We developed a candidate vaccine Baiya SARS-CoV-2 Vax 1, based on SARS-CoV-2 receptor-binding domain (RBD) by fusing with the Fc region of human IgG. The RBD-Fc fusion was produced in Nicotiana benthamiana. Previously, we reported that this plant-produced vaccine is effective in inducing immune response in both mice and non-human primates. Here, the efficacy of our vaccine candidate was tested in Syrian hamster challenge model. Hamsters immunized with two intramuscular doses of Baiya SARS-CoV-2 Vax 1 induced neutralizing antibodies against SARS-CoV-2 and protected from SARS-CoV-2 challenge with reduced viral load in the lung. These preliminary results demonstrate the ability of plant-produced subunit vaccine Baiya SARS-CoV-2 Vax 1 to provide protection against SARS-CoV-2 infection in hamsters.
Keywords
COVID-19
SARS-CoV-2
plant-produced subunit vaccine
receptor binding domain
protective immunity, hamster challenge
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pmcAbbreviations
ACE2 Angiotensin-converting enzyme 2
Alum Aluminum hydroxide
ANOVA Analysis of variance
BSL Biosafety level
COVID-19 Coronavirus disease 2019
CI Confidence interval
Dpi Days post infection
ELISA Enzyme-linked immunosorbent assay
Fc region Fragment crystallizable region
G Gram
GMT Geometric mean titer
IgG Immunoglobulin G
LOD Limit of detection
MN50 titer 50% microneutralizing titer
PBS Phosphate buffered saline
PFU Plaque forming units
RBD Receptor-binding domain
S Spike or surface glycoprotein
SARS-CoV Severe acute respiratory syndrome coronavirus
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2
SD Standard deviation
WHO World Health Organization
1 Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the global pandemic coronavirus disease (COVID-19), that has led to millions of infections with >6 million deaths worldwide [1]. The virus outbreak has caused a drastic impact on human health and global economy. SARS-CoV-2 belongs to the family Coronaviridae and are enveloped, positive-sense, single-stranded RNA viruses. Their genome encodes for both structural and nonstructural proteins [2, 3]. The main antigenic targets for neutralizing antibodies are the surface-exposed spike (S) glycoprotein present on the viral surface. The receptor-binding domains (RBDs) located in the S protein of SARS-CoV-2 interacts with cell surface receptor angiotensin-converting enzyme 2 (ACE2) mediating the viral entry into the host cell. Available reports in animal models showed that antibodies targeting against RBD or S protein correlate with protection. Anti-spike or RBD antibodies have been shown to cross-neutralize recently evolved SARS-CoV-2 variants [4], [5], [6], [7] .
Vaccination is the currently available long-term solution to prevent the illness and mortality associated with COVID-19. A variety of technologies have been explored to produce effective COVID-19 vaccines [8, 9] and several vaccines have been approved in many countries globally. Even though vaccines are available, the vaccination rate in many low-income countries are low due to the inequality in vaccine access and hence only a smaller number of people have received at least one dose of a vaccine in resource limited nations. In addition, the virus is emerging into new variants frequently with multiple spike mutations which may evade immunity acquired from past infection or vaccination. Hence safe, affordable, and effective vaccine that can protect against SARS-CoV-2 is highly essential to combat the pandemic.
We have previously reported that the plant-produced RBD-Fc based subunit vaccine adjuvanted with alum (Baiya SARS-CoV-2 Vax 1) induced robust anti-SARS-CoV-2 immune responses upon two intramuscular doses in mice and non-human primates [10]. Further, the vaccine has been shown to be safe, non-toxic in animal models and protects mice upon SARS-CoV-2 challenge [11]. In this study, we demonstrate the ability of Baiya SARS-CoV-2 Vax 1 to protect Syrian hamsters from SARS-CoV-2 challenge. We showed that the intramuscular vaccination induced neutralizing antibodies and there was a significant decrease in the level of infectious virus in the lungs of hamsters immunized with Baiya SARS-CoV-2 Vax 1. These results add to our preclinical data that the intramuscular injection of Baiya SARS-CoV-2 Vax 1 can protect hamsters against SARS-CoV-2 infection.
2 Materials and Methods
2.1 Ethical statement for laboratory animal care and use
All the animal experiments were carried out in accordance with institutional and national guidelines. Animal procedures complied with all relevant ethical regulations for animal testing and research and were approved by the Faculty of Veterinary Sciences, Mahidol University, Institutional Animal Care and Use Committee (FVS-MU-IACUC-protocol number MUVS-2020-07-30). All procedures throughout the study were designed to minimize animal suffering. Animal experiments are reported in compliance with the PHS policy on human care and use of laboratory animals. Mahidol University Institutional Biosafety Committee approved work with infectious SARS-CoV-2 virus strains under BSL3 and ABSL3 conditions
2.2 Adjuvants and excipients
Alhydrogel® adjuvant 2% (vac-alu-250) was procured from InvivoGen, USA. Vaccine excipients sucrose (107651) was purchased from Merck, Germany and glycine (PR0608) was obtained from Vivantis Technologies, Malaysia.
2.3 Vaccine formulation
Codon optimized gene sequence encoding for RBD-Fc fusion protein was subcloned into the plant expression geminiviral vector and transiently expressed in N. benthamiana. The infiltrated plant leaves were harvested, and the recombinant RBD-Fc protein was extracted and purified using Protein A affinity column chromatography (Expedeon, Cambridge, United Kingdom). The protein profiles of the purified antigen were analyzed with sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blotting analysis as described previously [10]. The candidate vaccine was prepared in phosphate-buffered saline (PBS) with alum adjuvant.
2.4 Challenge studies in Syrian hamsters
Female LVG golden Syrian hamsters (Mesocricetus auratus) approximately 6–8 weeks old were purchased from Beijing Vital River Laboratories (Beijing, China). Hamsters were housed in ABSL3 and were supplied with a standard diet and ad libitum access to autoclaved water.
Twelve hamsters were randomly divided into 2 groups of 6 per group and received either PBS (control) or 10 µg of vaccine (Figure 1 ). Animals were intramuscularly immunized at thigh muscle of hindleg with 50 µl of each test samples for 2 doses with 3-week interval (on day 0 and day 21). Blood samples were collected on day 14, and 35 prior to challenge for the quantification of RBD-specific IgG antibodies by ELISA. On day 42, hamsters were challenged by intranasal inoculation (50 µL) of SARS-CoV-2 (3.75 × 104 plaque-forming units), 6 weeks post-initial immunization.Figure 1 Schematic representation of Syrian hamster challenge study. Hamsters were divided into 2 groups (n = 6) ie., 10 µg-dose Baiya SARS-CoV-2 Vax 1 and control group. Hamsters were immunized on day 0 and 21 and were bled on day 14, 35 and 47. Hamsters were challenged intranasally with SARS-CoV-2 on day 42 and were euthanized on day 47 (5-days post infection, dpi).
Figure 1:
2.5 Evaluation of immune responses and neutralizing antibody titer
ELISA was used to measure the antigen specific antibody titers of serum samples [10]. Further, Baiya SARS-CoV-2 Vax 1 specific neutralizing antibody was assessed using two-fold dilutions of heat-inactivated serum and positive control in a microneutralization assay performed in Vero E6 cells as reported previously [12, 13].
2.6 Clinical observations
Hamsters were observed daily for overall health conditions during the study. Body weights were recorded at the time of vaccination, and then daily after challenge. The baseline body weights of all the animals were measured before virus infection. After challenge, animals were monitored for clinical signs such as weight loss, lethargy, anorexia, moribund and ruffled hair for 5 consecutive days.
2.7 Virus detection in hamster lung tissue
Virus titration was performed on oropharyngeal swabs and lung tissue samples. The left lobe of the lung collected from euthanized hamsters were weighed and homogenized in 1 mL serum-free MEM using pestle. Tissue homogenates were clarified by centrifugation at 13,000 rpm for 10 min at 4°C. Plaque assay was performed as described with some modifications [14]. Briefly, Vero cells (ATCC: CCL-81) grown in minimum essential medium (MEM, 61100-061, (Thermo Fisher Gibco, Waltham, MA, USA) supplemented with 10% fetal bovine serum were seeded at a concentration of 3.5 × 105 cells/well on the day before the assay. Serial dilutions of each sample were added to the wells. The plate was incubated at 37°C, 5% CO2 for 1 h and shaking the plates every 15 min. Then, the cells were overlaid with 1.5 mL/well of overlay medium containing MEM supplemented with 2% FBS and 1.5% carboxymethylcellulose (C4888, Sigma Aldrich, St. Louis, MO, USA). The culture was incubated at 37°C, 5% CO2 for three days for plaque development. Then the overlay was removed, cell monolayers were fixed with 10% formaldehyde, and stained with 1% crystal violet. Viral titers were reported as PFU/g of sample.
2.8 Statistical analysis
Statistical analyses were performed using GraphPad Prism version 9 software (GraphPad Software, Inc., CA, USA). Each specific test used for the analysis was indicated in the respective figure.
3 Results
3.1 Baiya SARS-CoV-2 Vax 1 induced the production of neutralizing antibodies
To assess the immunogenicity of the Baiya SARS-CoV-2 Vax 1, hamsters were administered twice by intramuscular injection with 10 µg of vaccine or with PBS as a negative control (Figure 1). Intramuscular immunization with subunit vaccine candidate, Baiya SARS-CoV-2 Vax 1 elicited significant serum IgG responses against the plant-produced RBD in hamsters on day 35 (GMT = 635), after 2 doses (Figure 2 a). Next, the neutralizing antibody titers were evaluated by using microneutralization assay. Neutralizing antibodies were elicited by our vaccine candidate in hamsters. Sera collected from Baiya SARS-CoV-2 immunized hamsters could neutralize SARS-CoV-2 virus in vitro (GMT = 160) (Figure 2b).Figure 2 Two intramuscular dose of Baiya SARS-CoV-2 Vax 1 generates high titer neutralizing antibodies. SARS-CoV-2 RBD-specific total IgG in the serum at day 14 and 35 was measured by ELISA (a) and 50% microneutralizing (MN50) titers (b) of the sera collected from immunized hamsters. Data presented as GMT ± 95% CI of the endpoint titer in each group (n = 6). The total IgG titers lower than cut-off are plotted as 100 (a). Values smaller than the limit of detection (LOD) are plotted as 0.5*LOD (b). Two-way ANOVA, Šídák test, was used. (**: p < 0.01, ****: p < 0.0001).
Figure 2:
3.2 Baiya SARS-CoV-2 Vax 1 reduced viral load in the lungs of vaccinated hamsters
The ability of our vaccine candidate to protect against SARS-CoV-2 challenge was evaluated in Syrian hamsters by intramuscular injection at day 0 and 21 before intranasal challenge with SARS-CoV-2. As illustrated in figure 1, all hamsters were challenged by intranasal infection with SARS-CoV-2 virus, at 6 weeks post-prime immunization in order to assess the protective efficacy of the vaccine. Clinical signs were observed daily for 5 consecutive days. All animals survived the challenge with SARS-CoV-2 until scheduled necropsy. Hamsters were weighed and observed daily for weight loss after the virus challenge. There were no adverse clinical signs and no significant differences in the body weight and body temperature between two groups (Figure 3 ).Figure 3 Body weight (a), percentage weight change (b) and body temperature (c) of the animals were monitored for 5 days after challenge (n=6). Data were plotted as mean ± SD. Two-way ANOVA, Šídák test, was performed among the groups. Dpi: Days post infection
Figure 3:
At 5 days post challenge, all animals were euthanized, oropharyngeal swab samples and lung tissue samples were collected for determination of viral titers. In plaque assay, which gives a measure of the amount of infectious virus in the lung and oropharyngeal swab, there was a significant reduction (p<0.01) in infectious virus in the lung of Baiya SARS-CoV-2 Vax 1 treated group compared to PBS treated control group. Indeed, the PFU/g tissue for all Baiya SARS-CoV-2 Vax 1 treated hamsters (1.7 × 103 ± 3.4 × 103 PFU/g) were lower than all measured PFU/g values for the PBS control group (8.5 × 105 ± 4.0 × 105 PFU/g). There were no PFU measured in the oropharyngeal swab of either the PBS control or the Baiya SARS-CoV-2 Vax 1 treated animals (Figure 4 ). These findings suggested that the intramuscular immunization of hamsters with Baiya SARS-CoV-2 Vax 1 provided protection against the lethal SARS-CoV-2 infection.Figure 4 Baiya SARS-CoV-2 Vax 1 immunized hamsters showed decrease in the viral load in the lung. PFU/g in lung tissue collected from SARS-CoV-2 challenged Syrian hamsters (n=6). Data expressed as mean ± SD. Unpaired t-test, Mann-Whitney test, was used (**: p<0.01).
Figure 4:
4 Discussion
Development of safe and effective vaccine against SARS-CoV-2 is highly essential to control the virus spread and end the global pandemic. The scientific efforts in last two years have resulted in promising SARS-CoV-2 vaccines, in which some are available for human use and multiple candidates are currently in clinical trials. There are several vaccines in development by employing different approaches, including protein subunit, inactivated, viral-vectored, and nucleic acid-based [8]. Each approach has distinct benefits and limitations. The efficacy of different vaccines was reported to vary differently against SARS-CoV-2 and its newly emerged variants.
The plant-produced subunit vaccine used here combines the power and speed of plant transient expression for rapid vaccine development. Plant expression platform has several advantages compared to other available expression platforms. Plant-based vaccines have the potential to address limitations associated with the other platforms especially response time and scalability during pandemic situation [15]. The proteins produced using plant expression system can be easily scalable with substantial yields [16, 17]. Using plant expression platform based on transient expression of SARS-CoV-2 antigens in N. benthamiana, we have recently demonstrated that a candidate subunit vaccine can be produced within two weeks of gene construct delivery [18]. We have also demonstrated that the plant-produced RBD-Fc with alum adjuvant induced antibody responses in mice and non-human primates which showed that this antigen could be considered as a promising vaccine candidate against SARS-CoV-2 [10]. In the present study, we continued to study the efficacy of our plant-produced subunit vaccine candidate, Baiya SARS-CoV-2 Vax 1 in hamster model and the results demonstrated that it can elicit a protective immune response when intramuscularly administered.
Although there are several proof-of-concept studies showed the expression of recombinant vaccine antigens in plants, very few candidates reached the clinical stage. Subunit vaccine antigens produced in plants have proved to be immunogenic in animal models [19], [20], [21], [22], [23], [24]. It is well known that the addition of appropriate adjuvants with subunit vaccine may enhance the production of neutralizing antibodies that confers protective immunity against the infection. Notably, clinical trials with plant-derived vaccine against diseases such as influenza (18-64 study NCT03301051; 65-plus study NCT03739112) [25], Rotavirus (NCT03507738) [26], COVID-19 vaccine (NCT04450004) [27] have demonstrated their safety and immunogenicity in humans. Clinical trials of other plant derived COVID vaccine developed by Kentucky Bioprocessing (NCT04473690) and Baiya Phytopharm Co., Ltd (NCT04953078, NCT05197712) are currently ongoing [28].
Though mice are commonly used lab animal for biomedical research, mice cannot be efficiently infected with wild type viruses. Hamsters are used as a potential infection model in the research of SARS-CoV-2 infection and other infections caused by respiratory viruses. Hamsters are known to develop similar clinical manifestations in the lungs exposed to SARS-CoV-2 like humans [29]. There have been multiple reports available for other vaccination studies performed in hamsters which shown protection against virus challenge [30], [31], [32]. Hence the protective efficacy of our vaccine was evaluated in Syrian hamster challenge model. Here, we employed a 10-µg dose of our vaccine, which was selected based on the immunogenicity of our vaccine tested earlier in mice and monkeys. Remarkably, 14 days following the second immunization, Baiya SARS-CoV-2 Vax 1 induced high titers of IgG and neutralizing antibodies in hamsters. The neutralizing antibody titer measured by microneutralization assay showed that the antibodies induced by Baiya SARS-CoV-2 Vax 1 could neutralize the SARS CoV-2. Even though there were no difference in the level of SARS-CoV-2 RNA in the lungs of the vaccinated hamsters (not shown), there was a significant reduction in the viral load of the Baiya SARS-CoV-2 Vax 1 vaccinated hamsters, suggesting the reduction in the level of infectious virus in lungs post-vaccination. Another study reported that the administration of one or two doses of ChAdOx1 nCov-19 in rhesus macaques significantly reduced the viral loads in lungs but there was no significant difference in SARS-CoV2 RNA loads in nasal swabs between control or vaccinated animals was observed [33]. The preliminary findings from this study showed that our vaccine can induce neutralizing antibodies and protected animals against a lethal SARS-CoV-2 challenge.
Additionally, stability profile of our vaccine candidate Baiya SARS-CoV-2 Vax 1 has also been assessed. Further, the safety pharmacology and toxicity studies performed in non-human primates and Wistar rats respectively showed that the vaccine is safe, and no unanticipated findings were observed throughout the study. Baiya SARS-CoV-2 Vax 1 was evaluated in different animal models and has demonstrated ability to elicit neutralizing antibody response against SARS-CoV-2 [11]. The study presented here has few obvious limitations, the most important of which were the durability of immune responses needs to be evaluated, protective efficacy of the vaccine against variants of concern at different doses were not tested, the cellular immune response of the vaccine is not measured and the effect of vaccine dose with and without adjuvant on the immunogenicity and efficacy in hamsters also not assessed.
In summary, we demonstrate that two immunizations with plant-produced vaccine candidate, Baiya SARS-CoV-2 Vax 1 elicits anti-RBD antibodies and provides protection from SARS-CoV-2 infection in Syrian hamsters. This recombinant subunit vaccine produced in plants could make a safe and effective vaccine against SARS-CoV-2 which can be well suited for the deployment of large-scale manufacturing of low-cost vaccine candidates. These results present the evidence of preclinical immunogenicity and efficacy of the Baiya SARS-CoV-2 Vax 1 in animal model.
Data Availability
All data supporting the findings of this study are available within the paper and are also available from the corresponding author upon request.
Author Contributions
W.P conceived the project. B.S, N.K performed the plant experiments and prepared the vaccine formulations. W.Pa and Y.A performed the hamster challenge experiments. S.M and A.T performed the virus neutralization assay. B.S drafted and revised the manuscript. All authors analyzed the data and approved the submitted version.
Funding
This research was funded by National Vaccine Institute, Thailand and Baiya Phytopharm Co., Ltd. Thailand.
Conflict of Interest
Waranyoo Phoolcharoen (WP) from Chulalongkorn University is a founder/shareholder of Baiya Phytopharm Co., Ltd. Thailand.
Data Availability
Data will be made available on request.
Acknowledgments
We appreciate the technical assistance provided by the technicians and staff at the experimental animal facility during the study. The author (NK) would like to thank The Second Century Fund (C2F), Chulalongkorn University for the doctoral fellowship.
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| 0 | PMC9744481 | NO-CC CODE | 2022-12-15 00:01:48 | no | Biotechnol Rep (Amst). 2023 Mar 13; 37:e00779 | utf-8 | Biotechnol Rep (Amst) | 2,022 | 10.1016/j.btre.2022.e00779 | oa_other |
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J Hosp Infect
J Hosp Infect
The Journal of Hospital Infection
0195-6701
1532-2939
Published by Elsevier Ltd on behalf of The Healthcare Infection Society.
S0195-6701(22)00379-6
10.1016/j.jhin.2022.11.023
Article
The need for systematic quality controls in implementing N95 reprocessing and sterilization
Goyal Neerav a∗
Goldrich David a
Hazard Will b
Stewart Wade c
Ulinfun Charles d
Soulier Justin e
Fink Gregory f
Urich Torrey g
Bascom Rebecca h
on behalf of
the N95 Taskforce
a Department of Otolaryngology-Head and Neck Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA
b Department of Anesthesiology and Perioperative Medicine and Neurosurgery, The Pennsylvania State University, College of Medicine, Hershey, PA
c Operational Excellence Program, The Pennsylvania State University, College of Medicine, Hershey, PA
d Department of Facilities, Administration, The Pennsylvania State University, College of Medicine, Hershey, PA
e Department of Nursing, The Pennsylvania State University, College of Medicine, Hershey, PA
f Facilities Infrastructure and Energy, The Pennsylvania State University, College of Medicine, Hershey, PA
g Department of Environmental Systems, Facilities Maintenance, The Pennsylvania State University, College of Medicine, Hershey, PA
h Department of Pulmonary Medicine, The Pennsylvania State University, College of Medicine, Hershey, PA
∗ Corresponding author. Division of Head and Neck Oncology and Surgery, Department of Otolaryngology – Head and Neck Surgery, Penn State Milton S Hershey Medical Center, Penn State College of Medicine, Penn State Cancer Institute, (P) 717-531-8945 (F) 717-531-6160,
13 12 2022
13 12 2022
13 9 2022
1 11 2022
9 11 2022
© 2022 Published by Elsevier Ltd on behalf of The Healthcare Infection Society.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Background
Due to increased requirement for personal protective equipment during the COVID-19 pandemic, many medical centres utilized sterilization systems approved under FDA Emergency Use Authorization for single-use N95 respirators reuse. However, few studies have examined the real-world clinical challenges and role of ongoing quality control measures in successful implementation.
Aims
To demonstrate successful implementation of quality control measures in mask reprocessing and importance of continued quality assurance.
Methods
A prospective quality improvement study was conducted at a tertiary-care medical centre. 982 3M 1860 or Kimberly-Clark Tecnol PFR95 masks worn by healthcare workers underwent sterilization using a vaporized hydrogen peroxide gas plasma-based reprocessing system. Post-processing qualitative fit testing (QFT) was performed on 265 masks. NIOSH laboratory mannequin testing evaluated the impact of repeated sterilization on mask filtration efficacy and fit. A locally designed platform evaluated the filtration efficiency of clinically used and reprocessed masks.
Findings
255 N95 masks underwent QFT. 240 underwent post-processing analysis. 205 were 3M 1860 masks and 35 were PFR95s. 25 (12.2%) of the 3M masks and 10 (28.5%) of the PFR95s failed post-processing QFT. Characteristics of the failed masks included mask deformation (n=3, all 3M masks), soiled masks (n=3), weakened elastic bands (n=5, 3 PFR95), and concern for mask shrinkage (n=3, 2 3M masks). NIOSH testing demonstrated that while filter efficiency remained >98% after 2 cycles, mask strap elasticity decreased 5.6% after reprocessing.
Conclusions
This study demonstrates the successful quality control implementation for N95 disinfection and highlights the importance of real-world clinical testing beyond laboratory conditions.
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pmcIntroduction
The current pandemic and global health crisis related to COVID-19 has infected more than 584 million individuals worldwide, with greater than 1 million deaths in the United States alone since the winter of 2019. In the United States, more than 91.9 million cases have been confirmed as of August 2022 [1]. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spread by aerosols and droplets expelled at increased rates with coughing. Studies have suggested that viable aerosols can linger in the air for up to 3 hours and can spread beyond six feet in environments with positive pressure room ventilation, as is commonly encountered in healthcare facilities [[2], [3], [4]]. Additionally, data has suggested settled viral particles can persist and remain viable on surfaces for up to 72 hours. With the risks of transmission and concerns related to the sequelae of COVID-19, the pandemic has had a significant impact on healthcare.
One specific area affected is the hospital supply chain. Personal protective equipment (PPE) including N95 respirators are in high demand across healthcare systems. These respirators are rated to filter 95% of particles 0.3 microns or larger and are used to protect healthcare workers from aerosol transmission of virus. In addition to the increased demand, there is significantly decreased supply with global manufacturers, many based in China, unable to resume operations. Due to these constraints, several federal recommendations were published regarding the potential re-use and extended use of medical grade N95s that are marketed and approved for single use. Prior literature related to the sterilization and re-processing of N95 respirators led to several institutions implementing programs to prolong their N95 supply [[5], [6], [7], [8], [9]]. The technologies utilized include vaporized hydrogen peroxide (VHP), ultraviolet germicidal irradiation (UVGI), heat, and hydrogen peroxide gas plasma (HPGP).
In considering new processes and technologies, quality systems play a critical role in the transitioning of any innovation into clinical practice. If quality systems are neglected, the lives of both the patient and provider may be placed at risk if the quality process fails to ensure that the product performs as intended and delivers the intended protection. As such, quality monitoring is a requirement of many regulatory bodies including the Food and Drug Administration (FDA). The FDA’s regulations are described in the Code of Federal Regulations Title 21 Part 820 entitled “Quality System Regulation” [10]. A complete listing of the requirements is beyond the scope of this article, but it is important to note that these requirements should be reviewed in the early stages of introducing any potential product or process.
From a device perspective, during normal FDA operations, the main unit that oversees medical devices is the Center for Devices and Radiological health. There are three major pathways for regulation based upon risk and are, in ascending order of risk Class 1-3 with most Class 1 devices exempt from premarket clearance and Class 3 devices requiring a rigorous process to demonstrate safety and efficacy before they can be used on patients. Alternatively, an Emergency Use Authorization (EUA) permits the use of unapproved medical products (drugs, biologics and devices) or the use of approved medical products in previously unapproved ways to diagnose, treat, or prevent diseases or conditions caused by chemical, biological, radiological, or nuclear (CBRN) agents. It is important to note that the EUA is not part of the normal pathway and can only be utilized during emergencies. The EUA is in effect for one year or for the duration of declared emergency by the Department of Health and Human Services.
This article will focus on the process, quality control measures, and results of a reprocessing method employed at a single institution and highlight the importance of continued in-hospital quality control even with methods cleared by the FDA under current EUA. Although not specifically mandated by an EUA, a quality management system was adopted early on at our institution to ensure that all reprocessed respirators functioned predictably to specification once distributed but also during their utilization; performance of the respirators were monitored so that issues were reported as they were identified and could be quickly corrected.
Methods
In the setting of an emerging pandemic and limited N95 respirator supply, the Penn State Milton S. Hershey Medical Center (PSMSHMC), a 628-bed academic medical centre, immediately investigated methods to prolong the N95 supply through reprocessing. A multidisciplinary team was assembled with experts from infection control, infectious disease, pulmonary/critical care, gastroenterology, facilities management, public health, occupational medicine, environmental health and safety, sterile processing, logistics and operations support, marketing, nursing, surgery, and anaesthesia (N95 Taskforce). Members included clinicians performing aerosol-generating procedures previously demonstrated to be at high risk for transmission of viable viral particles [11]. Ethical considerations included in crafting an appropriate reprocessing plan included ensuring multidisciplinary input into study design, maximizing equitable availability of reprocessed masks to all front-line clinical healthcare workers, and ensuring strict sterilization procedures and timely data analysis to ensure appropriate safety to participants. Participants using masks included in the study were informed of reprocessing and assented to quality control testing during mask fit and distribution process.
After reviewing available literature and considering hospital resources and expertise, the N95 Taskforce agreed to utilize the Sterrad® HPGP reprocessing system for mask sterilization. This process had received EUA from the FDA for up to 2 cycles of reprocessing. Additionally, this method allowed us to leverage available equipment and trained personnel to deploy a new process for N95 masks. The Sterile Processing Department at PSMSHMC owns five 100NX Sterrad® machines allowing for approximately 100 masks to be sterilized/reprocessed per hour. The specific sterilization procedures followed the Instructions for Use (IFU) of the ASP Sterrad® 100NX system using the 24-minute express cycle [12].
To design the process, the team identified areas of high mask usage, including the operating room, emergency department, endoscopy suite, and COVID testing areas. The group implemented several quality control measures for extended re-use and single-use reprocessing. Policies regarding N95 re-use and appropriate doffing and donning procedures were shared via hospital intranet, mailings, and messaging placed at mask collection areas.
The group also initiated universal mask fit testing after mask reprocessing to provide post-processing evidence that fit and filtration were not affected. Nurses trained in Occupational Safety and Health Administration (OSHA) qualitative mask fit testing (QFT) were assigned to a designated area where all personnel receiving a disinfected mask would undergo QFT using either a saccharine or bitter solution [13]. Testing of processed masks was performed utilizing a Draeger Accuro pump (Draeger Inc, Houston, TX, USA) with a hydrogen peroxide calorimeter tube. In addition, an ATI PortaSens II meter (ATI, Collegeville, PA, USA) was utilized to evaluate residual hydrogen peroxide levels from within the masks. Any personnel that failed QFT repeated QFT with a new mask of the same brand and size. If the repeat QFT failed, individuals were resized for a different mask that fit appropriately. Masks that failed fit testing underwent further evaluation assessing any external contributing factors including soiling of the internal lining or visible mask deformation.
The processes designed by the Taskforce are outlined in Figure 1 (mask collection and redistribution) and Figure 2 (mask sterilization).Figure 1 Mask Collection and Redistribution. This process aimed to return disinfected masks to the original healthcare worker to increase employee acceptance and to reduce additional stress on a mask by repeated deformation or fitting to different facial structures.
Figure 1
Figure 2 Mask Sterilization in Sterile Processing. The sterilization procedure once the masks were received in sterile processing.
Figure 2
Concurrent with the initiation of this process, we also sent masks to the National Institute for Occupational Safety and Health (NIOSH) lab in Pittsburgh, PA for filtration evaluation after 2 reprocessing cycles. These masks were tested per the NIOSH Standard Test Procedure TEB-APR-STP0059 using the TSI 8130 (TSI Incorporated, Shoreview, MN, USA) which includes testing for filtration as well as fit on standard mannequins [14]. Fit testing was performed using mannequins and the TSI PortaCount Pro+ 8038 (TSI Incorporated, Shoreview, MN, USA). This protocol also included testing the strength of the masks’ elastic straps.
Per NIOSH protocol, only unworn processed masks could be tested. In parallel, Taskforce members also designed a local testing rig to mimic the NIOSH testing protocol and test filtration efficiency using a Fluke airflow meter and a Fluke 985 particle counter (Fluke Corporation, Everett, WA, USA) designed to measure particles between 0.3 and 10 microns. This rig allowed for the testing of previously worn disinfected masks. Background particle counts in the air outside of the mask were compared to counts in the air drawn through the mask (Figure 3 ). This rig was used to evaluate the filtration efficiency of used masks that had been reprocessed twice and a few masks that failed QFT. The full test protocol can be found in the supplementary sections.Figure 3 The Local Mask Testing Rig. A) A front view of the rig demonstrating how the mask to be tested was secured in an airtight manner to the rig using a compression plate. B) A profile view of the rig showing the motor that generated airflow across the mask. C) A demonstration of the testing procedure with the particle counter.
Figure 3
Results
After 5 weeks of implementing the process in high-use areas, 982 masks underwent reprocessing for staff reuse. Of those, 255 masks underwent post-processing QFT (ppQFT) (26%). There were two types of masks reprocessed: the 3M 1860 and the Kimberly-Clark Tecnol PFR95 or similar Halyard Fluidshield, which were both available in regular and small sizes. Fifteen of the tested masks were excluded from the later analysis as the user required a different brand or size of mask than what was initially worn and reprocessed. Of the remaining 240 masks, 205 were 3M 1860 masks and 35 were PFR95s (Table I ). Twenty-five (12%) of the 3M masks failed ppQFT and 10 (29%) of PFR95s failed. Notable characteristics of the failed masks included deformation of the mask (n=3, all 3M 1860 masks), soiled masks (n=3, Figure 4 ), compromise of the elastic bands (n=5, 3 PFR 95), and an increased tightness of the mask fit on the individual (n=3, 2 3M 1860 masks). The remainder of the masks that failed ppQFT did not show visible soiling or deformation and the individuals did pass subsequent/repeat QFT with a new mask of the same size and brand. Draeger Accuro pump and PortaSens testing determined the presence of less than 1 part per million (range 0-0.7PPM) of residual or measured hydrogen peroxide at several locations on both brands of masks with at least a one-hour aeration period out of the sterilization pouch.Table 1 Breakdown of mask testing and noted failures
Table 1Mask Characteristic Number (%)
3M 1860
Reprocessed
Underwent QFT 216
Failures excluded due to incorrect initial fit 11
Failures included 25
Makeup 3
Visible Damage 3
Felt tighter 2
Elastics damaged 1
KC PFR 95
Reprocessed
Underwent QFT 39
Failures excluded due to incorrect initial fit 4
Failures included 10
Elastics damaged 3
Felt tight 1
Figure 4 Several masks that demonstrate significant soiling from facial cosmetics.
Figure 4
Data received from NIOSH regarding the filtration testing of PFR95s after 2 reprocessing cycles demonstrated that while the filter efficiency was intact after 2 cycles (>98% across all samples), there was evidence of compromised elasticity and a decrease in strap forces of 5.6% for the top and bottom elastic after reprocessing.
Two 3M masks that had passed fit testing after personnel use and 2 reprocessing cycles were tested with the local testing rig. Additionally, 2 masks that had failed fit ppQFT were tested. Table II depicts the results of this filtration testing for each of the four masks over five tests each.Table 2 Mask filtration results (all 3M 1860)
Table 2Test # Passed QFT Failed QFT
Mask 1 Efficiency (%) Mask 2 Efficiency (%) Mask 3 Efficiency (%) Mask 4 Efficiency (%)
1 96.5 97.1 84.5 80.9
2 96.5 97.4 85.6 82.1
3 97.1 97.2 85.6 82.3
4 96.3 97.1 83.8 81.5
5 96.6 97.1 84.0 81.8
Average 96.6 97.2 84.7 81.7
Discussion
Since the onset of the COVID-19 pandemic, several sources have described acute health system shortages of N95 respirators and rapid implementation of existing and novel sterilization methods to meet demand [[15], [16], [17], [18], [19], [20], [21], [22], [23], [24]]. However, few describe the quality control process critical to successful implementation, scaling, quality assurance and improvement of such systems.
In addressing the shortage of N95 respirators, our quality management systems focused on two components when reprocessing masks. The first process was quality assurance, in which we prospectively ensured that the chosen sterilization method was not only scalable, but also designed to allow the packaging, labelling, documentation and ancillary services to be supported within the hospital system. The second component was quality control, in which, following the implementation of a sterilization method, we tested and confirmed that the specifications of the original product were still being met prior to releasing the product to hospital practitioners.
Furthermore, we designed and implemented quality audits to assure that the quality system followed regulatory requirements (Quality System Regulation Section 820.22) [10]. The importance of this process can sometimes be lost in trying to deliver innovations rapidly to an end user. Some even view regulatory requirements as burdensome rather than as a mechanism to improve product effectiveness. On the contrary, with our experience we found that we were able to swiftly test and ensure a quality product despite monitoring and assessing a large quantity of samples. We began with a model based on what reprocessing methods were currently performed at other institutions and adapted to institution-specific needs and requests.
Initially, the process was designed such that masks would be sterilized and placed into a general pool. However, stakeholders and mask users were unwilling to wear a mask previously worn by another individual, despite sterilization. Additionally, we worried that a mask’s lifespan would be shortened if it had to fit different facial structures after each sterilization. Our process consequently evolved, allowing masks to be identified with single users through each sterilization. Similarly, other findings identified during real-time monitoring, such as aeration requirements based on residual hydrogen peroxide, led to changes consistent with continuous quality improvement (CQI) model [25]. We successfully modified our process in real time to accommodate user need and safety.
Importantly, the process implemented highlights the effectiveness of quality control measures when performed under real-world conditions. Bessesen et al. recognize the opportunities for error in mask disinfection and how well-designed standard operating procedures only provide adequate quality control when followed precisely [26]. Likewise, studies by Liao et al. and Ou et al. determining the effectiveness of methods of N95 disinfection under laboratory conditions note that factors associated with real-world clinical use can alter laboratory-determined contamination rates and filtering efficiency [18, 27]. They posit that users’ repeated donning of masks and associated fit and leakage changes might impact filtering efficacy and reusability as well. We demonstrate these findings under real-world conditions, as some of our post-processing mask failures were due to incorrect fit, deformities or elasticity changes after repeated use (Table II).
In the laboratory setting, studies demonstrate that changes to masks can also vary by sterile processing modality. For example, while Liao et al. observed no qualitative change in mask elasticity or fit after heat treatments, they found UV-treatment of masks could lead to improper fitting [19]. Price et al also note that previous studies of UVGI mask sterilization technology conduct fit tests on static mannequins, while dynamic testing on human subjects could expose fitting inadequacies not seen in artificial controlled settings [19]. Our utilization of the Sterrad® HPGP-based reprocessing system was chosen due to evidence from past studies demonstrating the effectiveness and superiority of VHP-based sterilization compared to other modalities, with little impact on mask fit or filtration efficacy [24, 28, 29]. VHP’s high filtration efficacy maintained after early cycles of sterilization was corroborated by NIOSH filtration testing of our masks after undergoing 2 reprocessing cycles, which showing 96-97% mask efficiency in those masks that also passed QFT after sterilization [29]. However, as noted, the masks undergoing NIOSH testing were not used under clinical conditions. Previous studies of HPGP have shown a reduction in filtration efficiency by >5% in some respirators associated with degradation of mask components, an issue seen among our masks that failed QFT as well (Table II, masks 3 &4) [23, 24, 28, 29].
Our study monitored the real-world effectiveness of mask reprocessing through QFT and demonstrated a mask failure rate of 12.2% (25/205) for the 3M 1860 after reprocessing. In performing a root-cause analysis of mask deformation, soiling and/or strap elasticity (qualitatively measured) were implicated. This demonstrated need for continued quality monitoring due to the many external factors impacting mask efficacy after repeated use regardless of sterilization method. This rate is similar to second-pass N95 autoclave reprocessing failure rate of 14% seen in a Canadian institution [21]. Previous studies of HPGP have shown a reduction in filtration efficiency by >5% in some respirators associated with degradation of mask components [23, 24, 28, 29]. This was also seen in our masks that failed QFT, as filtration testing of select QFT fail masks did show a decrease of filtration efficiency down to 80-85% (Table II, masks 3 &4).
The finding of decreased mask elastic strap force by 5.6% in the unused KC PFR 95 mask following reprocessing as tested by NIOSH emphasizes the need to identify contributors to reprocessing failure beyond filtration and shows that testing filtration rates alone may be an inadequate marker of reprocessing success. This study highlights the importance of incorporating quality control when implementing innovation in healthcare systems, and the feasibility of doing so in a timely fashion even during times of critical need.
More broadly, with the rapid emergence of many mask sterilization/reprocessing technologies to address mask shortages that may lack rigorous testing in a clinical setting, this study emphasizes the importance of internal quality assurance beyond reliance on external supplier assertions. For example, while previous testing of autoclave reprocessing of unused masks demonstrated functional efficacy through 10 cycles, one hospital system’s study of real-world clinical implementation found reprocessing inadequate beyond a single cycle [21]. We encountered similar unanticipated user-related issues contributing to mask failure, including mask deformity with contouring and use, reduced strap elasticity, and soiling due to facial oils and cosmetic use. These represent site-specific quality assurance issues that are not accounted for in the published literature which may also arise at other institutions and compromise mask efficacy/reusability. Importantly, many sterilization systems that received FDA EUA were authorized solely based on published laboratory-based data given the urgent need. We demonstrate how real-world clinical data reveals differences in efficacy that must be accounted for through internal QI.
This study’s strengths are based on its large sample size and demonstrate the efficacy of our quality control system, allowing real-time monitoring of mask testing and addressing challenges that arose under live conditions. The limitations of this study include the possibility of selection bias, as qualitative analysis was only performed in a subset of processed QFT masks. However, the 255 masks undergoing analysis were randomly chosen and represent a large sample size of >25% of those in circulation. Additionally, only 3M 1860 N95 and KC PFR 95 masks were examined in this study, limiting the generalizability of the utilized sterilization technology to other types of PPE. While other studies of Sterrad® and VHP reprocessing systems may be more broadly applicable, we suggest that institution- and site-specific assessment should be performed to evaluate local reprocessing efficacy and the need for alternative or additional sterilization protocols [24, 29]. Further study of mask quality control in other institutions can add to the general understanding of the challenges of implementing new systems during periods of critical need.
Conclusions
We demonstrate the process of creating a reproducible and scalable quality control system for N95 disinfection within a large academic hospital system. Our study highlights the importance of internal quality assurance and testing of new sterilization and reprocessing protocols in real-world clinical settings rather than solely under laboratory conditions. Quality assurance is achievable through multidisciplinary collaboration, evaluation, and rapid real-time adjustment to meet demand and address critical mask shortages during the COVID-19 pandemic.
Author contributions
NG, DG, WH, WS, CU, JS, GF, TU, NT, RB conception and design of the study, or acquisition of data, or analysis and interpretation of data, (2) NG, DG, WH, JS drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted. NG, DG, WH, JS.
All authors approved the final version of the manuscript.
Competing Interests
None.
Funding sources
This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.
Conflict of interest statement
The authors declare no conflicts of interest relevant to this article.
Appendix A Supplementary data
The following is the Supplementary data to this article:
Acknowledgements
We would like to acknowledge the significant contributions of the N95 Task Force members in addition to those designated in the author list, including Ross Rodgers MD, Margaret Wojnar MD, Duane Williams MD, Jennifer Maranki MD, Jennifer Toth MD, Scott Armen MD, Justin Kemp CMRP, Fibi Attia MD MPH, Kofi Clarke MD, Kevin Myers CHMM, Gargi Vora MD, Raymond Scheetz MS RBP. Kevin Bush MS EdD. We would also like to thank the numerous other Penn State Health clinicians and employees who helped successfully implement this quality control process.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.jhin.2022.11.023.
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| 36521581 | PMC9744483 | NO-CC CODE | 2022-12-15 00:01:48 | no | J Hosp Infect. 2022 Dec 13; doi: 10.1016/j.jhin.2022.11.023 | utf-8 | J Hosp Infect | 2,022 | 10.1016/j.jhin.2022.11.023 | oa_other |
==== Front
Complement Ther Clin Pract
Complement Ther Clin Pract
Complementary Therapies in Clinical Practice
1744-3881
1873-6947
Elsevier Ltd.
S1744-3881(22)00183-9
10.1016/j.ctcp.2022.101715
101715
Article
The effect of web-based Hatha yoga on psychological distress and sleep quality in older adults: A randomized controlled trial
Baklouti Souad ab
Fekih-Romdhane Feten cd∗
Guelmami Noomen ef
Bonsaksen Tore gh
Baklouti Hana a
Aloui Asma ai
Masmoudi Liwa b
Souissi Nizar a
Jarraya Mohamed b
a Physical Activity, Sport and Health Research Unit (UR18JS01), National Sport Observatory, Tunis, Tunisia
b High Institute of Sport and Physical Education of Sfax, University of Sfax, Sfax, 3000, Tunisia
c Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia
d Department of Psychiatry Ibn Omrane, Razi Hospital, Manouba, Tunisia
e Department of Human and Social Sciences, Higher Institute of Sport and Physical Education of Kef, University of Jendouba, Jendouba, Tunisia
f Postgraduate School of Public Health, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
g Department of Health and Nursing Science, Faculty of Social and Health Science, Inland Norway University of Applied Sciences, Elverum, Norway
h Department of Health, Faculty of Health Studies, VID Specialized University, Sandnes, Norway
i High Institute of Sport and Physical Education, University of Gafsa, Gafsa, Tunisia
∗ Corresponding author. Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia.
13 12 2022
2 2023
13 12 2022
50 101715101715
12 10 2022
9 11 2022
11 12 2022
© 2022 Elsevier Ltd. All rights reserved.
2022
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Background
To date, there has been very limited experimental research on the impact of Yoga on older adults’ mental health during the COVID-19 crisis. We aimed to explore the effect of a web-based Hatha yoga program on psychological and quality of sleep in older adults who self-isolated at home during the initial stage of the COVID-19 outbreak.
Methods
Two hundred volunteers of both sexes were split into experimental (Yoga group, YG) and control (Control group, CG) groups, in a web-based randomized controlled study. All participants were administered the Depression, Anxiety and Stress Scales (DASS-21) and the Pittsburgh sleep quality index (PSQI); at baseline and following an eight-week online Hatha yoga intervention.
Results
The YG showed significant reductions in depression (−56.1%; Z = 5.67, p < 0.01, r = 0.70) anxiety (−64.3%; Z = 5.27, p < 0.01, r = 0.65) and stress (−68.2%; Z = 5.86, r = 0.73) scores, while the CG showed a significant increase in depression. In addition, the total PSQI score of the YG was considerably lower during follow-up (3.38 ± 2.02, p < 0.05) than at baseline (4.8 ± 32, p < 0.05), which indicates an improvement of the quality of sleep. The proportion of individuals experiencing good sleep from the YG increased from 63% to 85% after the Hatha yoga intervention.
Conclusion
The use of a web-based Hatha Yoga intervention program was associated with a beneficial effect on the mental health and quality of sleep in older adults.
Keywords
COVID-19
Distress
Quality of sleep
Yoga
Older adults
==== Body
pmc1 Introduction
The study of psychological trauma in older adults is becoming a major field of research due to the current and projected growth of older adults' population worldwide. In most developing countries, globalization has resulted in rapid urbanization and out-migration of younger adults, which had a negative psychological impact on the well-being of older adults [1]. Many life and individual changes occur as people enter the old age period; which may, in turn, affect mental health and sleep quality. According to the World Health Organization, approximately 15% of older adults are likely to suffer from a mental health disorder (WHO, 2019). Also, older age is related to the likely occurrence of stressors that can significantly and negatively affect the course of aging [2]. Given these age-related issues, it is important to address older people's mental health needs and concerns. One of the major stressors that older adults have faced lately is the COVID-19 pandemic and the subsequent restrictions (social distancing and self-isolation measures) [3]. The older population has been the most vulnerable to COVID-19 morbidity and mortality [4], as well as social isolation and its harmful consequences on mental health [5]. Older adults showed a stronger emotional response to the COVID-19 crisis compared to people of other age groups [6], thus indicating a higher likelihood of psychological distress in this population [7]; Armitage, Nellums, 2020, [8]. For instance, one study showed that 37.1% of older adults had experienced depression and anxiety during the pandemic [9]. Therefore, actions to address the debilitating consequences of the pandemic need to be established and prioritized in older people.
A range of rehabilitative therapies may assist in dealing with the crisis, including yoga. In fact, various yoga organizations worldwide have recommended yoga to help persons remain mentally healthy during the COVID-19 pandemic (Ministry of AYUSH, 2020). Yoga is one of the widely accepted and structured lifestyle practices which promote the integration of the mind, body and soul (La Torre, 2020). This practice is known as an effective and safe intervention for individuals with depression or anxiety [10,11]. In the older population in particular, yoga has been found to promote both physical [12,13] and mental wellbeing [[12], [13], [14]].
We could find only a few experimental studies on the impact of Yoga on older adults’ health during the COVID-19 crisis. For instance, Yoga has been found to improve the immune system [15] and the well-being [16] of older adults. Interestingly, a study found that online delivery of a yoga program for older adults was as effective as face-to-face program for the majority of participants, and even more effective for some [17]. However, it is not known whether the practice of Hatha yoga is effective for improving mental health and sleep quality in older adults during the pandemic.
In the present study, we aimed to test the hypothesis that a web-based Hatha yoga program would improve psychological distress (i.e., depression, anxiety and stress) and sleep quality in a sample of Tunisian older adults who self-isolated at home during the initial stage of the COVID-19 outbreak, and could be used as a preventive measure against these mental health problems during life crises among older adults.
2 Methods
2.1 Data collection and participants
We adopted an online questionnaire designed in the English language. A link to the electronic survey was distributed by consortium colleagues via a range of methods: invitation via e-mails, shared in consortium's faculties official pages, ResearchGate, LinkedIn and other social media platforms such as Facebook, WhatsApp and Twitter. A snowball sampling strategy, focused on recruiting the general public living in Tunisia during the COVID-19 pandemic, was utilized. The online survey was first disseminated to the general public, and participants were encouraged to circulate it to older adults.
Survey participants were informed that their data will be solely utilized for research. In addition, as per Google's privacy policy (https://policies.google.com/privacy?hl=en), all responses are anonymous and private. Participants were also informed they could withdraw their consent at any time. By completing the survey, participants acknowledged the aforementioned approval form. This study was conducted in accordance with the Declaration of Helsinki (2013) and local regulations.
Individuals above the age of 65, of both genders, were eligible to participate. The sample size computation for the present randomized controlled study was performed using the sample size calculator G*Power version 3.1.9.6 (Franz Faul, University of Kiel, Kiel, Germany). The analysis displayed that a sample size 36 subjects would be sufficient to find significant differences (effect size = 0.6, p = 0.05, power [1-β] = 0.80) with an actual power of 80.94%. From March, 21st to June 25th, 2020, we collected data from 325 potential study participants via social media platforms. Based on survey's answers, the study excluded subjects who reported chronic diseases, orthopedic constraints, drug and alcohol use. Likewise, people with dementia, diagnosed mental illness, and inability to execute Hatha yoga were excluded. As shown in Fig. 1 , 200 individuals who met the inclusion criteria were randomly assigned to two groups. Only 160 subjects completed the study procedure due to dropouts and failure to complete the second questionnaire for the experimental group. The final sample included 160 participants (aged 65–80) who had given informed consent to participate: 65 and 95 subjects were assigned to the experimental (YG) and control (CG) groups respectively. During the research period, the wait-list CG received no intervention.Fig. 1 Flow diagram for study participants.
Fig. 1
2.2 Procedure
An eight-week period of meeting via the Google meet videoconferencing technology was used to deliver the web-based Hatha yoga intervention to participants in the experiment group. The duration chosen relied on the confinement period to see the effect of the intervention during the early stage of the pandemic. It also allowed for comparison with other studies [[18], [19], [20]], in which intervention periods have lasted between 3 and 6 months. A trained Hatha yoga instructor created the yoga class. Before the start of the intervention, the objectives of Hatha yoga for balance and health for the physical, mental, emotional and spiritual dimensions were explained. Participants were given a pamphlet with illustrations of the positions for self-practice.
The experimental group had Hatha yoga sessions of 80 min twice a week, which involved a computer, a camera and video analyses as equipment. The intervention was taught to be progressively challenging over the 8 weeks, and each session was built on tasks introduced during prior sessions.
The control group received no treatment. They received the same questionnaire as other research participants to measure mental health and sleep quality. After the 8-week intervention for the Hatha yoga Group, all participants completed a follow-up online questionnaire.
2.3 Hatha yoga training program
The Hatha yoga classes had a duration of 80 min to help ensure a deep enough practice and produce expected effects. The Hatha yoga exercise program was implemented as the intervention. It is a branch of yoga which consisted of Asanas (physical postures), Praṇayama (breathing exercises), and Dhyana (meditation). Hatha yoga uses gentle and slow moving forms, incorporating a variety of poses that are ideal for elderly for stress relief, relaxation and enhanced mental health benefits [21]. It can be adopted as a recourse to provide mental health and quality of sleep benefits during the pandemic outbreak. Participants in the intervention group were led by a certified Hatha yoga instructor, two times a week for 2 months. The 3 components of Hatha yoga are linked, complement and integrated with each other.
Asana: Yogasanas are known to significantly reduce stress and anxiety (Smith, Hancock, Blake-Mortimer & Eckert, 2007). They are psychophysical practices to culture body and mind. Participants were encouraged to stretch as fully as possible while not exceeding the limits of their comfort and hold the pose for less time if necessary. Repetition was consistent from week to week and linked pose to pose. Each pose was held for approximately 20–30 s, with rest periods lasting 30 s to 1 min between poses. A mixture of standing and seated poses was introduced and practiced. Props such as blankets, blocks, and straps were used. The instruction was to concentrate on their breathing and try to be relaxed.
Pranayama: Diaphragmatic breathing techniques were chosen with special consideration for the physical abilities of older adults. During inspiration, the respiratory flow develops the abdominal area and stretches the ribs and the different parts of the chest. During exhalation, the air will deflate starting from the bottom of the lungs, the ribs, and finally the whole chest. The classes emphasized breathing throughout all postures.
Meditation: It is composed of meditative asana focusing on thoughts and breath. The meditation posture used in the Hatha yoga intervention was Siddhasana which is stable sitting posture, with cross-legged, enabling meditation, aiming at training the body in keeping motionless.
Before starting the training, 10 min were devoted to welcoming participants and checking the availability of participants' equipment. Each Hatha Yoga session took about 80 Minutes to complete, and included four phases:1 Warm-up/Loosening exercises (10 min): This part contains postures to loosen up the body structure. Its objective is to increase range of motion and lubricate joints and also to avoid muscle soreness: ExpGreevasanchalana (Neck Mvt), Skandha chakra (Shoulder rotation), Katichakrasana (Hip exercise), Janu chakra (Knee Mvt).
2 Asanas (40 min): These are gentle stretching postures to increase range of motion and progressive muscle relaxation in older adults with special consideration for their physical abilities and tolerances: Standing Asanas: ExpTadasana, kati-cakrasana, Virabhadrasana I, II, and III; Prone Asanas: Exp Bhujangasana (cobra pose) and Dhanurasana (bow pose); Supine Asanas: ExpSetu Bandha Sarvangasana (bridge pose) and SuptaKapotasana (supine pigeon pose).
3 Pranayama (15 min): Three activities to rest the body, abdominal breathing is emphasized in each program phase.
4 Meditation (15 min): Two Poses (Savasana/Siddhasana) to facilitate a state of relaxation and meditation.
2.4 Survey questionnaire
The survey included an introductory page describing the background and the aims of the survey, the consortium and ethics information for participants. Then, a collection of validated and/or crisis-oriented brief questionnaires were included.
Sociodemographic and clinical data: Sociodemographic data were collected on gender (Male and Female), age (65–75 years; 76–85 years), level of education (High school graduate, diploma/equivalent or less; Bachelor's degree/; Master/Doctorate degree), family situation, (Single/Widowed/divorced; Married/Living as couple) current state of health (respondents were asked to rate their state of health physical condition and indicate any history of chronic illness) and employment status (Retired; Working).
Psychological assessment: Two measures were used, the Depression Anxiety and Stress Scales (DASS-21), and the Pittsburgh Sleep Quality Index (PSQI); in order to assess participants’ psychological distress and quality of sleep, respectively.
2.4.1 The DASS-21
We used the Arabic version of the DASS-21 [22]; Ali et al., 2017) that showed good reliability with a coefficient alpha = 0.883 [23]. This tool consists of 21 items, which comprise three sub-scales assessing the severity of depression, anxiety, and stress symptoms. Each sub-scale contains 7 questions and the answer for each question ranges from 0 (Did not apply to me at all) to 3 (Applied to me very much, or most of the time). Scores on each item of the DASS-21 will need to be multiplied by 2 to calculate the final score (See appendices, Table 1 ).Table 1 Participants characteristics.
Table 1Variables CG (N = 95) YG (N = 65)
N % N %
Gender
Male 56 57.14% 42 42.86%
Female 39 62.90% 23 37.10%
Age
65–75 years 74 61.67% 46 38.33%
76–85 years 21 52.50% 19 47.50%
Marital status
Single/Widowed/divorced 17 94.44% 1 5.56%
Married/Living as couple 78 54.93% 64 45.07%
Level of Education
High school graduate/diploma/equivalent or less 39 78.00% 11 22.00%
Bachelor's degree 34 61.82% 21 38.18%
Master/Doctorate degree 22 40.00% 33 60.00%
Current employment status
Retired 46 65.71% 24 34.29%
Working 49 54.44% 41 45.56%
Current state of health
Healthy 56 56.57% 43 43.43%
With risk factors for cardiovascular diseases 30 58.82% 21 41.18%
With a cardiovascular disease 9 90.00% 1 10.00%
Practice of regular physical activity before confinement
Yes 21 37.50% 35 62.50%
No 74 71.15% 30 28.85%
Need for psychosocial support before confinement
Never 76 64.41% 42 35.59%
Rarely 13 40.63% 19 59.38%
Sometimes 6 60.00% 4 40.00%
Need for psychosocial support during confinement
Never 49 50.52% 48 49.48%
Rarely 18 56.25% 14 43.75%
Sometimes 28 90.32% 3 9.68%
Note. CG: Control group; YG: Yoga Group.
Table 2 Shows the average scores and the Δ% differences for the two CG and YG groups before and after confinement.
Table 2Table 2. Means and standard deviations of study variables.
Variables CG (N = 95) YG (N = 65)
Before After Δ (Δ%) Before After Δ (Δ%)
Depression 7.52 ± 5.49 10.95 ± 9.45# 3.43 (45.7%) 7.29 ± 5.28 3.2 ± 3.58#* −4.09 (−56.1%)*
Anxiety 5.71 ± 4.28 6.88 ± 7.47 1.18 (20.7%) 5.6 ± 5.31 2 ± 2.85#* −3.6 (−64.3%)*
Stress 10.99 ± 6.57 11.58 ± 9.35 0.59 (5.4%) 11.32 ± 8.91 3.6 ± 5.01#* −7.72 (−68.2%)*
Sleep quality (PSQI global score) 4.17 ± 2.55 5.59 ± 3.43# 1.42 (34.1%) 4.83 ± 2* 3.38 ± 2.02#* −1.45 (−29.9%)*
Note. CG: Control group; YG: Yoga Group; PSQI: Pittsburgh Sleep Quality Index.
* Significantly different from CG at p < 0.05; # Significantly different from Before at p < 0.05.
2.4.2 The PSQI
We used the Arabic version of the Pittsburgh Sleep Quality Index (PSQI; Suleiman et al., 2010). The scale is a 19 item self-report questionnaire that evaluates subjective sleep quality and different aspects of sleep over a 1-month interval (Buysse, 1989). The subdimensions of the index include subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, use of sleeping medication, and daytime dysfunction. The responses to the items are weighted on 7 components with a scoring scale between 0 and 3. The total score ranges from 0 to 21, with scores equal to or greater than 5 indicating a poor sleep quality. The Arabic PSQI has a good Cronbach's alpha of 0.77. The modified one-factor model had good discriminative validity, and first order confirmatory factor analysis fitted it well [24].
3 Statistical analysis
Statistical tests were performed using STATISTICA 12 software (StatSoft, France). Data are presented in the text and tables as means ± standard deviations and in the figures as means and standard errors. The assessment of normality by the Shapiro-Wilk test revealed that the distribution of the scales scores deviated from the normal distribution, which imposed the use of nonparametric tests. The Mann Whitney test was used to compare the means of the experimental group and the control group, and the Wilcoxon test was used to compare the means before and after the intervention. The magnitude of change was calculated with r = Z/√n formula. Values of 0.5, 0.3 and 0.1 are considered large; medium and small, respectively [25]. The change recorded between before and after the intervention (Δ = After – Before), as well as the percentage of change ([Δ/Before) *100]), were also calculated. A Mc Nemar Chi-square (χ2) analysis was used to assess the changes in the two experimental groups compared to before the intervention. All the differences observed were considered to be statistically significant for a probability threshold of less than 5% (p < 0.05).
4 Results
The comparison of socio-demographic and clinical variables between Hatha yoga and control group participants is displayed in Table 1.
These tests revealed statistically significant differences in the DASS-21 subscale scores. For the YG, the post-test subscale scores were considerably lower than the pre-test in Depression (Z = 5.67, p < 0.01, r = 0.70), Anxiety (Z = 5.27, p < 0.01, r = 0.65) and Stress (Z = 5.86, r = 0.73).
For the CG, DASS-21 scores did not change significantly between time points. Despite the lack of a statistically significant change, the scores on these two sub-scales were higher post-test than pre-test. However, the Depression subscale score was much lower before confinement than during confinement (Z = 2.65, p < 0.01, r = 0.27). In addition, the PSQI scores differed significantly between before and during confinement for CG (z = 5.50, p < 0.05, r = 0.56) with a delta increase Δ% of 34.1%, and for YG (z = 5.69, p < 0.05, r = 0.71) with a delta decrease of 29.9%. The total PSQI score in YG was 3.38 ± 2.02 after the intervention, as compared to 5.59 ± 3.43 in the CG throughout the same time of confinement. The total PSQI score in the YG was considerably lower in the post-test (3.38 ± 2.02, p < 0.05) than in the pre-test (4.8 ± 32, p < 0.05), which indicates an improvement in the quality of sleep. Fig. 2 depicts the frequency of respondents reporting good and poor sleep quality before and during confinement, as well as before and after the Hatha yoga intervention.Fig. 2 Frequency (%) of individuals experiencing good (PSQI score ≤ 5) and poor (PSQI score > 5) sleep before and after the intervention for the YG (before and during confinement).
Fig. 2
After the Hatha yoga intervention, the frequency of individuals experiencing good sleep quality increased (85%), while the frequency of individuals experiencing poor sleep quality decreased (15%). For the CG, between pre-confinement and during confinement, the frequency of elderly people experiencing good sleep quality decreased from 76% to 58%; while the frequency of individuals experiencing poor sleep quality increased from 24% to 42%. On the other hand, the frequency of older adults experiencing good sleep quality increased from 63% (pre-intervention) to 85% (post-intervention) in the YG, while the frequency of individuals experiencing poor sleep quality decreased by 37%.
5Discussion
To our knowledge, this is one of the first studies to investigate the immediate impact of the Hatha yoga intervention on mental health and sleep quality in older adults in the initial stage of the COVID-19 outbreak. It aimed to investigate the effects of 2 months of web-based Hatha yoga intervention on mental health and quality of sleep-in elderly in Tunisia who self-isolated at home during this period. Findings indicated that the control group participants who received no intervention experienced significant depression, anxiety and stress as estimated using the DASS-21. This change among the control group participants is likely due to the negative effects of the Covid-19 pandemic and the restrictions in social life that were implemented during this period [26,27]; Wilson, Lee and Shook,2021). Furthermore, results showed that there were significant positive effects of the 2-month online Hatha yoga on mental health indicators in the experimental group. Older adults who received the Hatha yoga intervention reported lower scores of stress, anxiety, and depression and better sleep quality.
Our findings showed a substantial difference in the pre- and post-intervention DASS-21 scores for both the experimental and control groups. After a two-month intervention period, participants in the Hatha yoga group experienced a decrease in their levels of depression, anxiety, and stress (from 7.2 to 3.2; from 5.6 to 2; and 11.32 to 3.6 respectively), while the control group participants did not show any significant change in depression and stress. These findings indicate that Hatha yoga has a significant positive effect on all DASS-21 dimensions, thus confirming our hypothesis. These findings corroborate prior experiences with infectious diseases by indicating the increased presence of numerous psychological disorders such as stress, depression, irritability, insomnia, dread, bewilderment, and stigma during earlier periods of infection and quarantine [28,29]. In another studies [30,31], have confirmed that the practice of yoga can bring mental health benefits to older adults' population. Several studies have suggested yoga as a mechanism for reducing stress [[32], [33], [34], [35]], depression [36] and anxiety symptoms in older adults (Allen and Steinkohl, 1987). Yoga has been found to significantly reduce depressive symptoms (Krishnamurthy, Telles, 2007 [[37], [38], [39]]; and stress [40] in older adults. In fact, yoga has been found to aid in the development of resilience factors (Taylor, 2003). This may explain why the Hatha yoga group's DASS-21 scores significantly decreased. This is in line with previous findings suggesting that yoga dramatically lowers depressive symptoms and stress levels in older adults [[37], [38], [39],41].
Another finding of this study was that, after 2 months of Hatha yoga exercise, participants in the intervention group had significantly increased PSQI scores indicating a better sleep quality compared to controls. Particularly, sleep disturbances, use of sleep medication, sleep latency and daytime dysfunction significantly decreased, while sleep duration and habitual sleep efficiency showed no significant differences. Results found in this study further supported a previous study that applied the silver yoga exercise program in a community-dwelling elderly population [37,42], indicating that this exercise program could improve sleep quality of both community and institutionalized older adult populations. Similar findings were reported in that yoga improved different aspects of sleep (including less sleep disturbances and less daytime dysfunction) in a geriatric population after 6 months of practice [43]. The practice of yoga is based on stretching which massage blood vessels (Luskin et al., 2000), and on meditation that facilitate a state of relaxation [44], resulting in less sleep latency and fewer sleep disorders [37,42]. [37] reported that intervention group participants had shorter average duration of sleep but better habitual sleep efficiency than that of control group participants. Although WHO (2020) has proposed recommendations for older adults during confinement, there is a marked reduction in all physical activity, regardless of the level of intensity (vigorous, moderate etc.) during this period [45]. Findings of this study suggest that offering psychological first aid through telemedicine during major disasters such as a pandemic may be potentially beneficial for the management of psychological distress and poor sleep quality in older adults. Particularly, this study suggests that Hatha yoga delivered as a web-based intervention can be a useful, at least for the Tunisian older adult population.
5.1 Study limitations
There are a number of limitations to this study, which should be considered when interpreting its findings. Because there are many different kinds of Hatha yoga, the current findings cannot automatically be applied to other yoga forms. In addition, the majority of participants were in good health and had completed a degree beyond high school. There were considerable differences in sample sizes between the two groups. A larger sample size is required in future longitudinal study in order to replicate the findings.
6 Conclusion
Overall, the findings of this study showed that Hatha yoga training has the potential to improve mental health and sleep quality during major lifetime crises in older adults. Future studies should test the effects of other types of yoga interventions in more diverse populations, while including follow-ups at later time points to examine whether short-term effects are maintained over time.
Author statement
Author Noomen Guelmami contributed to the design and implementation of the research, to the analysis of the results and to the writing of the manuscript. Authors Souad Baklouti, Hana Baklouti, Asma Aloui, Liwa Masmoudi, Nizar Souissi, and Mohamed Jarraya helped to process the data and draft the manuscript. Authors Feten Fekih-Romdhane & Tore Bonsaksen helped write, review & edit the manuscript. All authors read and approved the final manuscript.
Appendices Table 1 Score of depression, anxiety and stress according to the degree of severity
Table 1 Depression Anxiety Stress
Normal 0–9 0–7 0–14
Mild 10–13 8–9 15–18
Moderate 11–20 10–14 19–25
Severe 21–27 15–19 26–33
Extremely severe 28+ 20+ 34+
Table 2 Hatha yoga training program
Table 2Session/Procedure Exercises Duration
Sukṣmavyayama (Loosening exercises/warm up) Greevasanchalana (Neck Mvt)/Skandha chakra (shoulder rotation)/KehuniNaman (Elbow Bending) 15 Minutes
MushtikaBandhanan movement of fingers and hand)/Katichakrasana (Hip ex)/Janu chakra (Knee Mvt)/Goolf Naman (Ankle Bending, Rotation)/
PadanguliNaman (Toe Bending)
(Same stretches completed in all sessions)
Yogasana (Physical postures) Standing 40 Minutes
Tadasana (Standing Mountain pose or seated, for those not comfortable standing)
Vrksasana (tree pose) (Can use chair for those not comfortable standing)
Virabhadrasana (warrior I)
PrasaritaPadottanasana (Wide-legged standing
forward bend)
Seated
Setu Bandha Sarvangasana (bridge pose) and SuptaKapotasana (supine pigeon pose)
Vakrsana (Twisted Pose)
Relaxation and breathing (repeated at the
completion of each session)
Praṇayama (Breathingexercises) Diaphragmatic breathing 15 Minutes
Sit and breathe, relaxation, emphasize exhale for relaxation
Talked about how to use breath to relax
Meditation Pose:Siddhasana/Savasana 15 Minutes
==== Refs
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| 36521407 | PMC9744484 | NO-CC CODE | 2022-12-15 00:02:30 | no | Complement Ther Clin Pract. 2023 Feb 13; 50:101715 | utf-8 | Complement Ther Clin Pract | 2,022 | 10.1016/j.ctcp.2022.101715 | oa_other |
==== Front
Complement Ther Clin Pract
Complement Ther Clin Pract
Complementary Therapies in Clinical Practice
1744-3881
1873-6947
The Authors. Published by Elsevier Ltd.
S1744-3881(22)00185-2
10.1016/j.ctcp.2022.101717
101717
Article
Yoga for COVID-19: An ancient practice for a new condition – A literature review
Capela Santos Denise a
Jaconiano Sónia b
Macedo Sofia cd
Ribeiro Filipa cd
Ponte Sara e
Soares Paula cdf
Boaventura Paula cdf∗
a ESESFM – Escola Superior de Enfermagem S. Francisco das Misericórdias, Lisboa, Portugal
b EAAD - School of Architecture Art and Design, University of Minho, 4800, Guimarães, Portugal
c IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
d i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
e Independent Researcher, Portugal
f FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal
∗ Corresponding author. i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal.
13 12 2022
2 2023
13 12 2022
50 101717101717
13 9 2022
15 11 2022
11 12 2022
© 2022 The Authors
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
A substantial proportion of people with acute COVID-19 develop post-COVID-19 condition (previously known as long-COVID) characterized by symptoms that persist for months after the initial infection, including neuropsychological sequelae. Post-COVID-19 condition frequency varies greatly according to different studies, with values ranging from 4 to 80% of the COVID-19 patients.
Yoga is a psycho-somatic approach that increases physical, mental, emotional and spiritual strength, and connection. Yoga practice enhances innate immunity and mental health, so it can be used as complementary therapy in the COVID-19 treatment, namely the post-COVID-19 condition.
In this article, we conducted a literature review on yoga and COVID-19, finding that an intervention comprising asana, pranayama, and meditation may be a strategy of choice for these patients’ recovery. However, further studies are needed to show its effectiveness in this, still unknown, context.
Keywords
Yoga
COVID-19
Post-COVID-19 condition
Mind-body therapy
==== Body
pmc1 Introduction
Currently, the world is facing an outbreak of a highly infectious disease named COVID-19. This disease is caused by the novel coronavirus SARS-Cov-2, which is a positive-sense single-stranded RNA virus [1]. In humans, this virus enters the host cells through the receptor angiotensin-converting enzyme 2 (ACE2) with the help of a spike (S) protein [2]. The infected individuals may present mild to moderate symptoms, with an important proportion requiring hospitalization due symptom severity and sudden deterioration [3]. The most common symptoms are profound fatigue, dyspnea, sleep difficulties, anxiety or depression, reduced lung capacity, memory/cognitive impairment, and hyposmia/anosmia [4].
For some patients the symptoms are harsh and longer lasting [5], and may result in the post-COVID-19 condition, characterized by the presence of COVID-19 symptoms with a duration of ≥2 months [4]. The frequency of this condition varies greatly according to different studies, with values ranging from 4 to 80% of the COVID-19 patients [4].
In a cohort of 97 post-COVID-19 condition patients which were followed-up prospectively from month 5, only 22.9% were completely free of symptoms at month 12 [6]. In a larger study, including 2320 adults recruited for the post-hospitalization COVID-19 study, discharged from hospital across the UK following hospital admission with COVID-19, a minority felt fully recovered at 1 year. This is important, considering there are no effective pharmacological or non-pharmacological interventions for post-COVID-19 symptoms [6]. Beyond the direct effects of SARS-CoV-2 infection involving the lung parenchyma, the post-viral long-term complications of post-COVID-19 condition mainly affecting the central nervous system are still largely unknown. Ongoing symptoms of inattention, executive function, memory loss, anosmia, ageusia, headaches, cerebrovascular accidents and meningoencephalitis have been diagnosed in patients under 60 [7]. More larger clinical studies are required to understand the duration and the long-term effects of the post-COVID-19 condition [8], since the condition may affect millions of people around the world [9]. According to the recent Delphi consensus to end the COVID-19 public health threat, the post-COVID-19 condition has emerged as a serious chronic condition still lacking adequate understanding and appropriate preventive or curative solutions [10]. The consensus recommended that research funding for this condition should be prioritized [10].
The growing field of Integrative Medicine research crosses with the intensive search for successful treatments for COVID-19 infection [11]. The practice of yoga, including pranayama and meditation, may modulate stress and inflammation, and possible forms of immune system enhancement, along with potential implications for counteracting some forms of infectious challenges [11,12]. The ability to proactively handle everyday life stress may lighten the constant activation of the endocrine system, increasing the effectiveness of the immune system [13].
In this article, we conducted a literature review on PubMed using the keywords “yoga” and “COVID-19”, to assess the suitability of yoga as a therapy for COVID treatment. Currently, there are no published data on the effects of yoga use for COVID-19 symptoms improvement, other than some scarce ongoing clinical trials. However, since yoga practice enhances innate immunity and mental health [14], it can be proposed as a complementary therapy in the COVID-19 treatment, namely the post-COVID-19 condition. The use of yoga to alleviate the COVID 19 burden in non-patients (e.g. health care workers, lockdown effects, anxiety/fear caused by the pandemic, social isolation) is also discussed.
2 Yoga as an ancient practice
Yoga is an ancient Indian practice aiming to achieve the equilibrium of mind and body by controlling person's emotions [15]. According to the Indian tradition and to archaeological evidence (namely seals containing postures that were found at Mohenjo-Daro), it has been said that yoga originated in the Indus Valley around 5000 years ago [16,17]. However, recent data refute this theory, arguing that prior to 500 BC there is very little evidence in South Asian textual or archaeological sources pointing to the existence of systematic, psycho-physical techniques that can be considered as what the word “yoga” later came to mean [18].
Yoga is mentioned in the classic Indian poem Mahabharata (400 BC - 400 AD), being discussed in the most famous part of that poem, the Bhagavad-gita [19]. Yoga was systematized by Patanjali in the Yoga Sutras around the 4th century AD [20,21]. Patanjali defined the ultimate goal of yoga (and of human existence) as self-realization (using a neo-Vedantic term), the final state of consciousness, the state of consciousness in which nothing can be discerned except the pure self [20]. Therefore, yoga has begun as a contemplative practice aiming at the transformation of the self through the systematic use of particular behavioral and spiritual practices [22]. In its spiritual approach, yoga postures were originally created for building muscles so the practitioner would be able to do seated meditation for hours.
Yoga relies on the holistic principle of connecting the body, mind, and consciousness [23]. It is a psycho-somatic approach which equilibrates all parts of one's life from the physical, mental, emotional to spiritual spectrum [7]. The practice of yoga unifies the mind and body through its three pillars: asana (body postures), pranayama (breathing exercise), and meditation with or without chanting mantras [12,23,24].
Ancient yogis did not consider yoga to be a therapy; for them yoga was a path to liberation, a way to end suffering [25]. However, they found that yoga allowed them to have more health, which was good for spiritual development, since illness was an impediment to the practice [25].
3 Yoga as a mind-body approach for health
Modern yoga emerged in the late nineteenth to the mid–twentieth century, from the bridge between the worlds of Indian spirituality and European physical culture [19,26], resulting in a practice with extraordinary international and cross-cultural appeal [26]. Nowadays, yoga has become an integral part of modern society, and its popularity is growing exponentially [22]. An example of yoga widespread cultural influence is the proclamation by the United Nations General Assembly of the International Yoga Day, which occurs at 21 June since 2014 [22].
Research on the psychophysiological effects of yoga practice began with the work of Sri Kuvalayananda in 1920 [27] who published his results in the first journal dedicated to yoga research (Yoga Mimamsa) that he launched in 1924 [21,24]. The techniques of yoga, which were originally conceived for the removal of human suffering, may be considered as a psychophysiological therapy [28]. Yoga began to be considered as a therapeutic intervention at the beginning of the twentieth century [22]. For instance, B. K. S. Iyengar adapted yoga for therapeutic purposes, and in this context has pioneered the use of props such as wood blocks, benches, bolsters, and straps while doing the postures [21], making them easier to perform in the context of a disease condition.
The use of yoga as a mind-body approach for health became widespread with the increase in both biomedical research on psychophysiology of yoga practices and clinical trials on yoga therapy, supported in part by the NIH in the USA, and the Ministry of AYUSH in India [22].
Yoga can reduce the fight or flight stress response by increasing vagal stimulation [23,29]. Psychosocial stress can reduce immunity against infections and overstimulate host inflammatory responses, leading to tissue damage and even death [23].
Yogic practices help in the management of stress and stress-induced disorders via downregulation of the hypothalamic–pituitary–adrenal (HPA) axis response to stress, thus improving parasympathetic activity [12,30,31]. The inhibition of the sympathetic area of the hypothalamus optimizes the body's sympathetic responses to stressful stimuli, reestablishing the stress-associated autonomous regulatory reflex mechanisms [32]. In addition to allowing for a predominance of the parasympathetic state, yoga may also promote effective extraction of oxygen by peripheral tissues [33].
Yoga has been reported as changing brain activation patterns and altering the perception of pain [34]. An increase in amygdala and frontal cortex activation has been observed after a yoga intervention, along with an increase in gray matter [34]. The observed increase in brain wave activity may explain the decreases in anxiety and increases in focus which occur after yoga training interventions [34].
Sometimes yoga is equated with physical exercise, but the aim of yoga is to control the mental modifications with physical postures as one of the scaffolds [35]. This is why asana are performed with slow movements, synchronized breathing and mindful awareness, differently from other physical exercises [35]. Compared to physical exercise, yoga may be more effective in improving health related conditions [29].
4 Why should we use yoga for COVID-19 disease?
The Eastern mind-body practices have become more popular since the COVID-19 pandemic, due to the mental health concerns the pandemic has created among the general population worldwide [36].
Yoga and meditation are known to help in alleviating mental stress and anxiety [12,37,38], having a positive effect on psychological wellbeing [37]. So, yoga may have an important role in the psycho-social aspects and recovery of COVID-19 patients who have been isolated and disengaged, namely through the adjustment of their anxiety feelings [37,39,40]. Stress, anxiety and depression may be associated with increased susceptibility to viral upper respiratory infections, suggesting that the assumption of an association between psychological distress and a weak immune response to COVID-19 infection is biologically plausible [41].
Yoga practice is a potential strategy for enhancing innate immunity and mental health, justifying its use as adjunctive treatment in COVID-19 [14]. Due to its immunity-boosting potential, yoga may diminish the severity of the disease, preventing the exaggerated immune response to the cytokine storm, which plays a pivotal role in the disease aggravation [3,14].
Yoga has been associated with various cardioprotective effects, preventing lung and cardiac injury, what is also important in COVID-19 [14]. In an early phase of COVID-19, a yoga intervention may offer an indirect antiviral effect due to its anti-inflammatory, anti-oxidation, and immune-enhancing features [3].
The apparent association of yoga with increased melatonin activity may be another aspect of its beneficial properties for COVID-19 infection [11], since melatonin plays some role in the treatment of viral infections [42].
Reduction of inflammatory markers and improvement in the activity of the specific immune cells involved in the pathogenesis of COVID-19 are mostly needed [30]. The probable usefulness of yoga in COVID-19 has been inferred from its effects on similar conditions such as acute upper respiratory infections, obstructive lung disorders, and so on [30].
The upper respiratory tract is the entrance for the SARS-CoV-2 virus, therefore the respiratory system health is very important [43]. Yoga practice has been reported as improving chronic obstructive pulmonary disease (COPD) [43], namely through the increase of tolerance to exercise [44]. COVID-19 disease has a high mortality due to lung infection, so yoga can be effective in preventing premature death of COVID-19 related lung infection [45].
Yoga is the oriental practice with the largest body of evidence in favor of potential benefits, either due to a greater volume of studies, or to the fact that it is the mind-body practice more widespread in the West [46]. Even though most studies do not have a very robust body of evidence, yoga seems to be a simple, safe and low-cost therapeutic alternative for quality of life improvement, positively influencing the physiological and biochemical parameters of the practitioners [46]. Yoga can be practiced by anyone, requires no infrastructure, and is a restorative individual activity which can be easily practiced during periods of social isolation such as the ones we have been experiencing with the COVID-19 pandemic [47], namely through sessions in a tele-yoga format [48,49]. Another possibility is the use of mobile applications, such as the Yoga of Immortals, which has been shown to significant decrease symptoms of depression and anxiety after an 8-week period regular use [50], and to alleviate insomnia [50,51]. A survey conducted in Australia found that the absence of the common benefits of practicing yoga in person, such as social interaction and attending a dedicated space, did not greatly diminish the perceived mood/mental health benefits of the tele-yoga practice [52]. So, yoga may be a simple and advantageous home-based practice for the prevention and post-recovery of COVID-19 [53,54].
In the context of the COVID-19 pandemic, yoga may improve mental health status, immunity against viral infections, systemic health parameters, quality of life, and/or chances of survival in patients with comorbidities [31]. However, the studies published to date are small and are not randomized control trials (RCTs), though RCTs are now being proposed [55]. Some published quasi-randomized controlled or quasi-experimental studies have shown that a yoga intervention can be an effective add-on practice for stress, anxiety, and depression reduction in COVID-19 patients [56,57].
5 How to use yoga for COVID-19 patients
Pranayama, one of the main components of yoga, appears to be a good strategy for these patients, not only for dyspnea relief, but for psychological well-being. Consistent practice of pranayama improves lung function and capacity by strengthening the inspiratory and expiratory muscles [30], increases vital capacity, reduces heart rate, and declines systolic blood pressure [58]. A slow breathing of 6–10 breaths per minute appears to be an “autonomically optimized respiration”, with an increased tidal volume which is achieved through diaphragmatic activation [59]. Breathing difficulty is one of the COVID-19 patients major discomforts; the patients experienced the valuable effects of pranayama in overcoming the breathing difficulty [60].
Anuloma-viloma, one type of pranayama characterized by alternating breathing through the nostrils, removes minor blockages, balances the flow of breath in both nostrils, and decreases heartbeat and blood pressure [45]. Sudarshan Kriya Yoga (SKY), an advanced controlled cyclic rhythmic breathing technique, is able to augment overall immunity against various microbial, fungal, and viral infections [31]. Since COVID-19 disease has a higher mortality due to lung infection, SKY may prevent premature death in this situation [45].
Bhramari, a pranayama with a prolonged exhalation producing a bee-like buzzing sound, helps to relieve stress and cerebral tension, and to manage depression, anxiety, and insomnia in COVID-19 patients [45]. The humming sound creates a vibration which calms the mind and the nervous system, producing an 8–21-fold increase in nasal nitric oxide comparing with a quiet exhalation [45]. Nitric oxide has an important role in the immune system: as a vasodilator it improves blood flow to the organs, causes an anti-inflammatory action in the arteries, and boosts immune defense promoting the destruction of viruses and other parasitic organisms [45]. Bhramari was reported as having a positive impact on psychological health and on sleep quality of COVID-19 patients during home isolation [61]. The patients were performing 20 min bhramari pranayama online during 15 days [61].
Asana proposed to COVID-19 patients should be easy to perform in order to not cause pos-exertion malaise, since fatigue is one of the more common COVID-19 symptoms. Isometric asana have been successfully used for chronic fatigue syndrome (CFS), a condition that shares some features with the post-COVID-19 condition, namely the severe fatigue. Significant fatigue improvement has been reported with isometric asana practice in CFS, supported by alterations in blood biomarkers [62,63].
Meditation has shown to have large effects on several inflammatory markers of COVID-19 patients [64,65] and should be used with standard care treatment in these patients [64,66] to promote general health and well-being [66]. Using meditation, convalescence periods tend to be shorter, and healing from illnesses is quicker [65]. Meditation might enhance neuroplasticity specifically through the mechanisms of relaxation and training of attention [67], allowing COVID-19 patients to better recover from the disease. Mindfulness meditation has potential for treatment of clinical disorders, and might facilitate cultivation of a healthy mind and increased well-being [68].
In India, the Ministry of AYUSH (Ayurveda, Yoga & Naturopathy, Unani, Siddha, and Homeopathy) produced guidelines for post-COVID recovery [69,70], including a yoga protocol focusing on the increase of respiratory and cardiac efficiency, on stress and anxiety reduction, and on immunity enhancement [70]. Marwah and Marwah [71] advise daily sessions of yoga, pranayama and meditation to boost the immune system. Actively promoting mind-body interventions which have shown empirical evidence, such as yoga, might benefit many COVID patients, with a minimal potential for harm [72]. Although more research is certainly needed, there is sufficient rationale, pre-clinical data, and evidence of safety from long-term clinical use of yoga for other common ailments [72].
6 Yoga for COVID 19 burden in non-patients (health workers, lockdown effects, anxiety/fear caused by the pandemic, social isolation)
Healthcare professionals (HCPs) face heavy stress loads [73], particularly in the COVID-19 pandemic context. In fact, according to the Delphi consensus, HCPs continue to experience unaddressed mental issues due to the pandemic [10]. This psycho-physical distress (burnout) compromises the well-being of the workforce and affects patients’ health [73].
A yoga intervention may be an important help to achieve a stable psycho-physical well-being in this stressful work environment [73]. HCPs who practiced yoga during the pandemic reported significantly less stress and psychological distress comparing with the ones who did not practice yoga [74,75]. In another study with HCPs, SKY was shown to have a positive impact on their well-being [76]. Participants reported increased sleep quality, improved satisfaction with life, and higher resilience after SKY [76]. The data reported are important for future multi-site RCTs studying the impact of yoga on HCPs well-being [76]. An RCT conducted to evaluate the effects of laughter yoga in the reduction of perceived stress and burnout levels, and the increase of life satisfaction of nurses, showed that laughter yoga was an effective method [77].
One of the most severely affected age groups due to the prolonged lockdowns are the young adults, especially students [78]. Yoga regular practice has the potential to positively impact students’ physiological, emotional, and immunological factors, affecting their wellbeing and academic performance [78]. SKY was shown to reduce the negative impact of the pandemic on the mental health of practitioners compared to non-SKY practitioners, helping fighting insomnia and other psychological disorders in the general population [79].
Home-office workers who performed a 10 min/day yoga practice for 1 month, using a web platform during the lockdown, experienced decrease in discomfort of the eyes, head, neck, upper back, lower back, right wrist, hips/buttocks and mood disturbance, compared to absence of changes, or even worsening of symptoms, in the control group [80].
7 Yoga protocols in the COVID-19 context
Yoga may play a significant role in the psycho-social care and rehabilitation of COVID-19 patients in quarantine and isolation, being particularly useful in relieving their fears and anxiety [81]. The Ministry of AYUSH has provided guidelines for prevention, rehabilitation and to increase immunity, with contraindications for each disorder the patient may be experiencing [81]. Protocols for COVID-patients and non-COVID patients affected by the pandemic are being developed, namely RCTs which are the gold standard for effectiveness research. Singh et al. [82] proposed a RCT to evaluate the use of yoga in ankylosing spondylitis non-COVID-19 patients. The yoga module was developed keeping in mind the COVID-19 pandemic, so the sessions will be delivered online by certified yoga therapists with over five years of experience through e-health modalities (online video classes) [82]. Dhamodhini et al., recently developed yoga protocols for mild and moderate depression, framed with pre-existing textbooks and scientific literature to target specific depression symptoms [82]. Similar to many other yoga protocols, theirs contains asana, pranayama, mudra (hand gestures), meditation, and relaxation techniques [82]. The recommended practice duration for mild and moderate depression was 45 min and experts insisted on daily practice for 12 weeks. Considering the COVID pandemic, the practices can be done online [82].
In an interesting approach for post-COVID-19 condition recovery and for HCPs, Anand et al. performed a RCT to evaluate the efficacy of a yoga-based breathing intervention [83]. Three groups including COVID-19 positive patients, COVID-19 recovered patients, and HCPs, were included. Simple breathing techniques were administered to COVID-positive patients, while both simple breathing techniques and long duration breathing technique were administered to COVID-recovered patients and HCPs [83]. Yogic breathing lowered D-dimer in all yoga groups when compared with controls; the authors suggest that lowering D-dimer by yogic breathing may be helpful in reducing thrombosis and venous thromboembolism in patients with COVID-19 [83]. The findings suggest that the severity of COVID-19 can eventually be modulated by this practice [83].
Yoga protocols may be useful to overcome social isolation, a situation that got worse with the pandemic. Recently, Yoga4Health was implemented by the NHS (UK); it is a pilot yoga intervention developed to be socially prescribed to patients at risk of developing specific health conditions (risk factors for cardiovascular disease, pre-diabetes, anxiety/depression or experiencing social isolation) [84]. A pilot study evaluation of Yoga4Health has shown that it is a highly acceptable intervention to services users, leading to several biopsychosocial improvements, suggesting yoga is an appropriate intervention to provide on social prescription [84].
Considering that the pandemic begun almost three years ago, and that we presently have many patients with different degrees of severity and duration of the post-COVID-19 condition, there is patient availability to implement large-scale RCTs allowing to clearly show yoga interventions effectiveness in this context. In the tested protocols, it will be important to include an active control group, since most studies compare the effect of yoga with a waiting list, not taking into account the placebo effect.
8 Conclusions
The psychological effects of the COVID-19 pandemic are of particular concern, distressing millions of people worldwide who are directly or indirectly affected by the COVID-19 disease. For post-COVID-19 recovery, there are still no general and adequate strategies, due to the multifactorial aspects of this syndrome, and to its novelty.
Mind-body approaches, which have been used as an adjuvant strategy to other ailments, are now beginning to be considered as possible approaches for COVID-19 patients, and HCPs affected by the pandemic. These low-cost and easy to use solutions will be of paramount importance to protect world's population against the associated symptoms of mental ill-health [85].
Yoga in particular, comprising asana, pranayama, and meditation, seems to be especially adequate for COVID-19 recovery, which is a situation characterized by intense fatigue, muscle weakness, dyspnea, and mental health issues. Due to its properties, yoga is being proposed as a strategy of choice.
One of the limitations of the present review is that most information on yoga effectiveness for COVID-19 recovery is derived from studies developed for the evaluation of other health conditions with similar symptoms. This is a consequence of the modernity of the disease, but yoga is already being prescribed for the COVID-19 recovery in countries like India an UK. Another limitation, which encompasses both COVID studies and previous studies with other pathologies, is that many studies are not RCTs, do not include a large number of patients, and do not have an active control group. More research is warranted to show yoga effectiveness for COVID-19 recovery, since currently there are no available treatments, namely to alleviate the mental health burden caused by the disease.
Funding
This work was supported through funding to P.B. from 10.13039/501100001871 FCT /10.13039/501100003381 MEC through National Funds and co-financed by the FEDER through the PT2020 Partnership Agreement under the project nº 007274 (UID/BIM/04293).
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| 0 | PMC9744485 | NO-CC CODE | 2022-12-15 00:04:04 | no | Complement Ther Clin Pract. 2023 Feb 13; 50:101717 | utf-8 | Complement Ther Clin Pract | 2,022 | 10.1016/j.ctcp.2022.101717 | oa_other |
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Vaccine X
Vaccine X
Vaccine: X
2590-1362
The Author(s). Published by Elsevier Ltd.
S2590-1362(22)00105-X
10.1016/j.jvacx.2022.100245
100245
Article
Factors of influenza vaccine inoculation and non-inoculation behavior of community-dwelling residents in Japan: Suggestions for vaccine policy and public health ethics after COVID-19
Komada Mayuko T. a
Lee Jung Su b
Watanabe Etsuko b
Nakazawa Eisuke c
Mori Katsumi c
Akabayashi Akira cd⁎
a Division of Nursing, Higashigaoka Faculty of Nursing, Tokyo Healthcare University, 2-5-1, Higashigaoka, Meguro-ku, Tokyo 152-8558, Japan
b Postgraduate School of Healthcare, Tokyo Healthcare University 4-1-17 Higashigotanda, Shinagawa-ku, Tokyo 141-8648, Japan
c Department of Biomedical Ethics, University of Tokyo Faculty of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
d Division of Medical Ethics, New York University School of Medicine, 227 East 30th Street, New York, NY 10016, USA
⁎ Corresponding author at: Department of Biomedical Ethics, University of Tokyo Faculty of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
13 12 2022
4 2023
13 12 2022
13 100245100245
29 6 2022
1 12 2022
2 12 2022
© 2022 The Author(s)
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
The aim of this study is to provide basic information that contributes to vaccine inoculation policy after COVID-19. We used the secondary data of the influenza vaccine inoculation behavior survey for community-dwelling adults conducted in 2011, before the COVID-19 pandemic, but after the 2009 novel influenza A (H1N1) pdm 09 pandemic. All factors such as socio-demographic characteristics, health-related behaviors, family environment, physical and social environment, and area of residence were adjusted, and factors related to vaccine inoculation behavior were analyzed. Those living with pregnant women had a significantly higher odds ratio of inoculation; this was self-evident in that those people considered infection to their family. Regarding the social environment, those aged 20–64 years with a significantly higher adjusted odds ratio of inoculation were those with “at least five people with which they interacted in the neighborhood”. This result can be interpreted in two ways relating to altruism in Japan. Finally, we indicated the importance of learning from the past, including the case of 2009.
Keywords
COVID-19
2009 novel influenza A (H1N1) pdm 09
Vaccination policy
Pandemic
Japan
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pmcIntroduction
Various vaccination strategies were discussed during the COVID-19 pandemic, such as prioritizing inoculations (resource allocation), issues of inoculation refusal, and public health significance of vaccines (i.e., preventing infection of others). There were several similar discussions approximately 10 years ago. This was during the 2009 novel influenza A (H1N1) pdm 09 pandemic. The prioritization of inoculations was discussed. The World Health Organization (WHO) [1] stated the following objectives: 1) integrated functioning of the health care system and protection of the basic foundations of each country, 2) reduction of morbidity and mortality, and 3) reduction of virus transmission in society. In this context, they stated that health care workers should be prioritized. In addition, the US Centers for Disease Control and Prevention (CDC) [2] stated that health care workers and emergency personnel should be prioritized given their impact on the medical system, after which pregnant women and those with concerns about exacerbation of illness should be prioritized. At the time, the CDC prioritized younger people aged 6 months to 24 years due to their collective actions and movement (i.e., from the public health belief that they would spread infection throughout society). The national awareness survey on H1N1 vaccine inoculation in Japan is of interest (2009, N = 600) [3]. At this point, H1N1 vaccine inoculation was decided to be voluntary. As a result, 1) 60% wanted inoculation, but 30% did not. The reason for wanting inoculation was “for self-protection,” and not wanting inoculation was “safety concerns”. 2) There was strong resistance against international vaccines (safety concerns), 3) there were concerns about vaccine effectiveness, and 4) parents actively recommended their children aged less than 15 years to get the vaccine. Prioritization of vaccine provision to healthcare professionals was supported by over 90% of respondents.
Therefore, society has had a considerable debate regarding inoculation policies at the time of the novel influenza A (H1N1) pdm 09 pandemics. Based on current knowledge (as of June 2022), the differences between H1N1 and COVID-19 were: 1) COVID-19 is more lethal than H1N1, but its lethality is incomparably low when compared to Ebola hemorrhagic fever or SARS; 2) COVID-19 appears to have higher infectivity, and 3) COVID-19 has a faster appearance of mutant variants. In this way, although there are differences (not yet confirmed as scientific fact), the discussions at the time of the H1N1 pandemic appear to be very helpful for the current COVID-19 pandemic.
Therefore, this study considered further learning from conventional influenza vaccine inoculation policy and people’s inoculation behavior. This present study aims to use the data of the influenza vaccine inoculation behavior survey for community-dwelling adults conducted in 2011, before the COVID-19 pandemic but after the 2009 novel influenza A (H1N1) pdm 09 pandemic. Secondarily, all factors such as socio-demographic characteristics, health-related behaviors, family environment, and physical/ social environment of the area of residence were adjusted; and factors related to vaccine inoculation behavior re-analyzed. Basic materials contributing to vaccine inoculation policy after COVID-19 and several recommendations will be provided. The present study may be useful for combating mild to moderate but highly contagious emerging infectious diseases rather than highly lethal ones such as Ebola hemorrhagic fever and SARS.
Summary of global status of influenza
Morbidity and mortality: Influenza affects 5–10% of adults and 20–30% of children worldwide early, with an estimated 3–5 million illnesses and 250,000–500,000 deaths yearly [4]. Meanwhile, 80% of influenza-related deaths are among older adults [5], with high complications risks, hospitalizations, and deaths among older adults ≥65 years [6], [7], [8], [9], [10], people with underlying illnesses [11], [12], [13], [14], [15], and children <five years. In addition, pregnancy has been reported to increase the risk of complications due to influenza morbidity among healthy adult females [16]. Thus WHO has indicated older adults, people with underlying illnesses, pregnant women, and children aged 6–23 months as high-risk individuals. Inoculation is recommended for those who are in regular contact with these high-risk individuals [17].
Factors related to influenza vaccine inoculation behavior: Previous studies
In 2011, the inoculation rate among Japanese people was 28.6% in those aged 13–64, years [18]. Research on factors related to vaccine inoculation behavior includes older adults [19], [20], [21], [22], people with underlying illnesses and outpatients [23], [24], [25], adults [26], [27], [28], [29], [30], health care workers [31], [32], and pregnant women [33], [34]. Furthermore, surveys have been conducted to examine the relationship between inoculation and socio-demographic characteristics (e.g., age, sex, educational history, and annual household income), health conditions (e.g., presence or absence of underlying illnesses), and health behaviors (e.g., exercise, drinking, and smoking habits). However, no study has examined the relationship between inoculation and the presence or absence of pregnant women in the same home. The physical environment of the residential area is also important. It was reported that the inoculation rate increases with secured access to medical institutions in the United States [19], [20]. The relationships between inoculation behavior and the degree of involvement with friends and neighbors have been investigated as social factors. A study in Italy showed that inoculation rates were high in environments where neighbors assisted when in need [35]. Inoculation is impacted by information provided by social networks, and the relationship between social participation and inoculation has also been investigated [36].
In this way, vaccine inoculation behavior is influenced by factors such as age, sex, educational history, work, illnesses while an outpatient, and health-related behaviors; simultaneously, the family environment and the physical and social environments of the residence are also involved. In Japan, the Immunization Act was revised in 1976, and up to 1994, to prevent exacerbation of the illness among the elderly, mass influenza vaccine inoculations were required for elementary and junior high school students, whose infection was likely to increase infection rates in the community [37]. However, the government suffered a series of lawsuits for damages and health impairment in elementary and junior high school students caused by the mass inoculations. The revision of the Immunization Act in 1994 excluded influenza from the target diseases for regular inoculation [37], [38]. After the abolition of mass inoculations for elementary and junior high school students, the number of deaths among community-dwelling older adults increased during the influenza epidemic [37]. Given the movement of recommending inoculation to older adults overseas, the Immunization Act was revised in 2001, and vaccine inoculation became recommended for older adults. Currently, according to the Immunization Act, inoculations are recommended for “≥65 years; alternatively, those ≥ 60 years and > 65 years, with disabilities that extremely restricted their activities of daily living due to the functions of their heart, kidneys, or respiratory organs; or those who have a degree of impaired immune function from human immunodeficiency virus that makes activities of daily life nearly impossible” [39].Given this background, we divided subjects into two age groups (20–64 years and ≥ 65 years) in this study and analyzed the data with the presence or absence of vaccine inoculations the objective variable and other factors as the explanatory variables.
Methods
1. Survey area and participants
This study used secondary data of the “Survey on Citizens’ Health Awareness, Health Condition, and Health Behaviors” conducted by a city in the Tohoku region. The survey involved distributing questionnaires in October 2011, retrieved by participants visiting the health and hygiene promotion committee within two weeks. Compared to the national survey results [40], the survey region had many families with three or more generations living together and a large amount of snow cover. Participants were 5,002 randomly selected people and stratified according to districts, sex, and age out of 99,653 citizens aged 20 years or older and under 80 years in the Basic Resident Register as of March 31, 2011. There were 26 districts in the city, and the extraction rate was changed to ensure equal distribution per district, and the number of men and women selected from each district was the same. A vaccine inoculation ticket (postcard) was mailed to the subjects at the time of the survey. The out-of-pocket cost of inoculation for influenza vaccine recommended for individuals (≥65 years, or ≥60 years and <65 years, and with underlying illnesses as stipulated by the Immunization Act) was JPY 1,500 (about USD 11) and 50% subsidy by city.2. Survey items
Socio-demographic characteristics included age, sex, educational history, annual household income, type of work, and illness during hospital visits. Health-related behaviors evaluated in the survey included general health examinations and cancer screenings in the past year. Exercise, eating, drinking, and smoking habits, family environment (including living with pregnant women), as well as the physical and social environment of the area of residence were assessed. The social environment included four-choice items on the number of people that the participants interacted with in the neighborhood (20 people or more, 5–19 people, four people or fewer, no acquaintances/interactions) was divided into two (≥5 people, ≤ 4 people) for analysis. Subjects were asked to answer either “yes” or “no” regarding whether the influenza vaccine inoculation was received in the past year.3. Ethical considerations
Self-administered anonymous questionnaires were used for the study. Consent to the survey was obtained by submission of the questionnaire. This study was approved by the Institutional Review Board of the University of Tokyo School of Medicine (approval number 1568-(4)).4. Statistical analysis
Percentages or mean values (standard deviation, SD) of socio-demographic characteristics, health-related behaviors, family environment, and the area of residence were calculated to understand the characteristics of the participants. In this study, participants were divided into ages 20–64 and ≥65 years. The presence or absence of influenza vaccine inoculation was set as the objective variable, and other items were set as the explanatory variables. The crude odds ratio was used to investigate relationships between inoculation behavior and each item. Furthermore, multiple logistic regression analyses we conducted by adjusting for all items of socio-demographic characteristics, health-related behavior, family environment, and environment of the area of residence.
In logistic regression analysis, the adjusted odds ratio of vaccine inoculation for those aged 20–64 years and vaccine non-inoculation for those ≥65 years were obtained. In the Japan, influenza vaccination is recommended for people aged ≥65 years and people with certain diseases aged 60–64 years. Therefore, we have decided to focus on the characteristics of those 1) who are non-vaccinated in the ≥65 years age group, and 2) healthy adults under 64 years old who are vaccinated although vaccinations are not recommended. Stata Ver.15 were used for analyses, and the significance level was set to 5% on both sides.
Results
1. Survey subjects and analysis subjects ( Table 1 ) Table 1 Socio-demographic characteristics of the analyzed participants.
20–64 years 65–79 years
n=3,162 n=1,103
Age 45.6 (12.7) 71.9 (4.2)
20–39 years 1,078 (34.1)
40–64 years 2,084 (65.9)
Sex
Female 1,622 (51.3) 559 (50.7)
Male 1,540 (48.7) 544 (49.3)
Educational history (final educational history)
Junior high school 250 (8.3) 546 (53.4)
High school 1,729 (57.6) 358 (35.0)
Vocational school / junior college / university / graduate school 1,024 (34.1) 119 (11.6)
Household income
Less than 2 million yen 475 (20.8) 243 (33.5)
2–6 million yen 1,341 (58.8) 407 (56.1)
6 million yen or more 466 (20.4) 75 (10.3)
Work
Work (all day) 1,723 (54.9) 67 (6.3)
Agriculture and forestry-industry / self-employed 469 (15.0) 246 (23.2)
Work (part-time) 366 (11.7) 41 (3.9)
Unemployed 580 (18.5) 706 (66.6)
Illnesses for hospital visits
Not going to hospital 2,328 (77.5) 295 (33.6)
Lifestyle-related illnesses† 555 (18.5) 509 (58.0)
Orthopedic illnesses‡ 122 (4.1) 74 (8.4)
For age, results show mean (standard deviation); for others, the number of people (%).
†:Includes diabetes, angina, myocardial infarction, asthma, hypertension, stroke, hypercholesterolemia, hypertriglyceridemia, gout, hyperuricemia, stomach/duodenal illnesses, hepatitis, liver cirrhosis.
‡:Includes lower back pain, knee joint pain, and osteoporosis.
Questionnaires were distributed to 5,002 participants, and 4,570 returned theirs (91.3%). Those whose age, sex, presence or absence of influenza vaccine inoculation was unknown or those outside the target age range (80 years or older) were excluded; Thus, 4,265 (85.2%) participants were analyzed.2. Influenza vaccine inoculation rate in Japan
The overall inoculation rate for those aged 20–79 years was 40.2% (1,714), with 33.8% for men and 46.3% for women. The overall inoculation rate was 31.7% (342) for those aged 20–39 years, with 22.6% for men and 40.6% for women (P < 0.001); 31.1% (648 people) for those aged 40–64 years, with 23.3% for men and 38.4% for women (P < 0.001); and 65.6% (742 people) for those aged 65–79 years, with 64.2% for men and 67.1% for women (P = 0.306). The inoculation rate for women was higher than for men in all age groups.3. Factors relating to influenza vaccine inoculation behavior
3.1. Relationship between 20–64 years vaccine inoculation behavior, ≥65 years vaccine non-inoculation behavior, and all survey items (univariate analysis, Table 2 ).Table 2 Associations between influenza vaccine inoculation/non-inoculation behavior and socio-demographic characteristics, health-related behavior, family environment, and physical/social environment of the area of residence (univariate analysis).
20–64 years 65–79 years
Vaccine inoculation behavior Vaccine non-inoculation behavior
OR (95%C.I.) p-value OR (95%C.I.) p-value
Age
20–39 years 1
40–64 years 0.97 (0.83, 1.14) 0.717
Sex
Female 1 1
Male 0.47 (0.40, 0.54) <0.001 1.14 (0.89, 1.46) 0.306
Educational history (final educational history)
Junior high school 1 1
High school 1.32 (0.97, 1.81) 0.081 1.07 (0.81, 1.42) 0.624
Vocational school / junior college / university / graduate school 2.23 (1.61, 3.08) <0.001 1.08 (0.71, 1.64) 0.726
Household income
Less than 2 million yen 1 1
2–6 million yen 1.44 (1.14, 1.83) 0.002 0.82 (0.59, 1.14) 0.228
6 million yen or more 1.89 (1.43, 2.50) <0.001 0.61 (0.34, 1.07) 0.083
Work
Work (all day) 1 1
Agriculture and forestry-industry / self-employed 0.58 (0.46, 0.74) <0.001 0.69 (0.40, 1.19) 0.179
Work (part-time) 0.80 (0.63, 1.03) 0.082 0.97 (0.44, 2.11) 0.929
Unemployed 0.94 (0.77, 1.15) 0.530 0.61 (0.37, 1.01) 0.057
Illnesses for hospital visits
Not going to hospital 1 1
Lifestyle-related illnesses† 1.35 (1.11, 1.64) 0.002 0.41 (0.31, 0.56) <0.001
Orthopedic illnesses‡ 1.35 (0.93, 1.98) 0.119 0.43 (0.25, 0.74) 0.002
General medical examinations
Present 2.23 (1.80, 2.75) <0.001 1
Absent 1 3.82 (2.78, 5.27) <0.001
Cancer screenings
Present 2.09 (1.78, 2.44) <0.001 1
Absent 1 2.52 (1.91, 3.32) <0.001
Exercise habits♯
Present 1.09 (0.90, 1.31) 0.395 1
Absent 1.47 (1.10, 1.97) 0.009
Consideration for eating habits
Present 1.66 (1.42, 1.93) <0.001 1
Absent 1 1.16 (0.90, 1.50) 0.260
Alcohol drinking habits§
Present 0.70 (0.59, 0.84) <0.001 1
Absent 1 0.81 (0.60, 1.10) 0.186
Smoking habits
Never smoked 1 1
Quit smoking 0.90 (0.75, 1.08) 0.252 1.06 (0.79, 1.41) 0.699
Smoking 0.47 (0.39, 0.57) <0.001 2.48 (1.66, 3.70) <0.001
Family composition
Couple 1 1
Single 0.63 (0.40, 0.98) 0.040 1.69 (1.06, 2.67) 0.026
2-generation household 0.84 (0.65, 1.10) 0.210 1.38 (0.99, 1.92) 0.057
3+ generation household 1.01 (0.76, 1.33) 0.949 1.01 (0.69, 1.49) 0.955
Other 0.86 (0.62, 1.20) 0.373 1.43 (0.91, 2.26) 0.120
Cohabitation with pregnant woman
Present 1.72 (1.19, 2.49) 0.004 1
Absent 1 0.64 (0.19, 2.10) 0.457
Cohabitation with preschool infant
Present 1.56 (1.30, 1.89) <0.001 1
Absent 1 0.76 (0.47, 1.21) 0.249
Cohabitation with elementary school student
Present 1.67 (1.40, 1.98) <0.001 1
Absent 1 1.37 (0.97, 1.93) 0.074
Environment of area of residence: physical
There are sidewalks on almost all roads
Yes 1.03 (0.88, 1.21) 0.691 1
No 1 1.09 (0.83, 1.44) 0.517
There are train stations / bus stops in neighborhood
Yes 1.03 (0.88, 1.21) 0.685 1
No 1 1.12 (0.85, 1.48) 0.411
There is a hospital that can be reached immediately in event of sudden illness
Yes 1.38 (1.18, 1.61) <0.001 1
No 1 1.45 (1.10, 1.91) 0.008
Environment of area of residence: social
Number of people with whom participant is interacting in neighborhood
5 or more 1.38 (1.18, 1.61) <0.001 1
4 or fewer 1 1.34 (1.01, 1.76) 0.039
There are neighbors who lend a helping hand when needing help
Yes 1.20 (0.98, 1.46) 0.082 1
No 1 1.40 (0.95, 2.06) 0.091
There is participation in community activities
Yes 1.27 (1.07, 1.51) 0.004 1
No 1 1.20 (0.88, 1.65) 0.253
OR:crude odds ratio.
C.I.: confidence interval.
†:Includes diabetes, angina, myocardial infarction, asthma, hypertension, stroke, hypercholesterolemia, hypertriglyceridemia, gout, hyperuricemia, stomach/duodenal illnesses, hepatitis, liver cirrhosis.
‡:Includes lower back pain, knee joint pain, and osteoporosis.
♯:At least twice a week, at least 30 min per session, except in winter.
¶:Following all apply: pay attention to nutritional balance, eat vegetables every day, no excess salt intake.
§:At least three times a week, at least one go (∼0.18 L) per session.
Socio-demographic characteristics: those aged 20–64 years with a significantly higher percentage of influenza vaccine inoculation included women, those with educational history of vocational school or above, those with a high annual household income, those who worked all day compared to people in agriculture, forestry, or fisheries, and those who visited the hospital for lifestyle-related illnesses. Those aged ≥65 years with a significantly lower percentage of vaccine non-inoculation was those who visited the hospital for lifestyle-related or orthopedic illnesses.
Health-related behavior: Those aged 20–64 years with a high influenza vaccine inoculation rate were found to have undergone general medical examinations and cancer screenings, made efforts to eat healthy without drinking alcohol, and exhibited a low rate of smoking. Those aged ≥65 years with a high rate of influenza vaccine non-inoculation were those who did not undergo general medical examinations or cancer screenings and smoked at a higher rate.
Family environment: Those aged 20–64 years with a high rate of influenza vaccine inoculation had a couple of households with three generations or more as opposed to single households in terms of family composition. Among families living together, those living with a pregnant woman, preschool infants, or elementary and junior high school students had a high rate of inoculation. Those aged ≥65 years with high rates of vaccine non-inoculation were those who lived alone. No significant differences were also seen among families living together.
Physical and social environment of the area of residence:
Physical environments among those aged 20–64 years with a significantly higher rate of vaccine inoculation included immediate healthcare access in the event of a sudden illness; social environments included those that interacted with five or more in the neighborhood and participation in community activities. Physical environments among those aged ≥65 years with a significantly higher rate of vaccine non-inoculation were those without immediate healthcare access in the event of a sudden illness. Social environments included those who interacted with four or fewer in the neighborhood.
3.2. Independent associations with influenza vaccine inoculation/non-inoculation behaviors (multiple logistic regression analysis, Table 3 ).Table 3 Associations between influenza vaccine inoculation/non-inoculation behavior and socio-demographic characteristics, health-related behavior, family environment, and physical/social environment of the area of residence (multivariate analysis).
20–64 years 65–79 years
Vaccine inoculation behavior Vaccine non-inoculation behavior
AOR (95%C.I.) p-value AOR (95%C.I.) p-value
Age
20–39 years 1
40–64 years 0.71 (0.54, 0.94) 0.017
Sex
Female 1 1
Male 0.51 (0.38, 0.67) <0.001 0.80 (0.40, 1.59) 0.520
Educational history (final educational history)
Junior high school 1 1
High school 1.71 (0.99, 2.98) 0.056 1.16 (0.67, 1.99) 0.597
Vocational school / junior college / university / graduate school 2.71 (1.53, 4.78) 0.001 1.17 (0.53, 2.57) 0.699
Household income
Less than 2 million yen 1 1
2–6 million yen 1.24 (0.91, 1.69) 0.179 1.15 (0.65, 2.03) 0.642
6 million yen or more 1.30 (0.90, 1.88) 0.168 0.81 (0.33, 1.96) 0.633
Work
Work (all day) 1 1
Agriculture and forestry-industry / self-employed 0.54 (0.35, 0.75) 0.001 0.95 (0.32, 2.84) 0.928
Work (part-time) 0.70 (0.49, 1.01) 0.057 1.19 (0.23, 6.08) 0.833
Unemployed 0.90 (0.65, 1.25) 0.538 0.60 (0.21, 1.70) 0.340
Illnesses for hospital visits
Not going to hospital 1 1
Lifestyle-related illnesses† 1.59 (1.19, 2.12) 0.002 0.60 (0.26, 0.74) 0.002
Orthopedic illnesses‡ 1.95 (1.18, 3.22) 0.009 0.44 (0.11, 1.22) 0.102
General medical examinations
Present 1.60 (1.11, 2.29) 0.011 1
Absent 1 1.89 (0.84, 4.27) 0.126
Cancer screenings
Present 1.32 (1.01, 1.73) 0.039 1
Absent 1 2.35 (1.18, 4.67) 0.015
Exercise habits♯
Present 1.02 (0.78, 1.33) 0.900 1
Absent 1 1.36 (0.80, 2.31) 0.261
Consideration for eating habits¶
Present 1.22 (0.97, 1.53) 0.093 1
Absent 1 0.61 (0.36, 1.04) 0.070
Alcohol drinking habits§
Present 0.86 (0.65, 1.13) 0.282 1
Absent 1 0.81 (0.43, 1.53) 0.523
Smoking habits
Never smoked 1 1
Quit smoking 1.43 (0.70, 1.93) 0.017 1.49 (0.75, 2.97) 0.254
Smoking 0.95 (0.44, 1.28) 0.722 1.63 (0.66, 4.02) 0.292
Family composition
Couple 1 1
Single 0.86 (0.44, 1.67) 0.652 1.59 (0.63, 3.99) 0.326
2-generation household 0.89 (0.61, 1.31) 0.551 1.71 (0.91, 3.21) 0.097
3+ generation household 0.87 (0.57, 1.33) 0.522 1.30 (0.55, 3.05) 0.552
Other 0.94 (0.58, 1.52) 0.807 1.02 (0.40, 2.62) 0.959
Cohabitation with pregnant woman
Present 1.92 (1.13, 3.25) 0.015 1
Absent 1 1.65 (0.08, 35.7) 0.751
Cohabitation with preschool infant
Present 1.19 (0.88, 1.60) 0.263 1
Absent 1 0.60 (0.22, 1.67) 0.328
Cohabitation with elementary school student
Present 1.75 (1.35, 2.27) <0.001 1
Absent 1 3.08 (1.30, 7.33) 0.011
Environment of area of residence: physical
There are sidewalks on almost all roads
Yes 1.23 (1.00, 1.53) 0.048 1
No 1 1.29 (0.77, 2.16) 0.335
There are train stations / bus stops in neighborhood
Yes 0.98 (0.78, 1.23) 0.876 1
No 1 1.20 (0.72, 2.01) 0.480
There is a hospital that can be reached immediately in event of sudden illness
Yes 1.41 (1.13, 1.77) 0.002 1
No 1 1.55 (0.92, 2.62) 0.102
Environment of area of residence: social
Number of people with whom participant is interacting in neighborhood
5 or more 1.36 (1.06, 1.74) 0.017 1
4 or fewer 1 0.99 (0.56, 1.74) 0.970
There are neighbors who lend a helping hand when needing help
Yes 0.95 (0.71, 1.28) 0.753 1
No 1 1.01 (0.48, 2.13) 0.980
There is participation in community activities
Yes 0.99 (0.76, 1.28) 0.940 1
No 1 1.01 (0.57, 1.79) 0.972
AOR:adjusted odds ratio.
C.I.:confidence interval.
†:Includes diabetes, angina, myocardial infarction, asthma, hypertension, stroke, hypercholesterolemia, hypertriglyceridemia, gout, hyperuricemia, stomach/duodenal illnesses, hepatitis, liver cirrhosis.
‡:Includes lower back pain, knee joint pain, and osteoporosis.
♯:At least twice a week, at least 30 min per session, except in winter.
¶:Following all apply: pay attention to nutritional balance, eat vegetables every day, no excess salt intake.
§:At least three times a week, at least one go (∼0.18 L) per session.
Socio-demographic characteristics
Independent associations with vaccine inoculation behavior in those aged 20–64 years showed a significantly lower odds ratios of inoculation in those aged 40–64 years compared to 20–39 years, men in terms of sex, forestry and fishery industry, and self-employed people compared to full-day workers. In addition, significantly higher odds ratios of inoculation were observed in those with vocational school backgrounds or higher compared to those with a junior high school background and those visiting the hospital for lifestyle-related and orthopedic illnesses compared to those without illnesses for which they visit the hospital. Independent associations with influenza vaccine non-inoculation behavior in those aged ≥65 years showed significantly lower odds ratios of non-inoculation (i.e., were more likely to be inoculated) among those visiting the hospital for lifestyle-related illnesses compared to those not going to the hospitals.
Health-related behavior
Independent associations with vaccine inoculation behavior in those aged 20–64 years showed that those with significantly higher odds ratios of inoculation underwent general medical examinations, cancer screenings, and those who quit smoking. Independent associations with vaccine non-inoculation behavior in those ≥65 years revealed significantly lower odds ratios of non-inoculation (i.e., were more likely to be inoculated) among those who underwent cancer screenings.
Family environment
Independent associations with vaccine inoculation behavior in those aged 20–64 years showed that those with significantly higher odds ratios of inoculation lived with pregnant women or elementary or junior high school students. In contrast, vaccine non-inoculation behavior among those ≥65 years revealed that those with significantly higher odds ratios in the non-inoculation group did not live with elementary or junior high school students.
Physical and social environments of the area of residence
In terms of physical environments, the independent associations with vaccine inoculation behavior in those aged 20–64 years showed significantly higher odds ratios of inoculation in those with sidewalks on almost all roads and immediate access to the hospital in the event of a sudden illness. Regarding social environments, people who interacted with at least five neighbors showed independent associations with vaccine non-inoculation behavior among those ≥ 65 years, although no significant differences were found for any items.
Discussion
The greatest strength of the present study is its use of data from the 2011 influenza vaccine inoculation behavior survey for community-dwelling adults, which was conducted before the COVID-19 pandemic but after the 2009 novel influenza A (H1N1) pdm 09 pandemic. The results obtained in this study were almost entirely consistent with what was indicated in previous research. In other words, the significantly lower odds ratio for the socio-demographic characteristics can be explained for men in terms of sex and those aged 40–64 years compared to those aged 20–39 years in terms of age (i.e., in a more important and responsible position, not enough time due to parental care and child-rearing). Compared to those who work all day, agricultural and forestry-industry/self-employed people are thought to potentially be able to obtain opportunities for inoculation (workplace inoculations) depending on the workplace. This result may indicate that the inoculation rate will increase if workplace inoculations are promoted with COVID-19.
Meanwhile, the adjusted odds ratio was significantly higher for highly-educated people in terms of educational history. It can be explained that people who went to the hospital for lifestyle-related and orthopedic illnesses had a high awareness of the illness. Those with significantly higher odds ratios in terms of health-related behaviors included those who underwent general medical examinations, those who underwent cancer screenings, and those who quit smoking; these are all people with high health awareness. In terms of the family environment, previous research [26] has investigated spouses, but the present survey was novel in that it considered cohabitation with pregnant women. However, the results showed that those with a significantly higher odds ratio of inoculation were those who lived with pregnant women and or with elementary or junior high school students. In terms of the physical environment, those with a significantly higher odds ratio were those with sidewalks on nearly all roads and immediate access to a hospital in the event of sudden illness; these results showed access was important.
The only interesting result in the present study is that regarding the social environment. Those aged 20–64 years with a significantly higher adjusted odds ratio of inoculation were those with “at least five people they interacted in the neighborhood.” This result can be interpreted in two ways. The first interpretation is that having many acquaintances and friends in the neighborhood resulted in the transmission of information related to the vaccine and the experience of actually being inoculated, which then impacted inoculation behavior. Secondly, people who interact and engage in social participation may get inoculated due to their awareness of the potential increased risk of infecting others. For example, according to Nagata et al., vaccinated persons are more confident of the vaccine's effectiveness and value its benefits to their families and communities [41]. As will be described later, this perspective is important for public health ethics and will play a major role in future policies.
Commentary on future vaccine policy in relatively wealthy Japan
#1 If men or people busy with work cannot get inoculated, what needs to be done for them to do so? Workplace inoculations, establishing inoculation sites on weekends and at night, and the introduction of mobile vaccine inoculation stations may be effective, but a shortage of public health nurses and general nurses was an issue in the current COVID-19 pandemic. In both cases, a shortage of human resources and funds is expected. Thus, it is important to introduce the practice of subcutaneous injection and intramuscular injection of the vaccine in the education of all medical professionals. The law should be revised to reflect this. In doing so, medical professionals can be mobilized in an emergency.
#2 The convenience of access and workplace inoculation systems have previously been indicated: paving more roads is surely not the sole solution. Particularly for regions with high snow cover or islands, what is the optimal solution? Is having a family doctor an effective strategy for normal healthy people? At the very least, it is strongly recommended that public locations (e.g., public halls, government offices, schools, parks) be organized to become inoculation sites in the event of an emergency. Specifically, such plans should be incorporated into installation standards.
#3 If educational history is relevant, then how can the health literacy of citizens be raised? Is raising health literacy for all diseases difficult, and it is sufficient to do so only if vaccine inoculation is necessary. Interventions at the primary and secondary educational levels to raise health literacy for all diseases are considerably labor intensive. It is perhaps possible in health education to pinpoint the importance of inoculation and the importance of gargling, and hand washing.
#4 Public awareness of individual freedoms and public interest (public awareness on “Public Health Ethics”).
The extremely valuable data obtained in the present analysis were the results regarding the social environment. The result that “those who interact with many people” had a significantly higher odds ratio of inoculation could be interpreted that such people inoculated themselves because contacting with a large number of people by engaging in social participation inevitably increases the risk of infecting the others (i.e., due to the public interest or a certain type of altruism). This is a crucial point in public health ethics. Namely, in an emergency, the question is, how should we consider the balance between the “rights of individual freedoms” and “public interest of the whole”, and to what extent are paternal interventions by the government acceptable.
Such ideas of public health ethics have been rarely discussed in Japan. Punitive measures have been considered for the behavior of some younger people during the present COVID-19 pandemic, but there was little understanding of public health ethics. Government-run COVID-19 vaccine inoculation campaigns for children were also extremely insufficient. The instruction manuals attached to the inoculation tickets given to households only emphasized the point of “preventing infection to their children.” In fact, the perspective of “preventing children from becoming vectors of infection to others and from spreading infection throughout the community (public interest),” which was a major objective of inoculation among children, was entirely missing from the instruction manuals. The explanation that emphasized individual interests only to increase inoculation rates was significantly lacking the perspective of public health.
Why Japan could not lock down is likely a political factor and is beyond the scope of this paper. However, during the present COVID-19 pandemic, some people self-quarantined with the thought that they should not infect the other people. The objective of this paper is not to evaluate the vaccine strategy for the present COVID-19 pandemic. We dug up old data from 10 years ago to indicate the importance of learning from the past. It is undeniable that we had known so much during the H1N1 pandemic. Once again, this statistical secondary analysis of epidemiological data indicate that Japanese have a temperament of certain type of altruism. We hope this paper will serve as a basic material for considering vaccine policy after the COVID-19 pandemic.
Limitations of this study
The first limitation is that this was a cross-sectional study, and the causal relationship between inoculation behavior and each factor was only speculated after considering the effects, and they were not identified. The second limitation is that the surveyed region was just one regional city, and care is needed when generalizing these results to metropolitan areas. The third limitation is that antiviral drugs were widespread at the time, which is thought to have had a large impact on ideas regarding influenza treatment and inoculation behavior, but such aspects cannot be discussed in the present paper.
Conclusions
Influenza is one of the oldest infectious illnesses in history. Global pandemics have repeatedly occurred since the modern era, with the Spanish flu that became widespread in 1918, the discovery of the influenza virus as the pathogen, the Asian flu that started in 1957, the Hong Kong flu in 1968, Russian flu in 1977, and the novel influenza A (H1N1) pdm 09 in 2009 [42]. In each instance, humankind should have been able to learn something regarding infection countermeasures. This issue will be revisited in the future. How did Japan learn from the novel influenza A (H1N1) pdm 09 in 2009? There were already major changes in people’s behavior with COVID-19. We have also found from epidemiological data that Japanese seems to have certain type of altruism. Further analysis and enlightenment of this aspect might be useful to the future vaccination strategy. Once the current COVID-19 pandemic has settled, a new strategy for vaccine inoculation is needed. We must learn from the past and share the wisdom of preparing for the next pandemic at the national and regional levels.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data availability
The authors do not have permission to share data.
Acknowledgements
None.
Funding
None.
==== Refs
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| 0 | PMC9744486 | NO-CC CODE | 2022-12-16 23:18:12 | no | Vaccine X. 2023 Apr 13; 13:100245 | utf-8 | Vaccine X | 2,022 | 10.1016/j.jvacx.2022.100245 | oa_other |
==== Front
Chem Phys Lett
Chem Phys Lett
Chemical Physics Letters
0009-2614
0009-2614
Elsevier B.V.
S0009-2614(22)00917-4
10.1016/j.cplett.2022.140260
140260
Research Paper
Identification of possible binding modes of SARS-CoV-2 spike N-terminal domain for ganglioside GM1
Das Tanushree
Mukhopadhyay Chaitali ⁎
Department of Chemistry, University of Calcutta, 92, A.P.C. Road, Kolkata, 700009, India
⁎ Corresponding author.
13 12 2022
13 12 2022
14026025 8 2022
5 12 2022
8 12 2022
© 2022 Elsevier B.V. All rights reserved.
2022
Elsevier B.V.
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Graphical abstract
Coarse-grained molecular dynamics simulations of the lipid bilayer mixture of POPC and cholesterol were carried out in the presence and absence of ganglioside monosialo 1 (GM1) with N - terminal domain (NTD) of SARS-CoV-2 spike glycoprotein. The interactions of GM1 with two different NTD orientations were compared. NTD orientation I compactly bind GM1 predominantly through the sialic acid and the external galactose moieties providing more restriction to GM1 mobility whereas orientation II is more distributed on the lipid surface and due to the relaxed mobility of GM1 there, presumably, the NTD receptor penetrates more through the membrane.
Keywords
SARS-CoV-2
N - terminal domain
lipid-bilayer
ganglioside
coarse-grained
==== Body
pmc1 Introduction
The gangliosides, minor yet essential components of biological membranes, constitute approximately 2–5% of total membrane lipids and are sequestered with other sphingolipids, cholesterol, saturated - chain phosphatidylcholines [1], [2]. Gangliosides may affect the lateral distributions of lipids in the membrane [3]. They participate in many physiological processes such as membrane fusion, viral budding, and protein sorting [4]. The most widely known ganglioside is the negatively charged ganglioside monosialo 1 (GM1) containing N-acetylneuraminic acid (Neu5Ac) or sialic acid, N-acetylgalactosamine (NAG), two galactoses, and one glucose moiety in its head group. An important structural feature of hydrogen bonding through the head groups provides extensive lipid-ganglioside and protein-ganglioside interaction [5].
Besides ganglioside being populated in the human plasma membrane of neurons [6], the sialic acid (Neu5Ac) linked to the head group of ganglioside is used by many viruses and bacteria as a receptor for cell entry [7], [8]. This phenomenon is well established for the influenza virus, polyomavirus, rotavirus, bovine coronavirus (BCoV), vibrio cholera, etc., but remains elusive for the severe acute respiratory syndrome coronavirus (SARS-CoVs), however, sialic acids are highly expressed on lung epithelial cells [9]. Our current motive is to understand the dynamics of the GM1-containing membrane in driving the spike glycoprotein of SARS-CoV-2 responsible for viral attachment and penetration into the mammalian plasma membrane. For the study, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), cholesterol (CHOL), and GM1 composing the ternary lipid bilayer mixture were selected to mimic the biological membrane.
The spike glycoprotein’s N - terminal domain (NTD) binds preferentially to gangliosides relative to other sphingolipids to penetrate the plasma membrane [10]. However, the approach of CoVs to utilize sialic acid linkages as sites of attachment and invasion in human host cells has not been sufficiently investigated. To our knowledge, only a few computer simulation studies support any direct or indirect interaction of SARS-CoV-2 with ganglioside GM1 in biological membranes [10], [11], [12]. Previous reports claimed that this NTD region is perceived by gangliosides on the lipid raft and must be considered the objective of neutralization of antibodies in vaccine strategies [10], [11] where a linear ganglioside binding domain (GBD) was identified that covers 52 residues of NTD stretching from D111–S162, is a characteristic combination of aromatic and basic residues. In particular, the QFN triad (Q-134, F-135, and N-137) residues at the tip of this domain interact with the sugar moiety of GM1 with CH-π stacking and electrostatic interactions [10], [11]. This indicates that NTD might be a potential receptor for gangliosides and its probable binding sites need to be further studied.
Thus the present study investigates the interaction of GM1 with two different orientations of the NTD sequence of the SARS-CoV-2 spike glycoprotein. Currently, intracellular processes including lipid bilayers such as particle insertion, and other dynamic phenomena occurring at large time and length scales are difficult to deal with at an atomic level in most existing resources so they require coarse-grained (CG) models [13]. Toward this goal, we ran a series of CG molecular dynamics simulations of NTD placed on a membrane bilayer containing 5 % GM1 for a long 10 μs. Indeed, to explore only the role of cholesterol in deriving the trans-membrane spike protein, simulations were also conducted in the absence of GM1 using a binary lipid bilayer mixture of POPC/CHOL. The CG simulation results show that GM1 acts as an antenna to capture NTD of SARS-CoV-2 whereas only the presence of cholesterol in the bilayer mixture was devoid of any interaction.
2 Method
2.1 System setup and simulation parameters
Molecular dynamics simulations of the N-terminal domain (NTD) of the SARS-CoV-2 spike glycoprotein (residues 13 – 305, retrieved from PDB ID: 6vsb using the UCSF Chimera supplemented with Modeller) [14] were performed in the bilayer consisting of a ternary mixture POPC/CHOL/GM1 molar ratio 7:2.5:0.5 and binary mixture POPC/CHOL 7:3 (Table S1) [2]. A coarse-grained representation of the NTD receptor was prepared using the martinize.py script [15] and a lipid system was built with the insane.py script [16]. The lipid bilayer was so structured that the GM1 cluster was present on the upper leaflet, with its head groups protruding onto the membrane. The supplementary Fig. S1 of the modelled membrane depicts the alignment of the GM1 head groups with reference to CG Martini bead mapping of GM1 ganglioside [17] by positioning a GM1 molecule over the lipid bilayer along the z-axis. The protein was placed above the lipid bilayer along the z-axis so that the initial distance between the receptor and each GM1 was at least 10 nm. We used a CG water bead [18] model and the system was neutralized with 0.15M NaCl. The simulation box size was 16×16×18 nm3. All simulations were performed using GROMACS version 5.1.4 [19], with martini force-field version 2.0 [15], [17], [20]. Energy minimization of the system was done using the steepest descent (1000 steps) followed by 10 steps of polak - ribiere conjugate gradient algorithm. The temperature of the system was kept constant at 300 K using the v-rescale algorithm [21] with a coupling constant (τt) of 1.0 ps. The semi-isotropic pressure coupling was sustained at 1 bar independently in the bilayer plane and perpendicular to the bilayer using berendsen barostat [22] with τp= 4.0 ps and compressibility of 4.5×10-5bar-1. The relative dielectric constant in water was set to 15 [23] because of the absence of partial charges in the standard martini water model [24]. The system was equilibrated for 100 ns followed by a production run in NPT ensemble using parrinello−rahman barostat [25] (τp=12psand compressibility = 3×10-4bar-1) and v-rescale thermostat using 20 fs time step. Periodic boundary conditions were maintained in all directions. Two simulations of 10 μs each were carried out at different initial orientations of the receptor (Fig. S1). Also, an independent replica was generated each for the chosen orientations of the receptor on the ternary mixture with random velocity. The lipid bilayers POPC/CHOL/GM1 and POPC/CHOL without the receptor were simulated as controls and we analyzed a total of 80 μs trajectory in this study. The trajectory analysis was done with GROMACS, visually inspected using VMD 1.9.3 software [26] and the plots were created using Matlab R2019b.
3 Results and discussion
3.1 Effect of SARS-CoV-2 NTD on lipid bilayer properties
The POPC/CHOL/GM1 and POPC/CHOL lipid bilayers were constructed along the XY plane, so with the Z axis intersecting the membrane perpendicularly. The bilayer thickness was estimated from the distance between the two peaks of the POPC phosphate head group in the density profile. Without the NTD receptor, after 10 μs simulation the thickness of the POPC/CHOL/GM1 bilayer was observed to be 4.23 nm, whereas, upon interaction with NTD, the thickness of the bilayer was marginally shrunk to 4.18 nm and 4.06 nm for orientation I and II. The interaction of NTD did not alter the area per lipid (AL) of the bilayers in any system as compared to the control. It was consistent with 0.51 nm2 for both (with/without NTD) bilayer systems. Here, one of the trajectories for both orientations was reported independently. The data analysed from the replicas were consistent with the shown trajectories and not included in this manuscript. The 10 μs simulation trajectory for the 7:3 POPC/CHOL bilayer did not show any interaction with NTD positioned at either orientation (Fig. S2) and we did not further analyse the trajectories.
3.2 Interactions between protein and lipid components
3.2.1 Number of contacts versus time
To investigate the interactions between NTD and the three lipid components POPC, CHOL, and GM1, we calculated the number of contacts using a cut-off ≤ 0.6 nm throughout the 10 μs trajectory (Fig. 1 a & 1b). The contacts were defined with reference to every bead of NTD and GM1, PO4 for POPC, and ROH for cholesterol. In the simulations, GM1 gathered around the NTD compared with POPC and cholesterol. After the systems attain the local equilibrium at 2 μs (NTD, orientation I) and 3 μs (NTD, orientationII) respectively, the average number of contacts between NTD and GM1 increased to 51.16 ±5.63 and 102.47 ± 5.44. The results do not reveal notable contacts with the other two lipid components.Fig. 1 Time evolution of the number of contacts between POPC, CHOL, and GM1 lipids and the spike NTD at (a) orientation I and (b) II with respect to the lipid bilayer membrane. Preferential partitioning matrix of the POPC/CHOL/GM1 bilayers: (c) without the receptor, (d) with the receptor (NTD orientation I), and (e) with the receptor (NTD orientation II). If any bead of lipid or receptor in the second group has contact with multiple beads in the first group then we counted it as only one contact.
3.2.2 Preferential partitioning of receptor and membrane lipids
The preferential partitioning of receptor and the lipids was computed as the relative number of contacts of an individual with each of the other components, normalized for the total number of components in the system [27], [28] PA=CAnA∑xCxnx
where PA refers to the preferential partitioning with component A, CA is the number of contacts with component A, and nA is the number of molecules of component A. Two molecules within 0.6 nm were regarded to be in contact. We estimated the preferential partitioning from the last microsecond simulation time for both sets and averaged over it. From Fig. 1c, GM1 exhibited the highest preference for interaction with itself (PA=0.8791) manifesting the formation of clusters. The preferential partitioning of GM1 with POPC was considerably lower (PA = 0.0661) and it marked the lowest for CHOL. Interestingly, CHOL shows more preference toward POPC (PA=0.5065) and vice-versa (PA=0.4595) than their self-association to rarely form clusters. Although the preferential partitioning of the membrane components prevailed finitely similar in the presence of the spike NTD, it is noteworthy that NTD accounts for the highest preference of interaction in the orientation I with the GM1 ganglioside PA= 0.9742 than orientation II with PA= 0.8907 resulted due to the formation of large clusters of GM1 responsible for captivating the SARS-CoV-2 spike NTD (Fig. 1d & 1e) followed by POPC (PA= 0.0222 and 0.0682) and cholesterol (PA= 0.0036 and 0.0411). Slight changes in the structure of sphingolipids (including gangliosides) significantly modify their partitioning between lateral domains in the biological membrane [29], this is also evident here due to dominating NTD-GM1 interaction as compared to GM1 for interaction with itself (PA=0.8209and0.7717).
3.3 Influence of the ganglioside GM1 in spike NTD binding
Fig. 1 depicted GM1 to be the capture lipid for the coronavirus spike NTD receptor. Previous reports have also shown GM1 to be crucial in engaging simian virus 40 (SV40) [30], cholera toxin [8], [31], serotonin1A receptor [28], etc. Thus, in order to understand the lipid-receptor interaction stability we computed the center-of-mass (COM) distance between the local GM1 lipid (any GM1 bead within 0.5 nm of protein) and the binding residues of NTD (any residue within 0.5 nm of GM1). Fig. 2 a shows that GM1 achieves the local equilibrium around spike NTD after 2 μs simulation time and appeared to be stable around the receptor throughout the 10 μs simulation with an average COM distance of 0.74 ± 0.06 nm and 0.71 ± 0.09 nm for NTD orientation I and II respectively. Further, the influence of spike NTD binding on the lateral mobility of lipids POPC, cholesterol, and GM1 in the bilayer system can be quantitatively estimated from their translational diffusion constants, D, calculated from the dependence of mean-square displacement (MSD) on time according to Einstein’s equation [32]. The lateral diffusion coefficient was found to be maximum for CHOL followed by POPC in the control system as well as the systems with the NTD. However, the lateral mobility of GM1 was quite interesting to observe in each of the systems. We noticed that the lateral diffusion coefficient is significantly lower for the GM1 in the case of the NTD orientation I than II (Table 1 ), that is the orientation I of NTD on the bilayer surface provides more restriction to GM1 mobility after virus attachment to the host membrane. Additionally, our study shows that the binding of NTD through the other site in orientation II ameliorates the lateral motion of GM1 lipid components. This was further entrenched with the radial distribution function (RDF) calculations. The data were averaged over the simulation trajectory's initial and final 1 μs. In the case of the first NTD orientation, with the evolution of simulation time, it was observed that within the first shell the peak height for local GM1 lipids around NTD at 0.5 nm increased significantly from 4.8 to 31.0 (Fig. 2b), however, the same peak for another orientation increased from 1 to 17. Thus, the probability of finding local GM1 at 0.5 nm away from NTD is higher for orientation I than for orientation II.Fig. 2 (a) The center-of-mass (COM) distance between spike NTD receptor and GM1 ganglioside all through the 10 μs MD simulation and (b) radial distribution function g(r) of local GM1 around the NTD receptor orientation I & II in POPC/CHOL/GM1 bilayer. The pairs of black & red lines and blue & green lines indicate the initial and the final 1 μs simulation time. The peaks are smoothed using MATLAB R2019b.
Table 1 Lateral diffusion coefficient (×10-7cm2/s) of different lipid components calculated from the last 1 μs trajectory.
System Lipid components
POPC CHOL GM1
Without NTD 2.37 ± 1.20 3.17 ± 1.53 0.23 ± 0.89
With NTD (orientation I) 2.22 ± 0.06 2.41 ± 0.18 0.61 ± 0.80
With NTD (orientationII) 2.71 ± 0.21 3.15 ± 0.13 1.60 ± 0.31
3.4 Residue-wise fractional occupancy of NTD around GM1
To analyze the interacting sites of spike NTD, we calculated the fractional occupancy in terms of a fraction of contacts with respect to each amino acid residue around GM1 over 10 μs of simulation (Fig. 3 ). In the first orientation of NTD, the highest occupancy was observed mainly at the part of the NTD tip β9-β10 loop region consisting of V143, Y145, K147, N148, N149, K150, S151, W152, and S155 followed by other β9 residues E132, Q134, F135, N137 (residues of QFN triad), and β13 P230, I231, and G232 around GM1. This binding mode is specific to the GBD stretch, and the QFN triad is highly conserved among SARS-CoV-2 variants, which has been suggested as a therapeutic and vaccine target as previously mentioned in studies by Fantini et al. [10], [11], [33]. However, in the second case, relatively lower occupancy was noticed for the interacting residues i.e., R21 to T33, F59, β2-β3 loop region residues H69, S71, G72, and N74, residues of β6 loop K97 and β12 strand N211, L212, V213, and R214. Klinakis et al. [34] identified residues of β9-β10 and β14-β15 (L230-A251) loops as an epitope for convalescent plasma containing neutralizing antibodies. They also revealed that β3-β4 is not directly engaged with antibody residues but their members A67, H69, and D80 stabilize the epitope β14-β15 loop through interloop interactions.Fig. 3 Fractional occupancy of amino acid residues from orientation I and II of NTD around ganglioside GM1 over 10 μs simulation of protein-lipid bilayer complexes.
Chi et al. [35] characterized the 4A8 antibody in convalescent Covid-19 patients that recognize a discontinuous epitope of the spike receptor NTD residues 144 to 158. Concerning this, our findings contribute to predicting the efficacy of ganglioside binding in the pocket observed by the NTD orientation I system, which is consistent with an earlier report [33] on the inhibition activity of the 4A8 antibody in the spike protein interaction with membrane gangliosides.
3.5 Lipid head groups distribution
Since the interactions of sialic acid (Neu5Ac) with viruses are predominant among all the head groups of GM1 [36], the distribution of individual lipid head groups of GM1 around the NTD receptor must be identified in unprecedented detail. We evaluated the probability density function (PDF) of the standard normal distribution at the values in the number of contacts possessed by each of the GM1 lipid head groups explicitly with the receptor over the 10 μs simulation time (Fig. 4 a & 4c). A broader distribution was obtained for the external Gal and Neu5Ac with μ±σ of 13.83 ± 6.79 and 11.02 ± 5.42 in the case of NTD orientation I followed by the GalNAc. The other two sugar moieties internal Gal and Glc show narrow distributions with higher probabilities of lesser contacts. However, all the head groups of GM1 show broader distributions around the orientation II of NTD with external Gal 18.49 ± 9.72 and Neu5Ac 20.33 ± 10.95 topping the list. Particularly, Q134, F135, N137, V143, Y145, and G232 in orientation I of NTD and T33, F59, G72, K97, N211, L212, V213, and R214 in orientation II were observed to be the key interacting residues with sialic acid. The mean (µ) and standard deviation (σ) of the normal distribution PDF for the obtained number of contacts between the different GM1 head groups and spike receptor NTD is shown in supplementary table S2. The dominating accumulation of external Gal and Neu5Ac could be clearly seen in the snapshot taken at the ultimate frame of the 10 μs trajectory (Fig. 4b & 4d). The higher density of GM1 sugars is probably due to their more compactness around the orientation I of NTD.Fig. 4 The normalized probability density function (PDF) of the contact number between individual GM1 lipid head groups and spike receptor NTD (a) orientation I and (c) orientation II over the entire 10 μs simulation. (b & d) The snapshots taken at the ultimate time frame of 10 μs highlight the accumulation of GM1 head groups around NTD orientation I and II respectively. The backbone and the side chain of the receptor are shown in mauve and yellow beads and the GM1 head groups as glucose (Glc) in pink, internal galactose (internal Gal) in ochre, N-acetyl-galactosamine (GalNAc) in blue, external galactose (external Gal) in red, and sialic acid (Neu5Ac) in green beads.
4 Conclusions
Gangliosides residing on the outer leaflet of the plasma membrane play a vital role in captivating protein virus receptors. Their close association with cholesterol help in controlling the fusion process [37]. We show here that GM1 binds to the SARS-CoV-2 spike N-terminal domain (NTD) by performing coarse-grain molecular dynamics simulations of the receptor in membrane bilayers with varying orientations of the receptor. The gangliosides’ interaction with the NTD receptor results in a binding site predominating with the β9−β10 loop region (V143 – S155) and the QFN triad observed from orientation I, fits well on the GM1 head group sialic acid and external galactose. The involvement of this QFN triad was previously identified by Fantini et al. [10], [11] in GM1 binding. Our CG-MD study shows maximum occupancy of β9-β10 region around GM1 than the binding site observed with the NTD orientation II (residues R21 to T33, β2-β3 loop region, and β12 strand). NTD becomes more compact around GM1 with a higher preferential partitioning value in the orientation I system. However, orientation II is more distributed on the lipid surface and due to the relaxed mobility of GM1 there compared to orientation I, we speculate that the spike NTD receptor is likely to penetrate through the membrane with this orientation. Thus, employing two different orientations of spike protein NTD receptor, we propose two binding sites, one with the tip containing the QFN triad and the other with the widely distributed mode of orientation II containing sugar receptor-interacting residues. Monitoring the binding orientations of the SARS-CoV-2 spike protein, which is responsible for protein-lipid interaction, we believe, will shed more light on receptor binding abilities in the cell membrane and provide molecular targets for a therapeutic strategy.
CRediT authorship contribution statement
Tanushree Das: Conceptualization, Methodology, Software, Validation, Investigation, Data curation, Visualization, Writing – original draft. Chaitali Mukhopadhyay: Conceptualization, Methodology, Software, Validation, Supervision, Writing – review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data availability
All the data are available in the manuscript and the associated supplementary file.
Acknowledgments
The authors acknowledge the Department of Chemistry, the University of Calcutta for all the research and computational facilities. Tanushree Das is grateful to the Government of West Bengal for granting her fellowship.
==== Refs
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| 0 | PMC9744490 | NO-CC CODE | 2022-12-15 00:01:49 | no | Chem Phys Lett. 2022 Dec 13;:140260 | utf-8 | Chem Phys Lett | 2,022 | 10.1016/j.cplett.2022.140260 | oa_other |
==== Front
J Hosp Infect
J Hosp Infect
The Journal of Hospital Infection
0195-6701
1532-2939
Published by Elsevier Ltd on behalf of The Healthcare Infection Society.
S0195-6701(22)00380-2
10.1016/j.jhin.2022.12.004
Review
The implementation of portable air-cleaning technologies in healthcare settings —a scoping review
Paz Alvarenga María Olimpia 1
Monteiro Dias Jessica Maria 2
José de Lavôr Araújo Lima Bruno 3
Leonidas Gomes Anderson Stevens 4
Queiroz de Melo Monteiro Gabriela 1∗
1 Dental School, Universidade de Pernambuco, Pernambuco, Brazil
2 Analytical Chemistry Laboratory, Instituto de Tecnologia de Pernambuco, Pernambuco, Brazil
3 Microbiology Testing Laboratory, Instituto de Tecnologia de Pernambuco, Pernambuco, Brazil
4 Department of Physics and Graduate Program in Dentistry, Universidade Federal de Pernambuco, Pernambuco, Brazil
∗ Corresponding author. Hospital Universitário Oswaldo Cruz - Faculdade de Odontologia da Universidade de Pernambuco – FOP/UPE, R. Arnóbio Marques - Santo Amaro, Recife – PE50100-130. +55 81 99996-6327.
13 12 2022
13 12 2022
25 8 2022
7 11 2022
2 12 2022
© 2022 Published by Elsevier Ltd on behalf of The Healthcare Infection Society.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Background
The COVID-19 pandemic revealed opportunities to improve prevention practices in healthcare settings, mainly related to the spread of airborne microbes (also known as bioaerosols).
Aim
This scoping review aimed to map methodologies used to assess the implementation of portable air cleaners in healthcare settings, identify gaps, and propose recommendations for future research.
Methods
The protocol was registered in the Open Science Framework (OSF) (doi: https://osf.io/8g9ap) and reported following the checklist provided by the Preferred Reporting Items For Systematic Reviews and Meta-Analysis—an extension for Scoping Reviews (PRISMA-ScR) statement. The search strategy was performed in five databases and one grey literature source.
Findings
At the last selection phase, 24 articles that fulfilled our inclusion criteria were summarised and disseminated. Out of these, 17 studies were conducted between 2020 and 2022; one of them is a protocol of a multicentre randomised controlled trial. The outcomes measured among the studies include airborne microbes counts, airborne particle concentrations, and rate of infections/interventions. The leading healthcare settings assessed were dental clinics (28%), patient's wards (16%), operating rooms (16%), and intensive care units (12%).
Conclusion
Most of the devices demonstrated a significant potential to mitigate the impact of bioaerosols. Although some indoor air quality parameters can influence the mechanics of aerosols, only a few studies controlled these parameters in their analyses. Future clinical research should assess the rate of infections through randomized controlled trials with long-term follow-ups and large sample sizes to determine the clinical importance of the findings.
Keywords
Healthcare Settings
Portable Air Cleaners
Aerosols
Airborne Transmission
==== Body
pmcIntroduction
The COVID-19 pandemic raised awareness of the high risk that represents respiratory pathogens spread by aerosols—particularly in enclosed spaces with poor ventilation [1]. Although it is not a new concern in health facilities since it has long been a top priority for the Centers for Disease Control and Prevention (CDC) [2], the pandemic outbreaks did evidence the need for evolution and innovation to mitigate the impact of aerosols.
Aerosols are liquid or solid particles suspended in the air by natural or artificial sources. Depending on their weight, these particles can remain suspended in the air for hours and travel long distances through the airborne route [3]. When aerosols transport microorganisms, such as bacteria, fungi, spores, and viruses, they are also known as bioaerosols [4]. In cases when it is imposible to reduce the sources of aerosols or the dilution ventilation is insufficient, the implementation of portable air cleaners has been proposed as a coadjutant measure in residential, commercial buildings, and healthcare settings [5].
The portable air cleaners use different technologies such as fibrous media air filters, generally rated as high-efficiency particulate air filters (HEPA) or Ultra-Low Particulate Air filters (ULPA), ultraviolet air filtration, and electronic air cleaners, including electrostatic precipitators and ionizers, alone or in combination [6]. Fibrous media air filters remove particles by capturing them on fibrous filter materials. Electrostatic precipitators and ionizers remove particles by an active electrostatic charging process. Ultraviolet air filtration reduces viable airborne microorganisms by killing or deactivating them [6]. Gas-phase air-cleaning technologies include adsorbent air filters such as activated carbon, chemisorbed media air filters, photocatalytic oxidation, plasma, and intentional ozone generators, designed to remove gaseous air pollutants or convert them to harmless [6].
The effectiveness of different portable air cleaners was reported to range from 12 to 99% depending on the technology used, setting, and outcomes assessments across the studies [7]. In theory, one can assume that lowering the airborne particle concentrations and airborne microbial counts in the indoor air would result in lower rates of infections. This scoping review aimed to map and summarise overall research (published and grey literature) assessing the implementation of portable air-cleaning technologies in healthcare settings. Additionally, to report the outcomes measured across the studies, the characteristics and range of the used methodologies, challenges, and limitations, and to propose recommendations for future research.
Methods
Protocol and Registration
This scoping review was registered in the OSF database (doi: https://osf.io/8g9ap), conducted following the guidelines for conducting systematic scoping reviews of the JBI Briggs Reviewers Manual [8], and reported following the checklist provided by the PRISMA-ScR statement (Supplementary Table A1) [9].
Eligibility criteria and search strategy
Our inclusion criteria were guided by the review question: What outcomes have been measured in existing research to assess the implementation of portable air cleaners in healthcare settings? Studies that aimed to assess the implementation of portable air-cleaning devices in healthcare settings (medical and dental clinics and offices, urgent care centers, large hospitals) in real or quasi-real-life scenarios compared to no implementation were considered. No limitations of language or publication date were established.
An initial limited search was performed in PubMed to analyze text words contained in the title and abstracts across the articles that fulfilled our eligibility criteria. The following MeSH terms and keywords were combined: Hospital* OR “Health Facilities” OR “Dental Clinic*” AND “Air Filters*” OR “Air Purifier*” OR “Portable Air Cleaner*” OR “Air Circulation” OR “Air Filtration” OR “High-Efficiency Particulate Air Filter*” OR “Ultraviolet Air Filtration” OR “Plasma Air Filtration.” After selecting keywords and index terms, a second search was performed by two independent reviewers. Five databases (PubMed, Embase, Scopus, Cochrane Library, and Web of Science) were used to identify all the published articles on the topic, and one grey literature source (Grey Matters) was used to identify unpublished articles (Supplementary Table A2).
The references list of included articles was also assessed to search for additional studies, and search alerts were activated in each database. Sources were last accessed in June 2022. All citations found were imported into a reference manager (EndNote, version 20.3, Thomson Reuters), and duplicates were removed automatically and manually.
Extraction of data and charting
Two independent authors (MA and JD) extracted and charted data from the included studies. The following information was tabulated: author, country, year of publication, aims, healthcare setting, description of the device used (commercial name, airflow settled, noise, and type of technology), and outcomes measured. The studies were also summarised and charted according to the outcome assessed, describing how these outcomes were measured (methodology and measurement tool) and reported results.
Results
Study selection
In total, we identified 2023 citations, and 425 duplicates were removed. After title and abstract analyses, we selected 31 articles for full-text reading of which one report was not retrieved. Six articles were excluded: one extended abstract [10], four experimental studies performed in a test chamber or a simulated room [[11], [12], [13], [14]], and one study in which the air filter was installed in the HVAC system [15]. Thus, 24 articles were summarised and disseminated in this scoping review. The PRISMA flow diagram for this scoping review is in Figure 1 .Figure 1 PRISMA 2020 flow diagram for this scoping review.
Figure 1
Characteristics of the included studies
Out of the 24 studies that fulfilled our inclusion criteria [[16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39]], 17 studies were conducted and published between 2020 and 2022 during the COVID-19 outbreaks. However, only one study described the detection of SARS-CoV-2 RNA in air samples collected in addition to other airborne microbes (a range of other bacterial, viral, and fungal pathogens) [23]. The outcomes measured—alone or combined—among the included studies were airborne microbial counts, airborne particle concentrations, and rate of infections or interventions, as shown in Figure 2 . The characteristics of the included studies are described in Table 1 , including the commercial names and technology of the devices tested, as well as the main technical descriptions when the authors or the manufacturers’ websites provided the information.Figure 2 Outcomes measurements across the included studies to assess the implementation of portable air cleaners in healthcare settings over time.
Figure 2
Table 1 Characteristics of the included studies, the devices used, and the outcomes measured in the different healthcare settings
Table 1Study/Country Healthcare setting (area/volume) Description of the PAC tested Outcomes measured (Yes = ✓/No = X)
Device CADR (m3/h) Noise (dB) Technology AM AP RI
Persson et al., 2022a [16]
Sweden ORs (NIc) in seven hospitals Novaerus Protect 800 260 45 Plasma X X ✓
Capparè et al., 2022 [17]
Italy Dental OR (20 m2/60 m3) in a hospital Professional XXL inn-561 NIc 38 & 58 HEPA 14 ✓ ✓ X
Oberst et al., 2021 [18]
Germany OR (21 m2/52 m3) in an orthopaedic clinic AP-40 Air filter 320 35 - 51 HEPA 13; activated carbon; plasma X ✓ X
Arikan et al., 2021 [19]
Turkey ICUs (105 m2/315 m3) in a hospital Novaerus Defend 1050 267 67 HEPA 13; activated carbon ✓ X ✓
Novaerus Protect 800 260 45 Plasma
Corrêa et al., 2021 [20]
Brazil Emergency care unit (NIc) Non-commercial device 781 NIc UV-C lamps ✓ X X
Maurais et al., 2021 [21]
Canada A dental OR and a mobile dental OR (NIc) MedEVAC-A 255 56 HEPA X ✓ X
AF400M HEPA 510 52 HEPA
XPOWER X-2580 Professional 510 NIc HEPA; activated carbon
Tzoutzas et al., 2021 [22]
Greece Dental OR (170 m2/510 m3) in a dental school Aurabeat AG+ NSP-X1 375 ≤58 UV lamp; silver Ion; plasma X ✓ X
Morris et al., 2021 [23]
United Kingdom Repurposed ‘surge’ COVID ward (39.52 m2/NIc) and ‘surge’ ICU (72.22 m2/NIc) in a hospital AC1500 HEPA14/UV 400-1000 ≤50 & ≤42 HEPA 14;
UV-C lamp ✓ X X
Medi 10 HEPA13/UV 700 - 1,300 35 -60 HEPA 13; ozone-free UV-C; activated carbon
Buising et al., 2021 [24]
Australia Patient’s ward (12.8m2/37m3) in a hospital AX5500K Air Purifier 467 21-50 HEPA 13; activated carbon X ✓ X
Lee et al., 2021 [25]
Australia A single-bed patient room (2m2/37m3) in a hospital Industrial air cleaner Model A 200 NIc HEPA X ✓ X
Industrial air cleaner Model B 400 NIc HEPA
Air Purifier AX60RR5080WD 467 NIc HEPA; activated carbon
Razavi et al., 2021 [26]
Canada A dental OR (9 m2/36 m3) in a dental clinic JADE, SCA5000C 260 & 530 NIc HEPA; UV-C lamps; activated carbon, PCO X ✓ X
Ren et al., 2021 [27]
United States 10 dental OR (NIc) in a dental clinic Honeywell 50250 425 NIc HEPA X ✓ X
Verbeure et al., 2021 [28]
Belgium Room for oesophageal HRM (20 m2/NIc) in a university hospital City M Air Purifier 435 16 - 53 HEPA/molecular X ✓ X
Messina et al., 2020 [29]
Italy An ISO-7b OR (NIc/90 m3) in a hospital Illuvia® 500 UV 850 NIc HEPA; UV-C lamps; PCO X ✓ X
Pouvaret et al., 2020 [30]
France A 12-bed adult haematology unit (NIc/66 m3) in a cancer institute Air handling unit R4000™ 8000 NIc ULPA 15; UV-C lamps ✓ ✓ X
Rao et al., 2020 [31]
United States Paediatric wards setting (NIc) in a hospital PECO Air Purifier MH1 NIc NIc PECO X X ✓
Anis et al., 2019a [32]
United States OR for joint arthroplasty in a hospital T1C-UVC system 850 NIc C-UVC chamber ✓ ✓ X
Bischoff et al., 2019 [33]
United States Emergency rooms (NIc) in a hospital Illuvia® 500 UV 850 NIc C-UVC; chamber
PCO ✓ X X
Ozen et al., 2016 [34]
Turkey A haematology ward (NIc) in a teaching hospital Uvion Air Aseptizör 2500 55 HEPA 14;
UV-C lamps X X ✓
Le et al., 2015 [35]
Vietnam ICU (NI/125m3) in a hospital A non-commercial device 250 NIc UV-A lamps; activated carbon; PCO ✓ X X
Abdul Salam et al., 2010 [36]
Singapore Six wards (NIc) in an acute tertiary-care teaching hospital HealthPro 150 350 NIc HEPA X X ✓
Hallier et al., 2010a [37]
United Kingdom Three separate dental OR (NIc) in a teaching dental hospital FlexVac™ 500 NIc HEPA ✓ X X
Chotigawin et al., 2010 [38]
United States A renal unit (86.4m2/259 m3) in a hospital A non-commercial device NIc NIc HEPA; PCO ✓ X X
Pelleu et al., 1970 [39]
United States Three dental OR (NIc/45 m3, 51 m3, and 92m3) NIc 1360 NIc HEPA ✓ X X
PAC: Portable Air Cleaner; CADR: Clean Air Delivery Rate; UV: Ultraviolet; AI: Average Irradiance; AM: Airborne Microbial Count; AP: Airborne Particles Concentration; RI: Rates of Infections or Interventions; HEPA: High-efficiency Particulate Absorbing filter; OR: Operating Room; ICU: Intensive Care Unit; PCO: Photocatalytic Oxidation; HRM: High-resolution Manometry; ISO: International Organization for Standardization; PECO: Photo-electrochemical Oxidation; C-UVC: Crystalline UV-C; ULPA: Ultra-Low Particulate Air filter.
a A study protocol or a pilot study.
b ISO 1 indicates the cleanest and ISO 9 the dirtiest air.
c NI: Not Informed.
The healthcare settings assessed were dental clinics, patient’s wards, operating rooms, intensive care units, single-bed patient rooms, emergency, renal and hematology units, and rooms for high-resolution esophageal manometry (Figure 2), including teaching hospitals and clinics in different countries (Figure 3 ) (Fig. 4).Figure 3 Different healthcare settings in which portable air cleaners were implemented were assessed across the included studies in this review.
Figure 3
Figure 4 Distribution where the included studies with different portable air-cleaning technologies were conducted.
Figure 4
Assessment of airborne microbial counts using portable air cleaners
Airborne microbial counts were assessed in 11 studies (three of them were assessed in addition to airborne particles), one randomized clinical trial, and 10 in-situ experiments in real-life scenarios by different sampling methods and measurement tools [17, 19, 20, 23, 30, 32, 33, 35, [37], [38], [39]] as shown in Table 2 . Pouvaret et al. [30] and Arikan et al. [19] assessed surface microbial counts in addition to airborne microbial counts by a surface swab test.Table 2 Summary of the methodologies, sampling methods, and outcomes assessing airborne microbes
Table 2Study Study design Source of aerosols Bioaerosols measured Sampling/calibration/analysis Indoor air parameters Outcomes reported using PACs
ACH T (°C) RH (%)
Capparè et al., 2022 [17] Randomised Clinical Trial Dental AGPs Airborne bacteria, yeast, and fungi Active sampling by impaction with Petri dishes containing TSA/250 L per point/direct counting on plates (CFU/m3) ---- ------ ------ A significant reduction in airborne bacterial and fungal counts
Arikan et al., 2021 [19] In-situ experiment in a real-life scenario Patients and procedures Airborne bacteria Active sampling by impaction with Petri dishes containing SBA/100 L per point/direct counting on plates (CFU/500 L) ------ 20 - 25 30 - 60 A significant reduction in airborne bacterial counts
Corrêa et al., 2021 [20] In-situ experiment in a real-life scenario Patients and procedures Airborne bacteria and fungi Passive sampling by sedimentation technique with Petri dishes containing BHI and SDA/NAa/direct counting on plates (CFU/m3) ------ ------ ------ A significant reduction in airborne bacterial and fungal counts
Morris et al., 2021 [23] In-situ experiment in a real-life scenario COVID patients and procedures Airborne SARS-CoV-2 and a range of other bacterial, viral, and fungal pathogens Active sampling by filtration and qPCR assays/NIb/nucleic acids were extracted from each sampler component ------ ------ ------ A significant reduction of airborne SARS-CoV-2 and other airborne pathogens detected
Pouvaret et al., 2020 [30] In-situ experiment in a real-life scenario Patients and procedures Airborne bacteria and fungi Active sampling by impaction with SCA and standard agar plates/100 L/min for 5 min per point/direct counting on plates (CFU/m3) 2 35 ------ A significant reduction in airborne bacterial and fungal counts
Anis et al., 2019 [32] In-situ experiment in a real-life scenario Patients and procedures Airborne bacteria Active sampling by impaction with blood agar plates/30 L/min for 10 min per point/direct counting on plates (CFU/m3) ------ ------ ------ A non-significant reduction in airborne bacterial counts
Bischoff et al., 2019 [33] In-situ experiment in a real-life scenario Patients and procedures Airborne bacteria Active sampling by impaction with blood agar plates (TSA II with SBA)/NIb/direct counting on plates (CFU/m3) ------ ------ ------ A significant reduction in airborne bacterial counts
Le et al., 2015 [35] In-situ experiment in a real-life scenario Patients and procedures Bacteria and fungi Passive sampling by sedimentation technique/NAa/direct counting on plates (CFU ml-1) ------ ------ ------ A significant reduction in airborne bacterial and fungal counts
Hallier et al., 2010 [37] In-situ experiment in a real-life scenario Dental AGPs Bacteria Active sampling by impaction with blood agar plates/100 L/min for 5 min per point/direct counting on plates (CFU/m3) ------ 21 - 24 ------ A significant reduction in airborne bacterial counts
Chotigawin et al., 2010 [38] In-situ experiment in a real-life scenario Patients and procedures Bacteria and fungi Active sampling by impaction with TSA and SDA plates/28.3 L/min for 3 min per point/direct counting on plates (CFU/m3) ------ ------ 74 - 76 A significant reduction in airborne bacterial counts but a non-significant reduction in airborne fungal counts
Pelleu et al., 1970 [39] In-situ experiment in a real-life scenario Dental AGPs Bacteria and fungi Active sampling by impaction with TSA plates/NIb/direct counting on plates (CFU/m3) ------ ------ ------ A significant reduction in airborne bacterial counts
AV: Aspirated Volume; T: Temperature; RH: Relative Humidity; CO2: Carbon Dioxide; TSA: Tryptic Soy Agar; CFU: Colony Forming Unit; PAC: Portable Air Cleaner; SBA: Sheep Blood Agar; BHI: Brain Heart Infusion; SDA: Sabouraud Dextrose Agar; qPCR: quantitative Polymerase Chain Reaction; CDC: Centers for Disease Control; SCA: Sabouraud-Chloramphenicol agar; AGP: Aerosol Generator Procedure; HVA: High Volume Aspiration.
a NA: Not Applicable.
b NI: Not Informed.
In all the studies, the sources of aerosols were patients and procedures performed during the sampling period. Table 2 also shows the calibration of the measurement tools (when reported), airborne microbes assessed, analysis method, and outcomes reported using portable air cleaners in each study assessing microbiological contamination. Regarding indoor air parameters that can influence microbiological results, only four of these studies assessed temperature or relative humidity [19, 30, 37, 38], and only one assessed the air changes per hour (ACH) in the room [30].
Assessment of airborne particle concentrations using portable air cleaners
The concentration of airborne particle or particle matter of different aerodynamic diameters was measured in 12 studies through in-situ experiments in real [17, 18, 21, 22, 26, [28], [29], [30], 32] and quasi-real-life scenarios [[24], [25], [26], [27]], alone or combined. Table 3 shows details of the measuring tools used (when reported), airborne particle sizes measured, and outcomes reported using portable air cleaners in each study assessing airborne particulate concentration.Table 3 Summary of the methodologies, measurement tools, and outcomes assessing airborne particles
Table 3Study Study design Source of aerosols Particles size (μm)/measuring tool Indoor air parameters Outcomes reported using PACs
ACH T (°C) RH (%)
Capparè et al., 2022 [17] In-situ experiment in a real-life scenario Dental AGPs 0.3, 0.5, 1.0 and 5.0/Particle counter system (Lasair III) NI1 ------ ------ A significant reduction in total airborne particles values
Oberst et al., 2021 [18] In-situ experiment in a real-life scenario Surgical procedures 2.5, 1.0 and 10/Particle measuring device (IGERESS, Shenzen, China) ------ ------ ------ A significant reduction in airborne particles values for all sizes measured
Maurais et al., 2021 [21] In-situ experiment in a real-life scenario Dental AGPs and dental non- AGPs 10 or smaller/Laser photometers sensor (DustTrakDRX) 6 & 13 ------ ------ A significant reduction in airborne particles values in all conditions assessed
Tzoutzas et al., 2021 [22] In-situ experiment in a real-life scenario AGPDs 10 and 2.5/Laser photometers sensor 7 23 - 26 30 - 60 A significant reduction in airborne particles values for the duration of the experimental period with a few exceptions
Buising et al., 2021 [24] In-situ experiment in a quasi-real-life scenario Glycerine-based aerosol (<1 μm) 2.5 or smaller/Laser photometers sensors (TSI DustTrak DRX 8533 and II8530) ------ ------ ------ A significant reduction in airborne particles values
Lee et al., 2021 [25] A numerical experiment in a quasi-real-life scenario Aqueous glycol solution (1.0 μm) 1.0 (predicted by the size of solution used) ACH calculating for predicting the clearance time 13.9 ------ ------ Airborne particles clearance time was significantly improved (3 times faster in under 10 minutes)
Razavi et al., 2021 [26] Numerical and in situ experiment in a real and quasi-real-life scenario Dental AGPs and simulated dental AGPs 0.3, 0.5, 1.0, 2.0, 5.0, and 10/Aerodynamic particle sizer spectrometer and two optical particle counters for predicting the clearance time 7.23 & a14.73 22 - 25 49 - 60 Airborne particles clearance time was significantly improved (at least 6.3 times faster)
Ren et al., 2021 [27] In-situ experiment in a quasi-real-life scenario Burning three sticks of incenses 0.3, 0.5 and 1.0/Aerosol particle counter (Lasair III 310C, Unites States) 3 to 45 22 - 23 34 - 52 A significant reduction in airborne particle accumulation and accelerated removal. Especially prominent in rooms with poor ventilation.
Verbeure et al., 2021 [28] In-situ experiment in a real-life scenario Patients undergoing an oesophageal HRM 0.3, 0.5, 1.0, 3.0, 5.0, and 10/Particle Counter (Lasair® II, Unites States) ------ ------ ------ A non-significant reduction in airborne particles values
Messina et al., 2020 [29] In-situ experiment in a real-life scenario Surgical procedures ≥0.3, ≥0.5, ≥1.0, ≥3.0, ≥5.0 and >10/Particle counter (Climet Ci-550) 15 ------ ------ A significant reduction in airborne particles values of all sizes
Pouvaret et al., 2020 [30] In-situ experiment in a real-life scenario Patients and procedures 0.3, 0.5, 1 and 5/Optical particle counter (Aerotrak® TSI, Unites States) following ISO 21501-4 standard 2 35 ------ A significant reduction in airborne particles values (above the ISO 6a class compared with ISO 7a and ISO 8a classes reached with no PAC)
Anis et al., 2019 [32] In-situ experiment in a real-life scenario Surgical procedures 0.5 – 10.0/Particle counter (BioTrak, TSI, Minneapolis, MS) ------ ------ ------ A significant reduction in total airborne particles values
T: Temperature; RH: Relative Humidity; CO2: Carbon Dioxide; PAC: Portable Air Cleaner; AGPs: Aerosol Generator Dental Procedure; ACH: Air Changes per Hour; HVAC: Heating, Ventilation, and Air Conditioning; HRM: High-resolution Manometry; ISO: International Organization for Standardization.
a ISO 1 indicates the cleanest and ISO 9 the dirtiest air.
In one study, in addition to particle concentration levels, they also assessed the aerosol size distribution with an aerodynamic particle size spectrometer [26]. Only in two studies was calculated the clearance time of the portable air cleaner [25]. Seven studies calculated the pre-existing ACH in the rooms (Table 3). Capparé et al. [17] mention that the pre-existing ACH was calculated, but the data is missing in the results. Only four studies assessed temperature and relative humidity [26, 27, 30, 40].
Rate of infections or interventions using portable air cleaners
Five studies measured the correlation or association between the implementation of portable air cleaners and decreased rates of infections or intervention [16, 19, 34, 36]. Three were non-randomized prospective studies [19], one was retrospective [36], and the other was a protocol of a multicentre randomized, double-blind, placebo-controlled trial [16]. This protocol is part of the EPoS trial1 that was conducted at seven hospitals from 2017–2022 to assess the implementation of air-cleaning devices and the incidence of surgical site infections in orthopedic surgery. Description of the impacts measured, study design, follow-up, and outcomes reported by the studies are summarised in Table 4 .Table 4 Summary of the general characteristics of the included studies in which rates of infections or interventions were assessed.
Table 4Study The potential impact assessed Study design Follow-up Outcomes reported using PACs
Persson et al., 2022 [16] Decreased rate of surgical site infections in ORs of seven hospitals Study protocol of a multicentre randomised, double-blind, placebo-controlled trial. They need approximately 45,000 patients to attain a power of 80% 60 months Results are not published yet.
Arikan et al., 2021 [19] Decreased rate of hospital-acquired infections in ICUs in a hospital Non-randomised prospective study 8 months Significant positive correlation with the decreased rate of hospital-acquired infections
Rao et al., 2020 [31] Improvement of health outcomes for patients admitted with respiratory distress in the paediatric hospital setting Non-randomised prospective study of 562 patients 3 months Non-significant association with the decreased overall length of stay in the hospital and ICU, intubation, nebuliser, and non-invasive ventilation use. However, the authors reported that these reductions were clinically meaningful with a significant impact on the healthcare system.
Ozen et al., 2016 [34] Decreased rate of infections in patients being treated for hematologic malignancies during construction near the hospital Non-randomised prospective study 12 months Significant association with decreased overall rates of infections. The preventive effect was more pronounced in patients with acute lymphocytic leukaemia, patients undergoing consolidation therapy, and patients with moderate neutropenia.
Abdulsalam et al., 2010 [36] Decreased incidence rate of invasive aspergillosis infection in a hospital Non-randomised retrospective study of 134 cases 31 months Significant association with the decreased incidence rate of invasive aspergillosis infection
PAC: Portable Air Cleaner; OR: Operating Room; EPoS: European Polyp Surveillance Trial; ICU: Intensive Care Unit.
Discussion
Most of the 24 studies included in this review (71%) were conducted after the COVID-19 outbreak from 2020 to 2022. Only one study assessed SARS-CoV-2 RNA in air samples collected in a ward and an intensive care unit adapted for COVID-19 patients [23]. Findings showed a significant reduction in detectable SARS-CoV-2 RNA when the devices were operating [23].
In summary, 20 of 24 studies demonstrated significant potential to prevent and mitigate the impact of bioaerosols in healthcare environments, regardless of the scenario and methodology used. In the remaining 4 studies (3 in-situ studies and one prospective study) the reduction of aerosols was non-significant [28, 31, 32, 38]. However, in the prospective study the authors commented that a as dental clinics, where economic issues or lack of guidelines may limit the installation of an appropriate ventilation system. According to the US Occupational Information Network (O*NET), which calculates risk levels for different occupations, dentists and clinical dentistry professionals are at the top of the risk scale when comparing “exposure to disease and infection” versus “physical proximity to other people” [41]. Across the nine different healthcare facilities of the included studies in this review, 28% of the studies that fulfilled our inclusion criteria were performed in dental clinics, followed by patient’s wards 16%, operating rooms 16%, and intensive care units 12%.
Limitations
Variability in aerosol measurement remains a challenge. Active air samplers exhibit high variability giving different results in the exact location simultaneously. A calibration following validated standards is strictly necessary, but it was not mentioned in all studies in this review.
Although the ACH sums up all methods of aerosol removal - natural or mechanical (e.g. unknown leakage, settling, opening windows, HVAC system, etc.) —which could significantly impact the measured outcome, only seven studies calculated the pre-existing ACH in the rooms. Also, temperature, relative humidity, and air velocity directly influence aerosols’ mechanics, but only seven studies controlled these parameters in their statistical analyses.
Methodologies and outcome measurements were not standardized in current research, compromising the overall quantitative measure of the magnitude of the effect. Although several studies assessed airborne microbial counts, the conclusions of these studies cannot be extrapolated to species that require specific growing conditions or different sampling requirements. Some species cannot be detected with conventional culture counting methods, requiring additional analysis that includes molecular identification methods.
Conclusions
Although the included studies assessed the outcomes using well-known methodologies, most of them lacked the complexity associated with analyzing indoor air quality in healthcare settings. Standardization of methods is necessary to obtain a body of evidence with less heterogeneity, which would allow for establishing the size of the effect, making recommendations, direct comparisons, and cost/benefit analyses of the implementation of portable air cleaners in healthcare settings. Given the global economic pressure on clinical settings and the rapid evolution of practices to live with COVID-19, the devices’ manufacturers should focus on efficiency and being affordable for their implementation in low- or medium-income countries.
Future research should assess (a) active airborne microbial sampling (at least overall fungi and bacteria) or quantitative PCR analysis, (b) airborne particles concentrations (<5μm), and (c) indoor air parameters (mainly ACH, temperature, relative humidity, and air velocity) to be controlled in statistical analyses, including the flow of people and the procedures performed during sampling. Most importantly, studies need to evaluate the influence of portable air cleaners on rates of infections through prospective randomized or non-randomized trials with long-term follow-ups and large sample sizes.
We recommend calculating the sample size for microbiological sampling, preferably based on a pilot study for assessing the variability of the setting since physical and biological variables may affect the aerosol mechanics or viability of microorganisms. A full description of these technologies, their design, ease of use, noise level, maintenance cost, and the energy consumption is necessary to compare the cost-effectiveness of the different devices tested.
Funding statement
This study was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Cod 001; and did not receive any specific grant from other funding agencies in the public, commercial, or not-for-profit sector.
Author Contributions
MA designed the study and drafted the paper with input from all authors. MA and JD performed the searches and data extraction. MA, JD, and BL analysed methodologies. GM and AG revised the manuscript critically for important intellectual content and final approval of the published version.
Declaration of Competing Interest
The authors have no conflict of interest to disclose. The funders had no role in study design, manuscript preparation, or the decision to publish.
Appendix A Supplementary data
The following is the Supplementary data to this article:
Acknowledgments
AG and GM thank FACEPE, CNPq, and CAPES for the continuing support of their research. This work was also supported in the framework of the National Institute of Photonics (INCT de Fotonica) project, grant CNPq 403233/2017-8.
1 The European Polyp Surveillance (EPoS) study is a large multinational project financed by multiple sources in the participating countries.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.jhin.2022.12.004.
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| 36521582 | PMC9744491 | NO-CC CODE | 2022-12-15 00:01:49 | no | J Hosp Infect. 2022 Dec 13; doi: 10.1016/j.jhin.2022.12.004 | utf-8 | J Hosp Infect | 2,022 | 10.1016/j.jhin.2022.12.004 | oa_other |
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Journal of Building Engineering
2352-7102
2352-7102
Elsevier Ltd.
S2352-7102(22)01746-6
10.1016/j.jobe.2022.105740
105740
Article
Airport terminal passenger forecast under the impact of COVID-19 outbreaks: A case study from China
Tang Hao ab
Yu Juan ab
Lin Borong ab∗
Geng Yang ab
Wang Zhe c
Chen Xi d
Yang Li d
Lin Tianshu d
Xiao Feng e
a School of Architecture, Tsinghua University, Beijing, China
b Key Laboratory of Eco Planning & Green Building, Ministry of Education, Tsinghua University, Beijing, China
c Department of Civil and Environmental Engineering, The Hong Kong University of Science and Technology, Hong Kong, China
d Beijing Daxing Airport, Beijing, China
e School of Business Administration, Southwestern University of Finance and Economics, Chengdu, China
∗ Corresponding author. School of Architecture, Tsinghua University, Beijing, China.
13 12 2022
15 4 2023
13 12 2022
65 105740105740
8 8 2022
7 12 2022
11 12 2022
© 2022 Elsevier Ltd. All rights reserved.
2022
Elsevier Ltd
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Passengers significantly affect airport terminal energy consumption and indoor environmental quality. Accurate passenger forecasting provides important insights for airport terminals to optimize their operation and management. However, the COVID-19 pandemic has greatly increased the uncertainty in airport passenger since 2020. There are insufficient studies to investigate which pandemic-related variables should be considered in forecasting airport passenger trends under the impact of COVID-19 outbreaks. In this study, the interrelationship between COVID-19 pandemic trends and passenger traffic at a major airport terminal in China was analyzed on a day-by-day basis. During COVID-19 outbreaks, three stages of passenger change were identified and characterized, i.e., the decline stage, the stabilization stage, and the recovery stage. A typical “sudden drop and slow recovery” pattern of passenger traffic was identified. A LightGBM model including pandemic variables was developed to forecast short-term daily passenger traffic at the airport terminal. The SHapley Additive exPlanations (SHAP) values was used to quantify the contribution of input pandemic variables. Results indicated the inclusion of pandemic variables reduced the model error by 27.7% compared to a baseline model. The cumulative numbers of COVID-19 cases in previous weeks were found to be stronger predictors of future passenger traffic than daily COVID-19 cases in the most recent week. In addition, the impact of pandemic control policies and passengers' travel behavior was discussed. Our empirical findings provide important implications for airport terminal operations in response to the on-going COVID-19 pandemic.
Graphical abstract
Image 1
Keywords
Airport terminal
COVID-19
Forecasting model
Machine learning
SHAP values
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pmc1 Introduction
The 2019 coronavirus disease (COVID-19) pandemic has unprecedentedly alerted people's life around the world since the first outbreak in early 2020 [1]. Working and studying from home has become the primary choice for many people amid the pandemic, which has influenced the operation and management of most non-residential buildings [[2], [3], [4]]. The use of transportation hub, such as airport terminals, has also been significantly alerted due to the reduced travel demands and the travel restrictions imposed by the government [5,6]. According to the International Civil Aviation Organization (ICAO), the total world air passenger traffic reduced by 60% in 2020 and by 49% in 2021 compared to 2019 [7]. The tremendous passenger uncertainty caused by the COVID-19 pandemic has created significant challenges for airport terminal operation and management. Developing optimized strategies for airport terminals to cope with pandemic-induced traffic fluctuations has been a topic of interest in recent studies [6,[8], [9], [10]].
Airport terminals are reported to consume approximately two to three times as much energy as typical non-residential buildings due to their functional and operational characteristics [11,12]. Improving energy efficiency while providing good indoor environmental quality (IEQ) is a primary objective for airport terminal operations and management [13,14]. Generally, more than 40% of the energy in airport terminals is consumed by the heating, ventilation, and air conditioning (HVAC) system to provide comfortable thermal environment for passengers [[15], [16], [17]]. The number of passengers is directly related to the demand for fresh air and the load of the air conditioning system [8,18]. Besides, operations of other airport service and applications such as lighting, elevator, hot water, baggage delivery, business service and ground handling service are also significantly affected by passenger patterns [6,19]. Energy consumption per passenger traffic has been used as an important indicator of airport energy efficiency in existing standards and studies [20]. Accurate passenger forecasting provides an essential foundation for optimizing the operation of HVAC and other building systems within an airport terminal building.
The pandemic has posed a huge challenge for future passenger forecasting. Traditionally, passenger profiles from previous years was considered an important baseline for forecasting [21]. In many existing studies, historical passenger traffic profiles have been used as the critical predictor of time series traffic forecasts in regression models and machine learning models [[22], [23], [24]]. Additional socioeconomic factors, such as national and regional gross domestic product (GDP), income levels, population, employment rates, and special events, were used to fine-tune the forecast [21,25]. Some studies have also attempted to predict travel demands with unconventional factors such as search engine queries [26,27] and social media data [28]. However, the outbreak of the COVID-19 pandemic has substantially increased the uncertainty of air travel demand, an effect that is difficult to address with the traditional predictors described above. It is necessary to include pandemic-related variables, such as the number of new cases, number of deaths, and pandemic control policies, in the forecasting model to account for the impact of the pandemic on air passenger [[29], [30], [31]]. However, few studies have been done on the above topics. More empirical studies are needed to explore which pandemic-related variables have strong predictive power for airport passenger traffic forecasts and the extent to which the inclusion of pandemic variables affects the accuracy of the model outcome.
Several studies have been undertaken to investigate air passenger traffic patterns in China during the COVID-19 pandemic to provide guidance to airports in dealing with these enormous challenges [[32], [33], [34], [35]]. However, most current studies focused only on the first outbreak of the pandemic during 2020 Spring, while the impact of later outbreaks has been largely overlooked. In the second half of 2020 and throughout 2021, outbreaks reoccurred intermittently in China, but with fewer cases and shorter durations during each subsequent outbreak, as shown in Fig. 1 . China reported a total of 35,107 COVID-19 cases in 2021, only 36% of the number in 2020, and none of the outbreaks were of similar magnitude to the first Wuhan outbreak in early 2020. Nevertheless, these intermittent outbreaks continued the depression in travel demand in 2021, with total air passenger traffic increasing by only 5.5% over 2020 [36]. Given the updates in pandemic control measures, evaluations of the virus and changes in people's psychological responses to the virus, little is known about whether these small-scale outbreaks yielded impacts on passenger traffic similar to those of the first major outbreak.Fig. 1 New daily confirmed cases of COVID-19 in China (data source: World Health Organization database, https://covid19.who.int).
Fig. 1
The acquisition of data is another limitation frequently mentioned in existing studies. Several open access and subscription databases were cited as the primary data sources in relevant studies, such as the Civil Aviation Administration of China (CAAC) database, the International Air Transport Association (IATA) database and the Official Airline Guide (OAG) database [33,37,38]. However, data on passenger traffic in China are not often available. The time series of the passenger data are often incomplete or have a low resolution, i.e., monthly data, which imposes many limitations on the analysis. As an alternative, the number of flights and available seats were most often used as indicators to characterize travel demands in the current study. Even so, the number of passengers is a more accurate indicator of travel demand than either of these two.
To address the limitations of current studies, this study quantified the impact of COVID-19 outbreaks in different stages of the pandemic on passenger traffic at Beijing Daxing Airport and developed a short-term airport passenger traffic forecasting model with selected pandemic variables. This study makes two major scientific contributions. First, the correlation between pandemic trends and daily passenger traffic was examined in the two years after entering the pandemic, covering multiple outbreaks that have occurred in China. This enabled us to compare the impact of outbreaks with different durations and total confirmed cases on passenger traffic. By analyzing patterns of passenger decline and recovery resulting from the early and late outbreaks, we revealed the changes in travel behaviors of passengers and discussed their association with the pandemic control policy, vaccine uptake and virus evolution. Second, a week-ahead passenger traffic forecasting model with historical pandemic variables was developed and compared to a baseline model with only conventional predictors. The predictive power of different pandemic variables was assessed using an explainable artificial intelligence approach called SHapley Additive exPlanations (SHAP) values.
The implications of this study are twofold. First, the correlation between pandemic trends and airport passenger fluctuations was revealed, which is informative for optimizing airport terminal operations to achieve better energy efficiency and IEQ. Second, this study demonstrated a framework of developing a machine learning forecasting model to account for the impact of pandemic situations on airport passenger forecast. This provides an important reference for airport managers to understand and forecast passenger patterns amid the pandemic.
The content of this paper is organized as follows: Section 2 presents an overview of the collected data. Section 3 introduces the adopted statistical methods and machine learning algorithm. In Section 4, we first present the results of the correlation analysis between pandemic variables and passenger traffic, followed by a time series analysis of passenger traffic changes at different stages during the five outbreaks in Beijing, and then present the results of the development, optimization and interpretation of the proposed passenger forecasting models. The impact of pandemic control policies and changes in passenger travel behavior during the COVID-19 pandemic are discussed further in Section 5.
2 Data collection
In this section, the data used to quantify the impact of the COVID-19 pandemic on airport passenger traffic and to build the forecast models are presented.
2.1 Passenger traffic data
The daily passenger traffic at Beijing Daxing Airport from January 1, 2020, to December 30, 2021, was obtained and analyzed. Daxing Airport began operations in September 2019 as the second international airport serving Beijing, in addition to the existing Beijing Capital International Airport. The daily passenger traffic, including arriving and departing passengers for both domestic and international flights, was collected, as shown in Fig. 2 . As the airport began operations in September 2019, passenger traffic was still in the process of growth in early 2020 and had not yet reached its design capacity when the pandemic occurred. Passenger traffic dropped sharply after the first outbreak in January 2020 and did not begin to recover until May 2020. The recovery period after the first outbreak did not last long, as another outbreak in Beijing in June 2020 caused a sharp drop in passenger traffic again (introduced in subsection 2.2). After the end of the second outbreak, passenger traffic experienced a long and steady recovery period, reaching its expected capacity of approximately 100,000 passengers per day in October 2020. However, passenger traffic continued to fluctuate in 2021 due to repeated small-scale outbreaks. There were three noteworthy drops in passenger traffic in January, August, and October 2021. Even so, from 2020 to 2021, annual passenger traffic increased by 56%.Fig. 2 Daily passenger traffic at Beijing Daxing Airport.
Fig. 2
Notably, the Chinese government has imposed strict restrictions on international flights since February 2020 to control the introduction of COVID-19 cases from abroad. At that time, Daxing Airport suspended international flight services, which did not resume by the end of 2021. Therefore, the correlation between pandemic trends and international flights was not investigated in this study. Only domestic passenger traffic will be discussed and analyzed in the following sections.
2.2 COVID-19 pandemic data
The COVID-19 pandemic data were collected from daily COVID-19 reports released by the National Health Commission (NHC) of the People's Republic of China (http://www.nhc.gov.cn/) and the municipal health boards. Reports from the NHC provided information on daily confirmed cases, daily deaths, daily imported cases, and daily cured cases for 34 provincial-level divisions (e.g., provinces, autonomous regions, municipalities, and special administrative regions) in China. The detailed city-scale pandemic data were released by the city's health commission, for example, the Beijing Municipal Health Commission (http://wjw.beijing.gov.cn/). National and city-scale COVID-19 pandemic data were collected from January 1, 2020, to December 31, 2021, matching the period of the collected passenger traffic data.
An obvious correlation was observed between the pandemic trends in Beijing and the air passenger traffic at Daxing Airport, as shown in Fig. 3 . The red bars represent the new daily confirmed COVID-19 cases in Beijing, and the blue line represents the daily total passenger traffic at Daxing Airport. Five COVID-19 outbreaks that occurred in Beijing in 2020 and 2021 were identified, as highlighted in light red in Fig. 3. We defined a COVID-19 outbreak as with at least 10 confirmed cases in the city. Therefore, those cases that appeared sporadically in between identified outbreaks were not considered. Note that this is not a consensus criterion for defining an outbreak but was based entirely on the pandemic situation in China at the time. The five outbreaks differed greatly in total cases and durations, with the earlier outbreaks being much more severe than the later ones. Statistics of the five outbreaks are presented in Table 1 . The first wave of outbreak lasted the longest and had the highest total number of confirmed cases from January 2020 to April 2020. The second wave lasted only 23 days but developed most rapidly, having the highest number of daily confirmed cases. The following three outbreaks were much milder in terms of the number of total cases and growth rate, with the smallest, the fourth outbreak, having only 13 confirmed cases. However, these mild outbreaks still dramatically reduced passenger traffic.Fig. 3 New daily confirmed COVID-19 cases in Beijing and daily total passenger traffic at Beijing Daxing Airport. The five outbreaks in Beijing are highlighted in light red. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
Table 1 Statistics of five COVID-19 outbreaks that occurred in Beijing in 2020 and 2021.
Table 1Outbreak Duration (days) Total cases Mean daily cases Peak daily cases
1 84 590 7 32
2 23 334 14.6 36
3 41 79 1.9 7
4 20 13 0.7 3
5 33 54 1.6 6
The pandemic trends in the five destination cities with the most connecting flights to Beijing Daxing Airport in 2020 and 2021 were also reviewed, as shown in Fig. 4 . The five cities were Chengdu, Chongqing, Guangzhou, Shenzhen, and Hangzhou. Following the same criterion, we identified five outbreaks that had at least 10 confirmed cases in the five cities, as highlighted in Fig. 4. However, there was less correlation between the number of daily confirmed cases in these cities and passenger traffic at Daxing Airport, except for the first and fourth outbreaks that overlapped with the first and fifth outbreaks in Beijing, respectively. The third outbreak occurred in Guangzhou, with a total number of 146 cases, slightly reducing passenger traffic but by a much smaller amount than the fourth outbreak in Beijing in late July 2021.Fig. 4 New daily confirmed COVID-19 cases in five destination cities with the most connecting flights to Beijing Daxing Airport and daily total passenger traffic at Beijing Daxing Airport. The five outbreaks are highlighted in light red. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 4
In addition, passenger traffic declined slightly in late June 2021, but without simultaneous COVID-19 outbreaks in both Beijing and major destination cities. This was primarily due to military activities and security missions affecting the flight schedule on the eve of the 100th anniversary of the founding of the Communist Party of China in Beijing on July 1, 2021.
3 Methodology
In this section, the statistical methods and machine learning algorithms adopted in this study are introduced. The methodology flowchart is shown in Fig. 5 . First, a correlation analysis was conducted to quantify the impact of various pandemic variables on daily passenger traffic at Beijing Daxing Airport. Then, the impact of multiple COVID-19 outbreaks that occurred in Beijing on airport passengers was characterized based on a time series analysis. Based on the collected data, two LightGBM models were trained, optimized, and compared, i.e., a baseline model with only conventional variables and a proposed model with additional pandemic variables. Finally, the predictions of the proposed model were interpreted using SHAP values and thus the importance of pandemic variables was measured.Fig. 5 Research methodology flowchart.
Fig. 5
3.1 Correlation analysis
Pearson's correlation, Spearman's rank correlation and Kendall's rank correlation were the most frequently used approaches in previous studies. As a parametric hypothesis test, Pearson's correlation assumes that both variables are normally distributed. However, the Shapiro–Wilk normality test indicated that neither the pandemic variables nor the passenger traffic variable in this study was distributed normally. Spearman's rank correlation and Kendall's rank correlation are both nonparametric methods that do not rely on the assumption of normal distribution, while Kendall's rank correlation is more suitable for handling variables that contain identical values (called “ties”). Because there were many ties in the investigated variables, Kendall's rank correlation was adopted in this study.
In Kendall's rank correlation, for a pair of observations (xi,yi) and (xj,yj) of two variables x and y, they are said to be a concordant pair if the elements of one pair are greater than or equal to or less than the corresponding elements of the other pair; otherwise, they are said to be a discordant pair. Thus, Kendall's correlation coefficient τB is mathematically defined as:(1) τB=nc−nd(n0−n1)(n0−n2)
where nc is the number of concordant pairs; nd is the number of discordant pairs; and n0, n1, and n2 are defined as:(2) n0=n(n−1)2
(3) n1=∑iti(ti−1)2
(4) n2=∑juj(uj−1)2
where n is the number of values; ti is the number of tied values in the ith group of ties for the first quantity; and uj is the number of tied values in the jth group of ties for the second quantity.
Kendall's correlation coefficient has a value between 1 and -1, where 1 represents a perfect positive relationship, 0 represents no relationship and −1 represents a perfect negative relationship. Based on the absolute value of the correlation coefficient, the effect size of the correlation was categorized as small (0.1 ≤ |τB| < 0.3), medium (0.3 ≤ |τB| < 0.5), and large (0.5 ≤ |τB|) [39].
3.2 LightGBM model
Machine learning (ML) methods are increasingly being adopted in studies for forecasting air travel demands because they are highly capable of addressing complex nonlinear relationships between variables, as well as their superior computational efficiency in handling massive data [40]. In this study, a tree-based ML algorithm named Light Gradient Boosting Machine (LightGBM) was employed to forecast week-ahead air passenger traffic at Daxing Airport based on historical pandemic data and passenger traffic data. LightGBM is a framework that was developed based on many effective gradient boosting decision trees (GBDTs), such as XGBoost, and has been found to be more accurate and faster in many scenarios. Like other ensemble learning algorithms, LightGBM grows multiple classification and regression trees (CARTs) sequentially based on training data, with subsequent trees being trained with the residuals of preceding trees, as shown in Fig. 6 . LightGBM has two important features that make it efficient and scalable: gradient-based one-side sampling (GOSS) and exclusive feature bundling (EFB) [41]. GOSS enables the algorithm to exclude a significant proportion of training data with small gradients, while EFB enables the algorithm to optimize the number of features by bundling exclusive features. Therefore, LightGBM accelerates the training process of traditional GBDTs by up to 20 times or more, with almost no loss of accuracy.Fig. 6 Illustration of the tree growth process in LightGBM.
Fig. 6
The performance of the ML model heavily relies on the optimization of model hyperparameters that control its learning process [42]. The conventional approaches for hyperparameter optimization are grid search, which exhaustively evaluates every position of a predefined search space of hyperparameters, and random search, which randomly evaluates the points in a predefined search space. Both methods require a large number of trials to locate the best set of hyperparameters, which is time-consuming. In this study, we used a more effective hyperparameter optimization framework called Optuna [43]. Optuna provided multiple hyperparameter-sampling and pruning algorithms that significantly improved the cost effectiveness of the optimization process. The TPESampler integrated in Optuna was used to sample hyperparameters from the predefined space in this study [44]. In each searching trial, the TPESampler fit two Gaussian mixture models (GMMs), one fitting the set of hyperparameters associated with the best objective value and the other fitting the remaining hyperparameter values. The hyperparameter value that maximized the ratio of the target value of the two GMMs was then chosen. The results of hyperparameter optimization are presented in subsection 4.3.
3.3 SHAP values
Although ML models have demonstrated great success in addressing complex forecasting issues, the interpretability of model prediction has been a critical barrier to adoption in many scenarios [45]. The superior performance of ML models is often achieved by increasing the complexity of the model, which makes it extremely difficult to interpret the output of this “black box”. To address this problem, scientific interest in the field of explainable artificial intelligence (XAI) has grown rapidly, and many approaches have been proposed to help interpret complex ML models [46,47]. An important implication is to understand the effect of the input variables on model prediction in terms of its magnitude and direction [48,49].
In this study, a unified approach called SHAP values was used to interpret the prediction of the resulting LightGBM models [50]. Different from many other approaches that can only provide an overall evaluation of variable importance on the entire dataset, SHAP values allow for a local measure of variable importance, i.e., variable importance is calculated for each observation in the dataset. Specifically, for each input variable, the SHAP values measure the change in the model prediction when conditioning on that variable. Therefore, the SHAP values of a variable can be positive or negative, depending on whether the variable contributes positively or negatively to the model prediction. For each observation, SHAP values attributed to all features collectively explain why model prediction differs from the base value (the mean of the target value in training data). Fig. 7 illustrates an example of the SHAP values for a model with five variables. The SHAP values attributed to variables 1, 2 and 5 are −1.5, −2.0 and −1.5, respectively, indicating that these three features have different degrees of negative impact on the model prediction. Meanwhile, the SHAP values indicate that variable 3 and variable 4 have positive contributions to the model prediction. Considering the effects of all features, the predicted value was lower than the base value by 2.5 in the model. After calculating the SHAP values for all observations, the higher the sum of the absolute SHAP values attributed to a variable, the more important that variable is.Fig. 7 An illustration of SHAP values.
Fig. 7
3.4 Software and package
Kendall's correlation analysis was performed in R with the base package “stats”. The LightGBM model was established in Python with the package “lightgbm” [41]. The optimization of the LightGBM model was performed in Python with the package “optuna” [43]. The SHAP values were calculated and visualized in Python using the “shap” package [50].
4 Result
4.1 Correlation analysis between pandemic variables and passenger traffic
Kendall's correlation analysis indicated that new daily confirmed cases in Beijing were the most relevant pandemic variables to daily passenger traffic at Daxing Airport, followed by national new daily cases and new daily cases in the five most connected destination cities, as shown in Table 2 . All the correlation coefficients reached a significance level of P < 0.001. Table 2 also shows a slightly higher correlation between the new confirmed cases and arriving passengers compared to departing passenger traffic. The results indicated that during the outbreaks, the number of people flying to Beijing decreased more than the number of people flying out of Beijing. This was partly due to the higher level of restrictions on travel to Beijing than to other Chinese cities during the outbreaks. In addition, the correlation between new daily deaths and passenger traffic was examined but turned out to have a very small effect size.Table 2 Correlation analysis of pandemic variables and daily passenger traffic.
Table 2Variables Kendall's correlation coefficient
Total passengers Arriving passengers Departing passengers
Beijing new daily cases −0.377*** −0.381*** −0.370***
National new daily cases −0.320*** −0.330*** −0.307***
New daily cases in the five most connected destination cities −0.213*** −0.212*** −0.214***
Beijing new daily deaths −0.114*** −0.110*** −0.114***
Significance level: ***, P < 0.001.
A significant hysteresis effect of the pandemic trends on passenger traffic is shown in Fig. 3. Passenger traffic declined rapidly with outbreaks of COVID-19 cases but recovered much more slowly after the outbreaks subsided. Trends in passenger traffic were sometimes determined not by new cases on the same or previous few days but by pandemic trends over a longer period of time before. This hysteresis effect cannot be fully explained by analyzing only the correlation between the number of cases and passenger traffic on a day-by-day basis. Therefore, we calculated the cumulative number of confirmed cases over the previous one to 100 days and its correlation with passenger traffic to account for this hysteresis effect, as shown in Fig. 8 . The cumulative number of cases had a much stronger correlation with passenger traffic than the daily number of cases. The correlation between the cumulative number of cases and passenger traffic had a U-shape, first increasing and then decreasing as the number of days counted increased. The cumulative number of cases in the previous 46 days had the strongest correlation (in absolute value) with passenger traffic, with a coefficient of −0.665, indicating a very large effect size. The results of the correlation analysis provided valuable information for variable selection in forecasting model development.Fig. 8 Correlation coefficient between passenger traffic and cumulative number of cases in Beijing.
Fig. 8
4.2 Passenger traffic trends during different stages of the outbreaks
In this section, we further investigated the passenger traffic trends during the five outbreaks that occurred in Beijing between 2020 and 2021, leading to a discussion of the difference in the impact of the outbreaks with different scales and durations. Fig. 9 (a) to (e) show the new daily cases (top panel) and daily passengers (bottom panel) during the first to fifth outbreaks in chronological order. Days with new cases reported are marked with red points. We identified three stages for a typical outbreak in terms of passenger flow and highlighted them in Fig. 9: the decline stage in red, the stabilization stage (at a low level) in yellow and the recovery stage in green. In Table 3 , we present the statistics for the five outbreaks, as well as the decline and recovery rates of passenger traffic resulting from each outbreak. The decline and recovery rates in percentage terms were calculated by dividing the decline and recovery rates by the number of passengers before each outbreak. The percentages of the decline and recovery rates are more representative than the absolute rates due to the different levels of passenger traffic prior to the outbreak. Finally, the number of days D needed to recover to preoutbreak levels after each outbreak was calculated using Eq. (5).(5) D=Dd+Ds+1r
where Dd is the number of days in the decline stage; Ds is the number of days in the stabilization stage; and 1/r calculates the number of days to recover where r is the percentage rate of recovery.Fig. 9 Daily confirmed COVID-19 cases and passenger traffic during the five outbreaks that occurred in Beijing.
Fig. 9
Table 3 Statistics on the decline and recovery stages of passenger traffic resulting from the five COVID-19 outbreaks in Beijing between 2020 and 2021.
Table 3Statistics Outbreaks
1 2 3 4 5
Total cases 590 334 79 13 54
Duration of decline (day) 25 6 39 12 17
Decline in percentage (%) 96 95 90 81 82
Decline rate (passengers per day) 1832 7814 2276 7811 4668
Decline rate in percentage (% per day) 3.8 15.8 2.3 6.8 4.8
Recovery rate (passengers per day) 530 1171 1997 2107 1170
Recovery rate in percentage (% per day) 1.1 2.4 2 1.8 1.2
Estimated number of days needed to recover to preoutbreak passenger traffic levels 189 64 96 78 105
All five outbreaks resulted in a sharp drop in passenger traffic, dropping between 81% and 96% from the preoutbreak level. Except for the third outbreak, the decline rates of passenger traffic at the beginning of the outbreaks were significantly higher than the recovery rates after the outbreaks. The average percentage decline rate for the five outbreaks was 6.7% per day, while the percentage recovery rate was only 1.7% per day. As a result, it took a longer period (64–189 days) for passenger traffic to recover to the preoutbreak level after each outbreak.
Some differences in the trends of passenger traffic during the early and late outbreaks were observed. The total number of confirmed cases in the first and second outbreaks was significantly higher than that in later outbreaks, which led to a higher percentage decrease in passenger traffic in these two outbreaks. Kendall's correlation analysis verified a significant correlation between the total number of cases in the outbreak and the resulting percentage decrease in passenger traffic (P < 0.05). Another difference was that the earlier outbreaks had a much longer stabilization stage than later outbreaks. In addition to the effect of the outbreak duration, the increasingly early appearance of the recovery stage was an important reason for the shorter stabilization stage in later outbreaks. In the first outbreak, daily passenger traffic began to recover only when no new cases were reported for two consecutive weeks. For the second outbreak, the recovery stage began as soon as no new cases were reported. In the fifth outbreak, passenger traffic entered the recovery stage while sporadic new cases were still being reported. The forward shift in the beginning of the recovery stage reflected a change in passenger travel behaviors during the COVID-19 pandemic, which was further discussed in subsection 5.2.
4.3 Week-ahead passenger traffic forecast model
Based on the collected data, two LightGBM models with different inputs were built to forecast the daily passenger traffic after one week. Model I, as a baseline model, was trained using conventional predictors, including historical passenger traffic variables, date characteristics and quarterly GDP. The quarterly GDP data were collected from the Chinese National Bureau of Statistics (http://www.stats.gov.cn/). In addition to above variables, Model II included historical pandemic variables, i.e., new daily confirmed cases in the previous 7–13 days and cumulative cases within the previous 2/4/6/8/10/12/14 weeks, excluding the week before the forecast date. The names and descriptions of the variables for the two models are shown in Table 4 .Table 4 Variables used in Model I and Model II.
Table 4Variables Description Model I Model II
N_pre_7/8/9/10/11/12/13 Daily passenger traffic 7/8/9/10/11/12/13 days prior ✓ ✓
Month Month, [1, 2, …12] ✓ ✓
Weekday Day of week, [1, 2, …7] ✓ ✓
Holiday Holiday, [0, 1] ✓ ✓
GDP Quarterly GDP ✓ ✓
Case_pre_7/8/9/10/11/12/13 New daily cases 7–13 days prior ✓
Case_pre_sum_2/4/6/8/10/12/14 Cumulative cases within the previous 2/4/6/8/10/12/14 weeks, excluding the week before the forecast date ✓
The collected data was randomly split into training data (60%), validation data (20%) and test data (20%). The validation data were used to optimize the hyperparameters, while the test data were used to evaluate the accuracy of model prediction. Table 5 presents the descriptions and search ranges of optimized hyperparameters, as well as the best set of hyperparameters for the two models located using Optuna [43].Table 5 The optimization of hyperparameters for the LightGBM models.
Table 5Hyperparameters Description Search range Optimization result
Model I Model II
feature_fraction Percentage of variables used to train each tree model [0.4, 1.0], float 0.99 0.43
bagging_fraction Percentage of data used to train each tree model [0.4, 1.0], float 0.97 0.82
learning_rate Weighting of new tree model added to the model [0.01, 0.2], float 0.18 0.18
bagging_freq Number of iterations to perform bagging [1,7], integer 6 2
num_leaves Number of leaves in each tree model [4,32], integer 18 31
min_child_samples Minimum number of data needed in a leaf [20,40], integer 20 21
Table 6 presents the accuracy of the two models on training, validation and test data measured by the CVRMSE (the coefficient of the variation of the root mean square error) and R2 (coefficient of determination). The mathematical definitions of the CVRMSE and R2 are shown in Eq. (6) and Eq. (7). A lower CVRMSE and higher R2 indicated better model accuracy, while a higher CVRMSE and lower R2 indicated the opposite. Both metrics showed a consistent result in that the inclusion of pandemic variables significantly improved the models' accuracy on training, validation, and test data. Specifically, compared to Model I, Model II showed a 27.7% decrease in the CVRMSE and an increase in R2 from 0.871 to 0.933 on the test data. Additionally, the difference in the performance of Model II on training and test data was smaller than that of Model I, indicating that the inclusion of pandemic variables did not cause overfitting problems.(6) CVRMSE=1y‾∑i=0i=n(yi−yˆi)2n
(7) R2=1−∑i=0n(yi−yˆi)2∑i=0n(yi−y‾)2
where y‾ is the mean of the observed values; yi is the ith observed value; yˆi is the ith predicted value; and n is the number of observations.Table 6 Model accuracy on training, validation, and test data.
Table 6Model CVRMSE R2
Training Validation Test Training Validation Test
Model I 0.114 0.210 0.231 0.972 0.914 0.871
Model II 0.069 0.143 0.167 0.990 0.960 0.933
The SHAP values were calculated to measure the contribution of input variables to model predictions. Fig. 10 shows the SHAP values of the 20 most important input variables. The horizontal coordinate reflects the SHAP values, and the color of the points represents the value of the variables in each observation. The variables are sorted in descending order in vertical coordinates based on the sum of the absolute SHAP values attributed to them. The closest and second closest daily passenger traffic values to the forecast date (N_pre_7 and N_pre_8) were found to have the most contributions to the model, which is not surprising in time series forecasting. The cumulative number of cases within the previous 6 weeks (Case_pre_sum_6) was the third most important variable. Considering that the week before the forecast date was excluded, this result was highly consistent with the result of the correlation analysis that the cumulative number of cases in the past 46 days had the highest correlation with passenger traffic on this day. In addition, the cumulative number of cases within the previous 2/4/10/8 weeks was also included in the ten most important variables. In contrast, the number of daily cases in previous days had much smaller impacts on model predictions, with the number of daily cases seven days earlier (Case_pre_7) being the only one of the ten most important variables. Other conventional factors, such as GDP, month, weekdays, and holidays, also did not have many impacts.Fig. 10 Variable importance measured by SHAP values.
Fig. 10
5 Discussion
Based on the results, we further discussed the impact of pandemic control policies, changes in passenger travel behaviors and implications of the forecast model to provide additional insight for policy formulation and airport operations.
5.1 Impact of pandemic control policy
The policy and regulations imposed by governments for pandemic control are a crucial factor that influence air travel demands patterns amid the pandemic [32,51]. Most countries around the world had- implemented various restrictions on domestic and international travel to contain the spread of the virus [52], among which China had one of the most stringent policies in force. At the time of research, China was one of the few countries that still adhered to a Zero-COVID policy, which calls for strict containment and closure measures and mass nucleic acid testing when cases emerge, with the goal of eliminating cases within a short period of time. In contrast, many other countries (e.g., the United States) had eased or completely removed their restrictions on domestic and international transport in response to the evolution of the virus, the increasing vaccination uptake rate, and economic considerations.
To explore the impact of different pandemic control policies, the air passenger traffic trends identified in this study were compared with another study that analyzed airports passenger traffic in the United States during 2020 and 2021 [21]. Fig. 11 presented the comparison of passenger recovery ratio between the United States and Beijing Daxing Airport. The ratio is defined as the daily passenger traffic divided by the maximum daily passenger traffic from 2020 to 2021. The passenger numbers in the US were collected by the Transportation Security Administration (data is available at https://www.tsa.gov/coronavirus/passenger-throughput). At the beginning of the COVID-19 pandemic, China and the US went through a similar decline stage, where passenger traffic rapidly decreased to approximately 10% of the max capacity in a few weeks. However, the recovery rate in China was much higher, with passenger traffic returning to approximately 75% of the max capacity within ten months after the first outbreak. In comparison, the passenger traffic at most analyzed airports in the United States did not recover to 50% of the pre-outbreak level after a year of entering the pandemic [21]. On the other hand, China's Zero-COVID policy has also caused greater volatility in air travel demands compared to the US aviation market. The passenger traffic in China decreased significantly whenever new COVID-19 cases arose. An example is that a small outbreak of only 13 cases in Beijing reduced air passenger traffic at Daxing Airport by 81% in less than 2 weeks in August 2021 (see Table 3). Although passenger traffic quickly recovered to preoutbreak levels within two to three months after these mild and short outbreaks, such uncertainty can be a significant challenge to airport and airline operations. In comparison, the US aviation market experienced a more stable recovery, even though the number of confirmed cases was much higher than that in China during the same period.Fig. 11 Passenger recovery ratio for the US and Beijing Daxing Airport.
Fig. 11
It is not beneficial to claim which pandemic control policies, be they strict or otherwise, are superior to others because multiple trade-offs involving social, cultural, and economic factors need to be considered. Even in terms of the impact on the aviation industry alone, there are short-term and long-term outcomes that need to be weighed. Strict containment policies can quickly quell an outbreak and clear COVID-19 cases in the short term but result in dramatic fluctuations due to recurring cases, while mitigation policies lead to a slower but steadier recovery in air travel demand. Looking ahead, it may be fruitful to explore the possibility of merging different policies to achieve optimization of outcomes in the short and long terms. For example, testing and quarantine regulations can be adjusted in a timely manner to regional pandemic conditions to avoid disproportionate losses due to a few small outbreaks with overly tight regulations. A comprehensive review of the policies adopted by different countries and quantification of their impact would provide more valuable insights to tackle this problem.
5.2 Changes in travel behaviors during early and late outbreaks
We observed several differences in the impact of the five outbreaks that occurred in Beijing in 2020 and 2021 on passenger traffic. The percentage of passenger decline was higher in the two outbreaks in 2020 than in the three outbreaks in 2021. Additionally, late outbreaks had higher recovery rates than the first outbreaks and required fewer days to return to preoutbreak levels. Similar findings were reported in Korea, where the recovery rate of domestic air passenger traffic after the second outbreak was higher than that after the first outbreak [51]. In addition, we observed a forward shift in the beginning of the recovery stages of later outbreaks compared to early outbreaks. Passengers did not begin to increase until there were no new cases reported for two consecutive weeks after the first outbreak but increased when there were still sporadic cases being reported in the later outbreak in 2021.
Changes in travel behaviors were the determining factor for different patterns of passenger decline and recovery between the early and late outbreaks. In the early days of the pandemic, serious concerns about contracting the COVID-19 virus led to a long hesitation period for passengers to resume their usual air travel plans. However, evidence from social media indicated that negative perceptions of COVID-19 changed with the start of the vaccination campaign [53]. Eighty-six percent of China's population is fully vaccinated with the last dose of the primary series, which is among the highest vaccination rates in the world (WHO data, https://covid19.who.int/table). The high vaccination rate might induce a psychological effect that helps people feel less anxious and fearful about the virus and feel reassured to take necessary trips when outbreaks are mild or subsided. The changing characteristics of COVID-19 could be another factor in alleviating passengers' concerns about traveling amid the pandemic. Epidemiological findings suggested that recent variants of COVID-19 were becoming increasingly infectious but caused less severe illness, fewer hospitalizations, and a lower risk of death than the original virus and previous variants [[54], [55], [56]]. In response to the uptake of the vaccine and the constant evolution of the virus, 87% of travelers agreed that COVID-19 will not disappear, so we need to manage its risks while living and traveling normally [57]. This evidence indicated that passengers are adapting to living with COVID-19 in hopes of striking a balance between mobility and pandemic control measures.
5.3 Implications of the forecast model
The results of model comparison showed that including pandemic variables significantly improved the accuracy of week-ahead passenger traffic forecast. The SHAP values further revealed that the cumulative COVID-19 cases in the previous weeks were stronger predictors than daily COVID-19 cases, indicating the hysteresis effect of pandemic trends on passenger traffic. However, in another forecast model research based on the U.S. aviation market, weekly economic index was found to be more important than pandemic variables [29]. Such difference is believed to be resulted by the different pandemic control policy adopted in the two countries. It can be inferred that stricter pandemic control policies would lead to a stronger correlation between pandemic variables and airport passenger traffic, resulting a more significant improvement of model performance after accounting for pandemic conditions. This association dictates that a forecast model based on data from one country will likely not be applicable to another country with a vastly different pandemic control policy. In addition, there are other contextual factors which can moderate the impact of COVID-19 pandemic on passenger travel behavior, such as the vaccination rate, virus variants, social and cultural factors, etc. It is a promising but challenging topic to quantify the impact of these factors and incorporate them into forecast models in an appropriate manner. Consideration of these contextual factors will be beneficial to further improve the performance of the forecast model proposed in this study.
6 Conclusion
The COVID-19 pandemic has caused unprecedented uncertainty in airport passengers, posing a significant challenge to airport terminal operations and management. In this study, we developed and tested a machine learning model for week-ahead passenger traffic forecasting using pandemic-related variables, which outperformed a baseline model using only conventional predictors, such as historical passenger data, time-related inputs, and quarterly GDP. The inclusion of pandemic variables reduced the model error on the test dataset by 27.7%, as measured by the CVRMSE, and increased the R2 of the model from 0.871 to 0.933. The SHAP values revealed that the cumulative number of cases in previous weeks contributed more to model prediction than the daily number of cases, indicating the hysteresis effect of pandemic trends on passenger traffic. Meanwhile, conventional predictors such as date characteristics and economic indices had little impact on model predictions under the current pandemic scenarios. These results further affirmed the importance of considering pandemic situations in air travel demand forecasting and provided valuable suggestions for variable selection and model development.
The impact of five COVID-19 outbreaks that occurred in Beijing from 2020 to 2021 on passenger traffic were quantified and compared. The five outbreaks recorded varying number of cases from 13 to 590, but all led to a rapid and dramatic drop in airport passenger traffic, ranging from 81% to 96%. A hysteresis effect of pandemic trends on air travel demand was observed, with the cumulative number of cases in the previous weeks correlating more strongly with passengers than the number of daily cases. As the number of days counted increased, the correlation between the cumulative number of cases and passenger traffic showed a U-shaped change, with the highest absolute correlation coefficient of 0.665 for the cumulative number of cases in the previous 46 days.
We also observed different air travel behavior patterns in early and later outbreaks. The early outbreaks resulted in a longer stabilization stage between the decline and recovery stages compared to later outbreaks. In the first outbreak, the air passenger traffic started to recover after two weeks when no new cases were reported. Contrarily, the air passengers traffic started to recover when there were still sporadic cases being reported in later outbreaks. These differences indicated an important change in people's travel behavior over different stages of the pandemic, i.e., they waited a shorter period of time to resume their regular travel plans once an outbreak subsided. A high vaccination rate, reduced virulence of the virus, and updates to travel restrictions may have assuaged passengers' concerns about air traveling. These findings provide important insight into the airport operations amid the COVID-19 pandemic.
Credit author statement
Hao Tang: Conceptualization, Methodology, Writing Original Draft, Writing - Review & Editing, Juan Yu: Conceptualization, Methodology, Writing Review & Editing, Visualization, Borong Lin: Conceptualization, Writing - Review & Editing, Funding acquisition, Yang Geng: Writing - Review & Editing, Zhe Wang: Writing - Review & Editing, Xi Chen: Data Curation, Li Yang: Data Curation, Tianshu Lin: Data Curation, Feng Xiao: Writing - Review & Editing.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data availability
The authors do not have permission to share data.
Acknowledgments
This study was supported by the 10.13039/501100019534 National Science Fund for Distinguished Young Scholars [Grant number 51825802], the National Science Fund for Key Program [Grant number 52130803], the 10.13039/501100009592 Beijing Municipal Science & Technology Commission [Grant number Z211100003021032] and the 10.13039/501100002858 China Postdoctoral Science Foundation [Grant number 2022M711816].
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57 IATA Air Traveler Response to Quality of Life 2021
| 0 | PMC9744493 | NO-CC CODE | 2022-12-15 23:17:48 | no | 2023 Apr 15; 65:105740 | utf-8 | null | null | null | oa_other |
==== Front
Cell Signal
Cell Signal
Cellular Signalling
0898-6568
1873-3913
Elsevier Inc.
S0898-6568(22)00321-7
10.1016/j.cellsig.2022.110559
110559
Article
COVID-19 signalome: Potential therapeutic interventions
Lundstrom Kenneth a
Hromić-Jahjefendić Altijana b
Bilajac Esma b
Aljabali Alaa A.A. c
Baralić Katarina d
Sabri Nagwa A. e
Shehata Eslam M. f
Raslan Mohamed f
Raslan Sara A. f
Ferreira Ana Cláudia B.H. gh
Orlandi Lidiane gh
Serrano-Aroca Ángel i
Uversky Vladimir N. j
Hassan Sk. Sarif k
Redwan Elrashdy M. l
Azevedo Vasco m
Alzahrani Khalid J. n
Alsharif Khalaf F. n
Halawani Ibrahim F. n
Alzahrani Fuad M. n
Tambuwala Murtaza M. o⁎⁎
Barh Debmalya np⁎
a PanTherapeutics, Route de Lavaux 49, CH1095 Lutry, Switzerland
b Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Hrasnicka Cesta 15, 71000 Sarajevo, Bosnia and Herzegovina
c Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Yarmouk University, P.O. Box 566, Irbid 21163, Jordan
d Department of Toxicology “Akademik Danilo Soldatović”, University of Belgrade — Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
e Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo 11865, Egypt
f Drug Research Center, Clinical Research and Bioanalysis Department, Cairo 11865, Egypt
g Campinas State University, Campinas, São Paulo, Brazil
h University Center of Lavras (UNILAVRAS), Lavras, Minas Gerais, Brazil
i Biomaterials and Bioengineering Laboratory, Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, c/Guillem de Castro 94, 46001, Valencia, Spain
j Department of Molecular Medicine and USF Health Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
k Department of Mathematics, Pingla Thana Mahavidyalaya, Maligram 721140, India
l Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, P.O. Box 80203, Jeddah, Saudi Arabia
m Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil
n Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
o Lincoln Medical School, University of Lincoln, Brayford Pool Campus, Lincoln LN6 7TS, UK
p Institute of Integrative Omics and Applied Biotechnology (IIOAB), Nonakuri, Purba Medinipur 721172, India
⁎ Corresponding author at: Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
⁎⁎ Corresponding author.
13 12 2022
13 12 2022
11055928 10 2022
21 11 2022
8 12 2022
© 2022 Elsevier Inc. All rights reserved.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
The COVID-19 pandemic has triggered intensive research and development of drugs and vaccines against SARS-CoV-2 during the last two years. The major success was especially observed with development of vaccines based on viral vectors, nucleic acids and whole viral particles have received emergent authorization leading to global mass vaccinations. Although the vaccine programs have made a big impact on COVID-19 spread and severity, emerging novel variants have raised serious concerns about vaccine efficacy. Due to the urgent demand, drug development had originally to rely on repurposing of antiviral drugs developed against other infectious diseases. For both, drugs, and vaccine development the focus has been mainly on SARS-CoV-2 surface proteins and host cell receptors involved in viral attachment and entry. In this review, we expand the spectrum of SARS-CoV-2 targets by investigating the COVID-19 signalome. In addition to the SARS-CoV-2 Spike protein, the envelope, membrane, and nucleoprotein targets have been subjected to research. Moreover, viral proteases have presented the possibility to develop different strategies for the inhibition of SARS-CoV-2 replication and spread. Several signaling pathways involving the renin-angiotensin system, angiotensin-converting enzymes, immune pathways, hypoxia, and calcium signaling have provided attractive alternative targets for more efficient drug development.
Keywords
SARS-CoV-2
COVID-19
Signalome
Antiviral drugs
Vaccines
Signaling pathways
==== Body
pmc1 Introduction
The pandemic of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) has resulted in more than 583 million infected patients and has caused more than 6.4 million deaths worldwide since its outbreak in late 2019 [1]. In the early phase of the COVID-19 pandemic neither drugs nor vaccines against SARS-VoV-2 were available. A race against time including the development of novel and repurposed antiviral drugs and vaccines commenced, resulting in some breakthrough, especially regarding COVID-19 vaccines [2]. However, there is still room for the development of more efficient drugs and vaccines against COVID-19 not the least because of the emerging novel SARS-CoV-2 variants, which have seriously compromised the potency of existing drugs and vaccines.
Signalosomes, a large supramolecular protein complex that can cluster or oligomerize, play an important role in SARS-CoV-2 infectivity and can also provide potentially interesting therapeutic targets for antiviral drugs against COVID-19. Due to the critical impact the COVID-19 signalosome has on both viral transmission and immune evasion, alternative therapeutic opportunities might be revealed. Although SARS-CoV-2 shares many characteristics with other coronaviruses, altered signaling pathways may contribute to the discovery of new COVID-19 therapeutics [3]. From this point of view, cellular interaction by angiotensin-converting enzyme 2 (ACE2) [[4], [5], [6], [7], [8], [9]] and cytokine storm [[10], [11], [12]] can be considered interesting. Furthermore, it has been demonstrated that SARS-CoV-2 trafficking can be facilitated by Golgi fragmentation via downregulation of Golgi-reassembly-stacking protein of 55 kDa (GRASP55) [13]. In addition, the Raf/MEK/ERK signaling pathway has been shown to have a significant impact on viral pathogenesis, suggesting that stimulation of the Raf/MEK/ERK pathway by SARS-CoV-2 can contribute to viral survival, and therefore inhibitors targeting the mentioned signaling axis could be promising antiviral drugs targets for COVID-19 [14].
The role of SARS-CoV-2 signaling in cell proliferation and death has caught the interest in establishing a network on virus-host protein-protein interactions by isolation of 26 SARS-CoV-2 proteins [15]. It was discovered that 332 human proteins were targeted by SARS-CoV-2, of which 69 FDA-approved drugs could be repurposed for COVID-19 treatment. Out of forty-six proteins being known to be associated with cancer or cancer candidates, 23 have been or are currently under clinical evaluation in cancer patients [16]. As cancer cells and pathogens employ similar molecular pathways for the control of apoptosis and evasion of host defense, infection with both RNA and DNA viruses has been associated with the activation of cellular oncogenes or decrease in tumor suppression leading to oncogenesis. This approach demonstrates that system-wide integration of protein–protein interactions that drive viral pathogenicity and cancer has the potential to identify important factors responsible for the dysregulation of cellular mechanisms and development of novel drugs [15]. In this review we present the importance of the COVID-19 signalosome pathways, which could open novel alternative approaches for therapeutic interventions against SARS-CoV-2.
2 Signaling and potential therapeutic implementations of SARS-CoV-2 key targets
In therapeutic and prophylactic attempts against SARS-CoV-2, especially related to vaccine development, the S protein has been a commonly used target. As the S protein binds to the ACE2 on host cells initiating viral cell entry, it represents an obvious target for both drug and vaccine development [17]. However, proteases and other SARS-CoV-2 structural proteins play important roles in signaling and have therefore received significant attention.
2.1 Proteases
Proteins associated with SARS-CoV-2 include proteases such as RNA-dependent RNA polymerase (RdRp), 3-Chymotrypsin-like Protease (3CLPro), Papain-like protease (PLpro) and Helicase (nsP13) Lpro [18], which have been considered as targets for antiviral drug development against SARS-CoV-2 (Table 1 ).Table 1 Proteases as targets for SARS-CoV-2 for the treatment of COVID-19.
Table 1Target/Drug Findings References
RdRp
RDV Blocking of viral infection in Vero cells [26]
Reduced lung inflammation and viral titers in monkeys [27]
FPV Shortened recovery time, reduced mortality rates for COVID-19 [28,29]
Approved for COVID-19 treatment in October 2020 [30]
RBV Shortened treatment, improved chest CT compared to LPV/RPV [31]
Significantly higher recovery rates in patients [34]
Sofosbuvir Clinical improvement in patients [35]
Improved viral clearance [36]
Galidesivir Approval in Russia, Bangladesh, Pakistan, Jordan, Egyp [36]
Anti-SARS-CoV-2 activity in Vero cells [37]
EIDD-2810 Shortened time from treatment start to negative PCR test [38]
(Molnupiravir) No improvement in negative conversion time or mortality [39]
Shortened recovery, lower mortality in patients [41,42]
No difference in hospitalization or number of deaths [43]
No clinical benefit, clinical trial discontinued [44]
Significantly reduced viral load in ferrets [45]
Inhibition of SARS-CoV-2 in mice [46]
Clinical trials on safety, tolerability and efficacy in progress [47,48]
Reduced hospitalization risk in two phase I trials [49]
Approved in the UK and by the FDA in the US [50]
3CLPro
Boceprevir Inhibition of SARS-CoV, MERS-CoV and SARS-COV-2 in cell [51]
Reduced SARS-CoV-2 RNA in Vero cells [51]
Ivermectin Reduced SARS-CoV-2 transmission in non-severe COVID-19 [52]
No difference in PCR positivity compared to placebo [53]
Paxlovid Meta-analysis showed no reduction in recovery time, mortality [54]
No clinical benefits compared to placebo in clinical trial [55]
89% reduced risk of hospitalization/death; FDA approval [56]
PLPro
Nathalene Inhibition of SARS-CoV-2 replication in Vero cells [57]
GRL-0617 Reduced viral infection in CaCo-2 cells [58]
Helicase LPro I
Quercetin IC50 of 8.1 μM against SARS-CoV helicase [59]
7-O-AMQ derivatives IC50 of 2.7–5.2 μM against SARS-CoV helicase [60]
Myricetin IC50 of 2.71 μM against SARS-CoV helicase [61]
3CLpro, 3-chymotrypsin-like protease; 7-O-AMQ der, 7-O-arylmethylquercetin derivatives; FPV, favipiravir; LPV, lopanivir; PLpro. Papain-like protease; RdRp, RNA dependent RNA polymerase; RDV, remdesivir; RPV, ritonavir.
2.1.1 RNA-dependent RNA polymerase (RdRp)
RdRp is a potential target as it is most conserved across several viral species including influenza virus, hepatitis virus C (HCV), Zika virus (ZIKV) and coronaviruses. In addition, RdRp plays an important role in viral RNA replication [19]. In the case of coronaviruses, RdRp catalyzes RNA genome synthesis by generation of a complementary minus strand RNA from the plus strand RNA template, which is initiated either by de novo (primer-independent) or primer-dependent RNA synthesis [20,21]. A number of RdRp inhibitors have been developed and previously evaluated as antivirals for other viruses. Due to the COVID-19 pandemic, they have now been repurposed for targeting SARS-CoV-2. In a molecular docking study, the RdRp of SARS-CoV-2 was modelled and targeted using different anti-polymerase drugs currently approved against other viruses [22]. The modelling suggested that remdesivir (RDV), ribavirin (RBV), sofosbuvir, galidesivir and tenofovir could be potent drugs against SARS-CoV-2 as they show high binding affinity to RdRp. Moreover, the guanosine derivative IDX-84, setrobuvir and YAK are potential candidates for SARS-CoV-2 therapy.
Previously, RDV has demonstrated therapeutic efficacy against Ebola virus (EBOV) in rhesus monkeys [23]. Moreover, RDV has shown favorable antiviral activity against different coronaviruses such as HCoV-229E, HCoV-OC43, SARS-CoV and MERS-CoV in vitro in human cell lines and primary cells [19]. Evaluation in a mouse model demonstrated that RDV reduced viral SARS-CoV loads and reduced pathological symptoms [24]. Similar results were obtained in MERS-CoV infected rhesus macaques [25]. In the case of SARS-CoV-2, RDV potently blocked virus infection in Vero E6 cells and based on RT-PCR and Western blotting analyses virus yields were significantly reduced [26].
Moreover, RDV reduced lung inflammation and virus titers in rhesus monkeys infected with SARS-CoV-2 [27]. In a placebo-controlled clinical study, the time to recovery of hospitalized COVID-19 patients was beneficial and the impact on mortality was positive [28]. In another study, COVID-19 patients receiving RDV had a median recovery time of 10 days compared to 15 days for the placebo group [29]. The mortality rate for patients treated with RDV was 6.7% compared to 11.9% for the placebo group by day 15, and 11.4% for RDV and 15.2% for placebo at day 29. The percentage of serious adverse events was also lower for RDV (24.6%) than placebo (31.6%). Moreover, patients treated with RDV had fewer respiratory tract infections. In October 2020 RDV was approved by the FDA for COVID-19 treatment in hospitalized adult and pediatric patients [30].
Favipiravir (FPV), a guanine analogue which selectively inhibits viral RdRp with a broad antiviral activity has been applied against influenza A, B and C viruses, EBOV, and Lassa virus (LASV) [31,32]. FPV has also shown synergistic effect in combination with the influenza virus neuraminidase (NA) inhibitor oseltamivir in mice [32]. FPV and interferon-α (IFN-α) treatment was compared to control treatment with lopinavir/ritonavir (LPV/RTV) in a phase I clinical trial [33]. The study showed that there were fewer adverse events for FPV treatment, the viral clearance time was shorter for patients treated with FPV (4 days) compared to the control group (11 days), and significant improvement in chest computed tomography (CT) was observed after FPV treatment (91.43%) compared to 62.2% in LPV/RPV treated patients. In another clinical trial in China, FPV showed significantly higher recovery rates and shortened latency to relief for pyrexia and cough compared to umifenovir [34]. Moreover, a retrospective observational study in Thailand showed clinical improvement in COVID-19 patients by day 7 [35] and a prospective, randomized, open-label trial comparing early and late FPV treatment in hospitalized COVID-19 patients in Japan suggested a trend toward better viral clearance on day 6 for the early treatment group (66.7%) compared to the late group (56.1%) [36]. Despite observation of clinical benefits for mild and moderate COVID-19 cases and need of large randomized controlled trials, FPV has been commercialized in countries such as Russia, Bangladesh, Pakistan, Jordan, Egypt, and Saudi Arabia [36].
Another guanosine analogue, ribavirin (RBV) has also been evaluated for COVID-19 treatment. Anti-SARS-CoV-2 activity of RBV was demonstrated in Vero E6 cells infected with SARS-CoV-2 [37]. Furthermore, in silico analysis indicated a broad-spectrum impact of RBV on Vero E6 cells. RBV also decreased transmembrane protease, serine 2 (TMPRSS2) expression at both mRNA and protein levels and can potentially provide antiviral activity against SARS-CoV-2. In an open-label randomized, phase II trial the triple combination of IFN-β-1b, LPV/RTV, and RBV was compared to LPV/RTV in hospitalized COVID-19 patients [38]. The combination therapy resulted in a significantly shorter time (7 days) from start of treatment to negative nasopharyngeal swab than for the control group (12 days). However, in another study, intravenous RBV administration was compared to supportive therapy in patients with severe COVID-19, which indicated that RBV therapy was neither associated with improved negative conversion time for SARS-CoV-2 nor an improved mortality rate [39].
Sofosbuvir, a potent RdRp inhibitor, has been subjected to several clinical trials in COVID-19 patients [40]. In a phase I trial, 35 COVID-19 patients received sofosbuvir and daclatasvir and 27 individuals were given RBV [41]. The encouraging results demonstrated a median duration hospitalization of only 5 days for the sofosbuvir/daclatasvir group compared to 9 days for the RBV group. The mortality was also much lower (6%) for sofosbuvir/daclatasvir treatment compared to 33% after treatment with RBV. In another clinical trial, sofosbuvir/daclatasvir treatment was compared to standard of care alone [42]. The clinical recovery in the sofosbuvir/daclatasvir arm was better (88%) compared to 67% in the control arm. The median duration of hospitalization was also significantly shorter in patients receiving sofosbuvir/daclatasvir (6 days) compared to the control patients (8 days). In a single center, randomized, controlled phase I trial, sofosbuvir/daclatasvir combined with RBV was compared to standard of care [43]. There was no difference in median duration (6 days) of hospital stay between the groups, the number of intensive care unit (ICU) admissions was not significantly lower for patients receiving sofosbuvir/daclatasvir, and there was no difference in the number of deaths between the two groups. Although there were trends suggesting better recovery and lower death rates in patients treated with sofosbuvir/daclatasvir, the randomized trial was too small to make definitive conclusions.
Galidesivir, an adenosine nucleoside analogue that blocks viral RNA polymerase, has also been presented as a target for anti-SARS-CoV-2 therapy [62]. Although some promising findings were obtained in preclinical studies early-stage clinical trial results showed no benefit of galidesivir compared to placebo and the study was discontinued [44]. Another COVID-19 drug, the ribonucleotide analogue EIDD-2801, showed a significant reduction in SARS-CoV-2 viral load in the upper respiratory tract and completely suppressed spread to untreated contact animals in a ferret model [45]. Moreover, EIDD-2801 inhibited SARS-CoV-2 in human epithelial cells in culture and several coronaviruses in mice [46]. The first-in-human phase I trial has been conducted in healthy volunteers to assess the safety, tolerability and pharmacokinetics of EIDD-2801 [47]. Molnupiravir (EIDD-2801) has also been subjected to a multi-center, randomized, double-blind, placebo-controlled phase II clinical trials for the evaluation and safety in hospitalized COVID-19 patients [48]. Moreover, a significant reduction in both hospitalization and death rates in patients with mild COVID-19 was seen in two phase I clinical trials [49]. Initially, molnupiravir was approved in the UK, but the efficacy of only 30% reduced risk of hospitalization delayed granting EUA by the FDA [50].
2.1.2 3-chymotrypsin-like protease (3CLPro)
The 3CLpro also called Mpro is the main protease pivotal for the replication of SARS-CoV-2 [63]. A number of inhibitors against 3CLPro were identified by computational molecular modelling of 3987 FDA approved drugs, of which 47 were selected for inhibition studies of SARS-CoV-2 specific 3CLPro in vitro. For instance, boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin and micafungin showed inhibition against 3CLPro. Boceprevir as well as calpain inhibitors inhibited SARS-CoV, MERS-CoV and SARS-CoV-2 in cell culture and further showed a synergistic effect with RDV [51].
Ivermectin, an FDA-approved parasitic broad spectrum anti-parasitic agent [64], has demonstrated anti-viral activity against a wide range of viruses [65]. Moreover, ivermectin has been shown to limit infections of RNA viruses, but has also been effective against DNA viruses [65]. In Vero cells infected with SARS-CoV-2 ivermectin caused a 93% reduction in viral RNA in the medium (released viral particles) and 99.8% reduction in cell-associated viral RNA at 24 h. At 48 h an approximately 5000-fold reduction in viral RNA was observed [52]. Ivermectin has also been subjected to a pilot, double-blind, placebo-controlled, randomized clinical trial for the evaluation of the efficacy of a single dose for the reduction of transmission of SARS-CoV-2 in patients with non-severe COVID-19 [53]. The viral load and infectivity were determined by detection of SARS-CoV-2 RNA by PCR from nasopharyngeal swabs 7 days post-treatment. The results indicated that there was no difference in the proportion of PCR positives in the ivermectin and placebo groups. Although a marked reduction of self-reported anosmia/hyposmia, a reduction of cough and a tendency of lower viral loads and lower SARS.CoV-2 IgG titers were reported, additional larger clinical trials are needed to demonstrate efficacy of ivermectin. Furthermore, a meta-analysis on ivermectin treatment of ambulatory and hospitalized COVID-19 patients on randomized controlled trials and retrospective cohorts was carried out [54]. Twelve studies including 5 retrospective cohort studies, 6 randomized clinical trials, and 1 case series, showed no reduction in mortality or reduced patient recovery time after ivermectin treatment. Moreover, all studies presented a high risk of bias and a very low certainty of evidence. For this reason, there is insufficient certainty and quality of evidence to support the recommendation of using ivermectin for COVID-19 prevention and treatment. The FDA stated that ivermectin has not been approved for prevention or treatment of COVID-19 www.fda.gov/animal-veterinary/product-safety-information/faq-covid-19-and-ivermectin-intended-animals). In a recent clinical trial in Brazil, patients with COVID-19 were treated with ivermectin and compared to placebo [55]. The study demonstrated no significant effects of ivermectin on secondary outcomes or adverse events. There was no reduction incidence of hospital admission due to progression of COVID-19 or prolonged emergency department observation among outpatients. In contrast, interim results from a phase II/III study on the 3CLpro inhibitor Paxlovid in 1219 adults showed that the risk of COVID-19 related hospitalization and death from any cause was 89% lower than for those individuals who received placebo [56]. The FDA granted EUA for Paxlovid in December 2021.
2.1.3 Papain-like protease (PLpro)
In search of drug targets, the PLpro domain as part of the non-structural protein 3 (nsp3) of SARS-CoV-2 has been considered for evaluation of PLpro inhibitors due to their vital involvement in viral replication [66]. In this context, data mining of the conformational database of the FDA-approved drugs identified 147 potential SARS-CoV-2 inhibitors [67]. For instance, PLpro inhibitors such as ubiquitin (Ub), interferon-stimulated gene product 15 (ISG15) and naphthalene were evaluated for SARS-CoV-2 inhibition [57]. However, Ub showed a less marked reduction compared to SARS-CoV, and ISG15 was more prominent against MERS-CoV inhibition. In contrast, naphthalene demonstrated both inhibition of SARS-CoV-2 PLpro activity and SARS-CoV-2 replication in Vero E6 cells [57]. In another approach, the PLpro inhibitor GRL-0617 showed impaired cytopathogenic effect, maintained the antiviral interferon pathway, and reduced viral replication in infected CaCo-2 cells [58].
2.1.4 Helicase (nsP13) Lpro
In the case of SARS-CoV-2, the helicase encoded by nsP13 is critical for viral replication and therefore poses a potential alternative target for anti-COVID-19 therapy [68]. Application of homology modelling and molecular dynamics made it possible to generate structural models of the SARS-CoV-2 helicase and perform a virtual screening of 970.000 chemical compounds. Lumacaftor and cepharanthine displayed significant inhibition of purified recombinant SARS-CoV-2 helicase with IC50 values of 0.3 and 0.4 nm, respectively. Lumacaftor can act as a chaperone for protein folding and cepharanthine has already previously been described as an inhibitor of SARS-CoV [69]. Bananins have proven efficient inhibitors of the ATPase activity of the SARS-CoV helicase in the IC50 range of 0.5–3 μM and due to the high homology between SARS-CoV and SARS-CoV-2 helicases (99.8%) [69], they could also be potential targets for COVID-19 therapeutics [70].
Interestingly, flavonoid phytomedicines such as caflanone, equivir, hesperitin, myricetin, and linebacker have been considered as potential prophylactics or therapeutics against SARS-CoV-2 [71]. Especially equivir has demonstrated inhibition of helicase activity contributing to the prevention or reduction of viral entry. Although in silico modelling and in vitro testing have proven promising, the poor bioavailability of flavonoids has hampered in vivo applications [72]. For this reason, flavonoids have been encapsulated in nanoparticles (nanodrones) or conjugated as targeting moieties on nanodrones [73]. Previously, quercetin [59], 7-O-arylmethylquercetin derivatives [60], and myricetin [61] have demonstrated IC50 affinities in the range of 2.7–8.1 μM against SARS-CoV helicase making them potential agents against SARS-CoV-2 due to the high homology of SARS-CoV and SARS-CoV-2 helicases.
2.2 Structural proteins
The SARS-CoV-2 structural proteins have been common therapeutic targets, especially for vaccine development (Table 2 ). The most commonly studied target is the S protein (S) [17]. However, other structural proteins such as the envelope (E), nucleocapsid (N), and membrane (M) proteins can also be attractive for development of prophylactics and therapeutics.Table 2 Structural proteins as targets for SARS-CoV-2 for the treatment of COVID-19.
Table 2Target/Drug Findings Ref
Spike
Drugs & mAbs High binding affinity against SARS-CoV-2 S [78]
Hesperidin Binding affinity for both SARS-CoV/SARS-CoV-2 S [80]
CR3022 mAb Neutralization of SARS-CoV/SARS-CoV-2 in Vero cells [81]
47D11 mAb Targeting of highly conservative S epitope [82]
S309 Improved half-life of S309, phase II/III trial in progress [83]
VIR-7831 (Sotrovimab) High binding affinity to SARS-CoV-2 S RBD [84]
LY-CoV555 (Bamlavinimab) Good safety and tolerability in phase I [85]
Lower severity of COVID-19 compared to placebo in phase II [86]
LY-CoV016 (Etesimivab) No significant improvement, phase III discontinued [89]
LY-CoV555 + LY-CoV106 EUA by the FDA for mild-to-moderate COVID-19 [90]
REGN10987 + REGN10933 Targeting of SARS-CoV-2 S epitopes [91]
Decreased lung titers in hamsters, reduced viral load in macaques [92]
Vaccines Good safety profile, reduced viral load in phase II/III [93]
NVX-CoV2373(Rec—S) Prevention of SARS-CoV-2 and COVID-19 in phase III [94]
FDA authorization for use in adult and pediatric COVID-19 patients [95]
Ad5-S nb2 Protection against SARS-CoV-2 in macaques [98]
ChAdOx1 nCoV-19 >90% vaccine efficacy in Phase III [99]
Conditional marketing authorization granted in the EU and the UK [100]
rAd26/rAd5-S Protection against SARS-CoV-2 in macaques [101]
>90% vaccine efficacy in clinical trials [102]
Ad26.COV2·S Emergency use authorization in China [103]
Protection against SARS-CoV-2 in macaques [104]
DNA-S 62.1–90% vaccine efficacy in clinical trials [105]
DNA INO-4800 Emergency use authorization in the UK [106]
DNA INO-4800 Good safety, robust immunogenicity in animal models [107]
LNP-mRNA-1273 Good safety and tolerability in Phase I/II [108]
91.6% vaccine efficacy in Phase III [109]
RNA BNT162b1/b2 Emergency use authorization in Russia in July 2020 [110]
RNA BNT162b1/b2 Protection against SARS-CoV-2 in macaques [111]
RNA BNT162b2 Strong immunogenicity of clinical trials [112]
Emergency use authorization by the FDA [113]
Protection against SARS-CoV-2 in macaques [114]
Safety and tolerability, robust immunogenicity in phase I/II [115]
Durable immune responses in phase I [116]
Protection against SARS-CoV-2 in mice [117]
Protection against SARS-CoV-2 in primates [118]
Phase I: SARS-CoV-2 specific robust immune responses [119,120]
Phase III: 94.1% vaccine efficacy [121]
Vaccine approval in the USA, UK, and Europe [122]
Protection against SARS-CoV-2 in macaques [123]
Phase I/II: Good safety and immunogenicity [124,125]
Phase III: 95% vaccine efficacy [126]
Vaccine approval in the USA, UK and Europe [127]
Envelope
Amantadine Potential target for SARS-CoV-2 inhibition [128]
Gliclazide Potential targets for COVID-19 therapy [129]
Memantine Potential targets for COVID-19 therapy [129]
Nucleocapsid
N epitopes Screening of B and T cell epitopes for vaccines [130]
PJ34 Inhibition of HCoV OC43 replication [131]
P3 Antiviral activity against MERS-CoV [132]
Membrane
M epitopes Targets for vaccines and T cell therapy [133]
Ad, adenovirus; Ch-VSV, chimeric vesicular stomatitis virus with SARS-CoV-2 spike protein; LNP, lipid nanoparticle; mAb, monoclonal antibody; MVA, modified vaccinia virus Ankara; NDV, Newcastle disease virus; P3, 5-benzyloxygramine inhibitor; PJ34, N protein inhibitor.
2.2.1 Spike protein (S)
The S protein plays a prominent role in SARS-CoV-2 infection by binding to the angiotensin converting enzyme 2 (ACE2) promoting viral entry into host cells [74]. The S protein contains the receptor binding domain (RBD), which is essential for binding to ACE2 [75]. For this reason, SARS-CoV-2 S has frequently been targeted for the development of antiviral drugs, monoclonal antibodies, and vaccines [76].
In the context of antiviral drug development, a number of small molecule compounds have demonstrated high binding affinity against the S protein [77]. Although this is the case for many anti-hypertensive, antifungal, antibacterial, anti-coagulant drugs and natural flavonoids, they are not predicted to cover the binding interface of the S-ACE2 complex. In contrast, hesperidin is predicted to occupy the middle shallow pit of the surface of the RBD of the S protein. Superimposing the ACE2-RBD complex to the hesperidin-RBD complex indicated that hesperidin may disrupt the interaction of ACE2 and RBD and interfere with viral entry. Due to this anti-viral activity, hesperidin, a classical herbal medicine used as an antioxidant and anti-inflammatory agent, might constitute a treatment option for COVID-19 through improving the host immune response against infection [78]. As hesperidin is present in citrus fruits such as oranges the role of nutrition should not be underestimated as a means of prevention of COVID-19 [79].
One therapeutic approach comprises of developing monoclonal antibodies (mAbs) against SARS-CoV-2. In this context, the potential of mAbs for therapeutic interventions has been addressed. The cross-reactivity of the mAb CR3022 against SARS-CoV was analyzed related to its cross-reactivity to SARS-CoV-2 [80]. Although the epitope of CR3022 did not overlap with the SARS-CoV-2 RBD, potent binding of KD 6.3 nM was obtained, indicating that CR3022 could be developed alone or in combination with other neutralizing antibodies for the prevention and treatment of COVID-19. In contrast, some of the most potent SARS-CoV-specific neutralizing antibodies targeting the ACE2 binding site of SARS-CoV did not show binding affinity to the SARS-CoV-2 S. It is therefore necessary to developed novel mAbs, which specifically bind to the SARS-CoV-2 S RBD. For this reason, a human mAb was identified from a collection of 51 SARS-CoV-2 S hybridomas from immunized transgenic H2L2 mice [81]. The human mAb 47D11 exhibited neutralizing antibodies against both SARS-CoV and SARS-CoV-2 S proteins. The 47D11 mAb demonstrated potent inhibition of Vero E6 cell growth infected with SARS-CoV-2 S and SARS-CoV S pseudotyped vesicular stomatitis virus (VSV). Moreover, neutralization by 47D11 was also achieved in Vero E6 cells infected with SARS-CoV-2 and SARS-CoV. It was also shown that 47D11 targeted the RBD of SARS-CoV-2 and SARS-CoV. Furthermore, the S309 mAb, isolated for a convalescent SARS patient in 2003, targeted a highly conservative S protein epitope and therefore also neutralized SARS-CoV-2 [82]. To extend the half-life of S309, the VIR-7831 mAb (sotrovimab) was engineered and is evaluated in a phase II/III trial [83]. Moreover, LY-CoV555 (bamlanimiab), a fully humanized neutralizing IgG1 mAb, targets the SARS-CoV-2 S RBD, showing the highest binding affinity among 500 evaluated antibodies [84]. The safety, tolerability and pharmacokinetics of intravenous LY-CoV555 has been under evaluation in hospitalized COVID-19 patients in a phase I trial [85]. Interim results from a phase II trial showed a slightly lower severity of symptoms in COVID-19 patients treated with LY-CoV555 compared to placebo and appeared to accelerate the natural decline in viral load [86]. Moreover, another mAb, LY-CoV016 (etesemivab), targeting another S protein epitope has been engineered [87]. In a phase II/III study, LY-CoV555 was applied to 577 non-hospitalized COVID-19 patients as monotherapy or in combination with LY-CoV016 [88]. No difference in viral load could be detected after treatment with LY-CoV555 or placebo. However, the combination of LY-CoV555 and LY-CoV016 showed a statistically significant reduction in viral load. Additionally, although LY-CoV555 showed comparable safety to RDV, a phase III trial was discontinued because no improvements were detected in hospitalized COVID-19 patients [89]. However, positive findings from studies on LY-CoV555 led to the emergency use authorization (EUA) by the FDA for treatment of mild-to-moderate COVID-19 in adult and pediatric patients [90]. The mAbs REGN10987 (imdevimab) and REGN10933 (casirivimab) have been engineered to target different epitopes of the SARS-CoV-2 S RBD [91]. Preclinical studies with the REGN-COV2 mAb cocktail (REGN10987 + REGN10933) showed greatly decreased lung titers in golden hamsters and reduced viral loads in rhesus macaques [92]. Interim results for a phase II/III trial generated a good safety profile and reduced viral load in COVID-19 patients [93]. In a phase III study, it was demonstrated that the REGN-COV2 mAb cocktail prevented symptomatic COVID-19 and asymptomatic SARS-CoV-2 infections in households where previously uninfected individuals came into contact with SARS-CoV-2 infected persons [94]. In October 2021, REGN-COV2 was authorized for the treatment of mild-to-moderate COVID-19 in adult and pediatric (age 12 and older) patients, who are at high risk for progression of severe COVID-19 [95].
The majority of prophylactic and therapeutics initiatives related to the S protein involves vaccine development although inactivated viral particles have also been used. The large number of preclinical and clinical studies have been reviewed in detail elsewhere [96,97], and therefore, only a summary is presented here and in Table 2. Both the full-length S protein and specific regions such as the RBD have been applied as antigens for induction of immune responses. Vaccine candidates have been generated by recombinant protein expression, delivery of viral vectors, virus-like particles, or nucleic acids. All above mentioned approaches have elicited robust immune responses in immunized animals and in many cases provided protection against SARS-CoV-2 challenges in rodents and primates (Table 2). Several vaccine candidates have also received EUA.
In this context, the vaccine candidate NVX-CoV2373, a nanoparticle-encapsulated full-length SARS-CoV-2 S protein expressed in insect cells, protected the upper and lower airways of immunized cynomolgus macaques from SARS-CoV-2 challenges [98]. The NVX-CoV2373 vaccine candidate was evaluated in a phase III study, where over 90% efficacy was observed with most breakthrough cases caused by contemporary variant strains [99]. Both the EU and Great Britain have granted Conditional Marketing Authorization (CMA) for NVX-CoV2373 [100].
Adenovirus vectors have been frequently used for COVID-19 vaccine development. For example, the human adenovirus serotype 5 (Ad5) (Ad5-S nb2) [101] and the chimpanzee adenovirus ChAdOx1 [104] expressing the full-length SARS-CoV-2 S protein provided protection against challenges with SARS-CoV-2 in macaques after two immunizations. In an approach to reduce any immune response against the adenovirus vector itself leading to compromised vaccine efficacy, a prime-boost strategy of prime vaccination with Ad26-SARS-CoV-2 S followed by Ad5-SARS-CoV-2 vaccination showed efficacy in preclinical animal models [107]. Moreover, the Ad26.COV2·S vaccine based on the Ad26 serotype is unique in that sense that only a single immunization is required for induction of neutralizing antibodies and protection in macaques [111]. In the context of clinical trials, the Ad5-S nb2 vaccine demonstrated over 90% efficacy [102] and has received EUA in China [103]. Several clinical trials for ChAdOx1 nCoV-19 demonstrated safe delivery and high vaccine efficacy [105] and EUA was granted in the United Kingdom in December 2020 [106]. Moreover, the Ad26.COV2·S vaccine candidate has also shown strong immunogenicity in clinical trials [112] and has received EUA from the FDA in February 2021 [113]. The rAd26-S/rAd5-S (Sputnik) showed also good tolerability and 91.6% efficacy in phase I/II [108] and phase III [109] trials. Controversially, the Sputnik vaccine was granted EUA in Russia before any results from preclinical studies had been published and the vaccine had been tested in only 76 volunteers [110]. Other viral vectors such as lentiviruses, vaccinia viruses, Newcastle disease virus (NDV), measles viruses, VSV, Venezuelan equine encephalitis virus (VEE), and influenza virus have also been applied for COVID-19 vaccines as previously reviewed [134].
In the case of nucleic acid-based vaccines, plasmid DNA expressing the full-length SARS-CoV-2 S gene demonstrated protection against SARS-CoV-2 challenges in immunized macaques [114]. In the case of clinical trials, intradermal administration combined with electroporation of plasmid DNA carrying the full-length S protein (INO-4800) showed excellent safety and tolerability and either humoral or cellular immune responses in a phase I [115]. Furthermore, durable antibody responses were detected in another phase I study on INO-4800 [116].
In the case of mRNA-based vaccines, lipid nanoparticle (LNP)-encapsulated mRNA vaccine candidates have proven efficient in eliciting immune responses and providing protection in mice [117] and primates [118] based on expression of the prefusion-stabilized full-length SARS-CoV-2 S. Additionally, the LNP-mRNA vaccine candidates BNT162b1 and BNT162b2, containing the SARS-CoV-2 S RBD and full-length SARS-CoV-2 S protein sequences, respectively, provided protection in immunized macaques [123]. In the context of clinical evaluations, the LNP-encapsulated mRNA-1273 induced SARS-CoV-2-specific immune responses in all participants in a phase I trial [119]. Moreover, another phase I study demonstrated higher neutralizing antibody titers with a dose of 100 μg RNA compared to 25 μg [120]. In a phase III, the mRNA-1273 vaccine candidate showed, aside from transient local and systemic reactions, no serious adverse events and provided 94.1% efficacy preventing serious COVID-19 manifestation [121]. The mRNA-1273 vaccine received EUA in the USA in December 2020 and later in a number of countries [122]. The other advanced mRNA-based vaccine has demonstrated good safety and immune responses in phase I/II clinical trials for both the LNP-mRNA S RBD (BNT162b1) [124] and LNP-mRNA full-length S [BNT162b2) [125]. Furthermore, a two-dose administration of BNT162b provided 95% protection against COVID-19 in adults in a phase III study [126]. The BNT162b vaccine was the first COVID-19 vaccine to be approved in several countries [127].
2.2.2 Envelope (E)
The coronavirus envelope (E) protein is assembled into cation-selective ion channels, which are involved in virus budding and release and host inflammation responses [135]. Heaxamethylene amiloride (HMA) [136] and amantadine [137] block the channel activity of the E protein and present potential antiviral and vaccine targets. In the case of amantadine, antiviral therapeutic effects have been demonstrated against influenza virus [137] and lack of E protein has been shown to attenuate in vivo damage in SARS-CoV infected mice [128]. Furthermore, screening of SARS-CoV-2 E channel inhibitors identified Gliclazide and Memantine as potential targets for COVID-19 antiviral drugs [129].
2.2.3 Nucleocapsid (N)
Related to the SARS-CoV-2 nucleocapsid (N) protein, it was demonstrated that a number of epitopes could be identified as potential vaccine targets by screening of SARS-CoV-derived B and T cell epitopes [130]. It was found that the identified set of SARS-CoV epitopes mapped identically to SARS-CoV-2 and thereby present potentially interesting targets for vaccine development against COVID-19. In another approach, it was demonstrated that in addition to ORF6 and ORF8, the SARS-CoV-2 N protein strongly inhibited the type 1 interferon signaling pathway, which could reveal novel targets for drug and vaccine development [138]. Furthermore, structure determination of the N protein has provided insight into novel drug targets against SARS-CoV-2 [139]. Blocking of the RNA binding activity of the N protein affects viral RNP formation and genome replication. For instance, the compound PJ34 has previously been shown to target the ribonucleotide binding site at the N-terminal domain of the N protein (N-NTD) of the HCoV-OC43, leading to inhibition of viral replication [131]. Comparison of the corresponding binding site for PJ34 in the SARS-CoV-2 N-NTD structure indicated that the key residues were conserved [139]. Alternatively, the normal N protein oligomerization can be blocked, leading to termination of RNP formation or abnormal aggregation. In this context, the 5-benzyloxygramine (P3) inhibitor was shown to mediate MERS-CoV N-NTD non-native dimerization and induction of N protein aggregation, resulting in potent antiviral activity against MERS-CoV [132]. It was discovered that almost all residues in the binding cavity of P3 in the SARS-CoV-2 N-NTD were conserved in comparison to MERS-CoV, making this approach attractive for drug development against COVID-19.
2.2.4 Membrane protein (M)
The SARS-CoV-2 membrane (M) protein is composed of three transmembrane domains forming the structural blocks of viral particles that support viral assembly [140]. The M protein functions together with the E, N and S proteins in the process of RNA packaging [141]. Moreover, the M protein plays a role in intracellular homeostasis and elicits neutralizing antibodies. In this context, SARS-CoV-2 specific T cells expanded from convalescent COVID-19 donors recognized immunodominant viral epitopes in conserved regions of the SARS-CoV-2 S, N and M proteins [133]. This allowed the identification of several highly conserved epitopes of the M protein, which could be attractive targets for vaccine and T-cell therapy. This approach should support the prevention of early treatment of SARS-CoV-2 infections in immunocompromised patients.
3 SARS-CoV-2 infected host signaling pathways targets and potential therapeutic implementations
Surface proteins of invading microbes, proteins expressed on their surface are the first ones to be recognized by the immune system. Moreover, systemic and specific immune actions are activated against pathogens. For some diseases, however, microbes can evade the immune system leading to pathological conditions. Thus, strengthening the immune response through synthetic drugs might help to restore the body's defense system and fight against the infection. Therapeutic targets have been searched for to combat SARS-CoV-2 infections. As mentioned previously,the SARS-CoV-2 proteases and structural proteins have been evaluated as potential targets for drug and vaccine development. However, it is essential to increase the scope to other proteins, which are involved in the regulation of SARS-CoV-2 infection. These targets and drug development efforts are described below and summarized in Table 3 .Table 3 Therapeutic targets from signaling pathways.
Table 3Target/Drug Findings Ref
RAS
ACE2
APN01 Decrease in IL-6 plasma levels [152]
TMPRSS2
Camostat mesylate TMPRSS2 inhibition [153]
Reduced viral infectivity in COVID-19 patients [153]
Bromhexine hydrochloride Prevention of viral entry [153]
ER & Golgi
Cathepsin L
Ddec-RVKR-CMK Inhibition of MERS-CoV entry [154]
EST Inhibition of SARS-CoV entry [155]
MDL-28170 Inhibition of SARS-CoV entry [156]
Oxocarbazate Inhibition of SARS-CoV entry [157]
SSAA09E1 Inhibition of SARS-CoV entry [158]
Immune pathways
Tociluzimab Attenuated inflammation, inhibition of IL-6 signaling [159]
Sarilumab Attenuated inflammation, inhibition of IL-6 signaling [159]
Fedratinib, ruxolinitinib JAK/STAT inhibitors, attenuated cytokine storm [159]
Fingolimod, Infliximab, adalimumab S1Pr1 agonist, diminished cytokine storm [160], [160]
Serine protease inhibitors Blocking of TNF-α, decreased inflammatory process Decreased expression of TNF-α and IL-6 [160]
Anakinra Inhibition of cytokines [159]
Decreased mortality, reduced hospitalization in phase III [161]
Quercetin Suppression of inflammasomes [159]
Flufenamic acid Selective inhibition of NLPR3 inflammasome [161]
Hypoxia
Heparin No improved survival in critically ill COVID-19 patients [162]
Improved survival in noncritically ill COVID-19 patients [163]
Melatonin Reduced hypoxia, ferroptosis, hemoglobin denaturation [164]
Calcium pathways
Bepridil Reduced infection by prevention of host cell entry [172]
Amlodipine Reduced infection by prevention of host cell entry [172]
Nifedipine Reduced infection by prevention of host cell entry [172]
Vitamin D Downregulated TLR2/TLR4, reduced inflammation [172]
Other pathways
Apilimod Clinical evaluation in progress [166]
Tetrandine (TPC2 inhibitor) Potential inhibition of virus entry and replication [167]
Clinical evaluation in progress [168]
Ddec-RVKR-CMK (ecanoyl-Arg-Val-Lys-Arg-chloromethylketone); ER, endoplasmic reticulum; EST [(23,25)trans-epoxysuccinyl-l-leucylamindo-3-methylbutane ethyl ester]; MDL-28170 (calpain inhibitor III, or Z-Val-Phe-CHO); RAS, renin-angiotensin system; SSAA09E1 {[(Z)-1-thiophen-2-ylethylideneamino] thiourea}; TLR, toll-like receptor; TPC, two-pore channel.
3.1 Renin-angiotensin system (RAS)
The RAS pathway is one of the essential biochemical pathways of various neurovascular disorders. It has become apparent that the mechanism of RAS facilitates other functions besides blood pressure (BP) regulation. The RAS plays a vital role in pathophysiological impairment, including stroke and retinopathy in various neurovascular disorders. Angiotensin II (Ang II) is a polypeptide hormone cleaved by the Angiotensin converting enzyme (ACE). Angiotensin I (Ang I) itself is generated by angiotensinogen cleavage of the renin enzyme. Even though the renin precursor, prorenin, previously presumed to be inactive, its cleavage was also shown to be catalyzed when coupled to its receptor, (pro)renin receptor [142]. Ang II induces two distinct brain receptors, type 1 Ang II (AT1R) receptor and type 2 receptor (AT2R). AT1R is prevalent in adults showing its inflammatory and vasoconstrictor impact. Additionally, AT1R is divided into two subtypes AT1a and AT1b in rodents. AT2R is highly expressed during growth and in lower quantities in adulthood and may cause adverse effects, promoting vasodilation and reduced infection.
The Kallikrein Kinin System may present another potential association between RAS and vascular injury. It is well understood that bradykinin breaks down into desArg9-bradykinin, involved in endothelial dysfunction by activating the B1 receptor [143]. RAS is positioned at the center of COVID-19 pathogenesis with the discovery of ACE2 as the host cell receptor for SARS-CoV-2. In addition, since protease is involved in the angiotensin peptide metabolism affecting the regulation of the immune system, future RAS constituents might play a role in the pathogenesis of COVID-19. RAS is a regulatory proteolytic cascade with diverse physiological roles in various organs, like the heart, kidneys, and lungs [144]. RAS dysregulation is a well-established process for the development of many comorbidities, like hypertension and diabetes, known to increase the susceptibility to COVID-19 [145]. The first-line therapy strategy for both reduced cytokine generation and prevention of organ damage is the development of AT1R blockers (ARBs) and ACE inhibitors (ACEi). These promising effects have also been identified for recombinant ACE2 and Ang (1–7). Thus, there is a clinical potential to use ARB and ACEi combined with viral-targeted treatment to improve patient responses to SARS-CoV-2 infections [146]. However, it has been reported that there is an association between patients with severe COVID-19 and chronic use of ARB and ACEi. The upregulation of the expression of ACE2 caused by ARB and ACEi treatment may be one potential mechanism, as previously discussed, although expression of ACE2 in the lungs has not yet been studied in this scenario. This tentative theory led to a discussion of whether treatment with ARB and ACEi should be discontinued to reduce the susceptibility to COVID-19. However, there was immediate consensus that the ARB and ACEi treatment should be retained as there is insufficient evidence to support the removal of existing hypertension and diabetes treatment strategies [147]. The aim is to preserve controlled comorbidities and to prevent secondary incidents in COVID-19 patients. In a retrospective analysis, it was [148] confirmed that the mortality rate associated with COVID-19 in patients treated with ARB/ACEi was considerably lower than in untreated individuals [148]. Drugs such as the ACEi lisinopril, and the ARB losartan demonstrated increased expression of ACE2 mRNA in cardiac mice by lisinopril and losartan alone [149]. In combination, lisinopril and losartan increased the ACE2 activity, not the expression of ACE2 mRNA.
3.1.1 ACE2
The comparison of SARS-CoV and SARS-CoV-2 is essential, as ACE2 is also the functional receptor for SARS-CoV. It was determined that ACE2 is expressed in 0.64% of all human lung cells and 83% of ACE2 expressing cells are type II alveolar (AT2) epithelial cells, indicating that these cells may act as a viral reservoir [150]. Furthermore, gene expression analysis demonstrated that multiple viral lifecycle-related genes were significantly overrepresented in ACE2-expressing AT2 cells, suggesting efficient SARS-CoV-2 replication capacity in the lungs. Therefore, several potential therapeutic approaches have been investigated to target ACE2. Structural biology approaches have identified interacting regions in the SARS-CoV/SARS-CoV-2 and ACE2 allowing engineering of antibodies and small molecules, which may block the SARS-CoV/SARS-CoV-2 viruses from attaching to the ACE2 receptor. Moreover, overexpression of ACE2 in soluble form may competitively bind to and neutralize SARS-CoV-2 and rescue ACE2 cell activity, which negatively regulates the RAS for protection of lung damage [151]. Noticeably, recombinant human ACE2 (rhACE2; APN01, GSK2586881) was shown to be stable without adverse hemodynamical consequences in healthy participants and a small cohort of ARDS patients. APN01 administration quickly reduced the proteolytic target of angiotensin II peptides, resulting in decrease of plasma IL-6 levels [152].
3.1.2 TMPRSS2
The transmembrane serine 2 (TMPRSS2), also known as Epitheliasin, activates S2 protein proteolytic binding of SARS-CoV-2 to the ACE2 receptor for entry into host cells. In vitro experiments have shown that inhibition of TMPRSS2 does not entirely obstruct the entrance of viruses into host cells. Camostat mesylate is currently in clinical evaluation. It was demonstrated that camostat mesylate efficiently inhibited TMPRSS2, resulting in reduced viral infectivity in COVID-19 patients [153].
3.1.3 Furin
Although TMPRSS2 is the main enzyme that contributes to the entry of SARS-CoV-2 into host cells, this function is also present in several other serine proteases. Serine proteases, trypsin, elastase, and furin cleave the S protein in the SARS-CoV and MERS-CoV viral envelopes. Furin is a member of the network of trans-Golgi and is highly expressed in endothelial and pneumocyte cells. It was recently demonstrated with the ability to cleave SARS-CoV-2, as well [169]. Thus, viral cell entry relies on particular ACE2 binding and TMPRSS2 cleavage, but other serine proteases, such as plasmin, can replace the main proteases. Autopsies of COVID-19 patients have provided abundant fibrin deposition associated with increased action of plasmin activity. Plasmin can stimulate human macrophages to promote the development of pro-inflammatory cytokines such as IL-6, IL-8, IL-10, and TNF, in addition to its cleavage activity on viruses. An elevated IL-6 plasma level is a biomarker for “cytokine release syndrome” in COVID-19 patients with terrible outcomes [154]. The use of TMPRSS2 inhibitors, including Camostat mesylate and Bromhexine hydrochloride, has been recommended as potential therapeutics. They prevent viral penetration mediated by TMPRSS2 and operate as an inhibitor of TMPRSS2, respectively [153].
3.2 Endoplasmic reticulum and Golgi trafficking
Enveloped animal viruses have often been used to analyze protein transport and secretion, given that viral membrane proteins hijack the host cell protein transportation machinery, pursuing the same intracellular routes as endogenous host cell proteins. Therefore, membrane glycoproteins of most enveloped viruses migrate via the constitutive secretory route through the endoplasmic reticulum (ER) and Golgi apparatus onto the plasma membrane, where the assembly and budding of progeny virus occurs [170].
3.2.1 Cathepsin L (CatL)
Cathepsins represent a class of proteases that recycle cellular proteins inside the lysosomes. These proteases consist of serine, aspartate, and cysteine peptidases and are involved in endo- or exopeptidase activity. During translocation from the ER to the Golgi apparatus and the lysosomal and endosomal compartments, cathepsins are synthesized as inactive proenzymes or zymogens. Cathepsins require a reduced pH (between 4.5 and 5.0) for optimal activity, as found in the lysosome [171]. In different physiological processes, cathepsins play a significant role in cellular functions such as apoptosis, antigen treatment, remodeled extracellular matrix, and immune reactions of major histocompatibility complex (MHC) class II. Cysteine cathepsin is excessively secreted and is often associated with inflammation of different pathological conditions. In inflammatory cells, high levels of CatL can thus be activated under inflammatory conditions [172]. Viral S2 comprises the putative fusion peptide; the heptad repeats HR1 and HR2 and participates in the viral membrane fusion. The S1 subunits connect to the ACE2, and the S2 fuses during the entry of the virus, which allows viral genomes to reach the host cells. A cleavage by a host protease is required as a type I fusion protein to activate the fusion potential of the S protein. Host proteases such as proprotein convertases (furin), extracellular proteases (elastase), cell surface proteases (TMPRSS2) and lysosomal proteases (CatL and CatB) can be cleaved through several phases of the infection cycle. It has lately been reported that the endosomal cathepsin L protease enzyme being utilized during cell entry rather than cell exit through the endosomal route. Several efforts to create CatL inhibitors have been advocated due to the biological importance of CatL. The first CatL cystatin inhibitor was isolated from Aspergillus in 1981, and additional molecules have been extracted since then. Inhibitors include epoxy succinic acid, beta-lactams, vinyl sulfone, and acyl hydrazine by-products [173]. The most reversible are aliphatic, cycloketone, aldehyde, and nitrile derivatives. In another approach, 10 FDA approved drugs with CatL inhibitory activity have been suggested as safer and more efficient for prevention of SARS-CoV-2 cell entry and replication [173]. Among these are clofazimine, rifampicin, saquinavir, astaxanthin, dexamethasone, clenbuterol and heparin. Moreover, Ddec-RVKR-CMK (ecanoyl-Arg-Val-Lys-Arg-chloromethylketone) has previously shown inhibition of MERS-CoV entry [154], while EST [(23,25)trans-epoxysuccinyl-l-leucylamindo-3-methylbutane ethyl ester] [155], MDL-28170 (calpain inhibitor III, or Z-Val-Phe-CHO) [156], oxocarbazate [157] and SSAA09E1 {[(Z)-1-thiophen-2-ylethylideneamino] thiourea} [158] can block SARS-CoV entry.
3.3 Immune pathways
By inhibiting the expression of STAT1-activated genes, SARS-CoV2 suppresses the signaling pathways regulated by IFN, a crucial cytokine, released by virus-infected cells to recruit adjacent cells to boost anti-viral immune responses [174]. In the light of this, genes from a subset of IFN activated genes (IFIT1, IFITM1, IRF7, ISG15, MX1, and OAS2) have been identified as possible therapeutic targets for COVID-19 therapy [175]. On the other hand, the strategy of combating excessive inflammatory responses often present in COVID-19 patients is to target a critical regulator of cellular inflammation whilst keeping antiviral pathways unaffected [159]. Several drugs have been repurposed to act to the immune response and manage the cytokine storm induced by the viral infection. Some of these include tocilizumab and sarilumab (IL-6 receptor antagonists), which attenuate the inflammatory process by inhibiting IL-6 signaling. The JAK/STAT inhibitors fedratinib and ruxolinitinib attenuate cytokine storm, the S1Pr1 agonist fingolimod, diminishes cytokine storm, and infliximab and adalimumab block TNFα and decrease inflammatory processes [160]. Moreover, serine protease inhibitors inhibit NF-kb and decrease TNFα and IL-6 expression [160]. Anakinra is also used for inhibition of cytokines downstream of inflammasomes, including IL-1β, and has been subjected to phase III clinical trials for COVID-19 (www.clinicaltrials.gov, NCT04330638 and NCT04324021), [159]. Interim results from a phase III trial demonstrated a decrease in 28-day mortality and reduction in hospitalization [161]. Quercetin, an antioxidative flavonoid naturally present in plants, suppresses inflammasomes, including NLR family pyrin domain containing 3 (NLRP3), by decreasing ASC micrometer-sized structure production and oligomerization. Non-steroidal anti-inflammatory drugs (NSAIDs), particularly those of the fenemate class (e.g., flufenamic acid), selectively inhibit NLRP3 by reversibly targeting volume-regulated anion channels that control Cl2 transport across the plasma membrane [159,161].
3.4 Hypoxia
COVID-19 hypoxia has a complicated etiology that encompasses thrombosis, pulmonary infiltration, viral invasion in pneumocytes, excessive cytokine secretion, dysregulated renin-angiotensin-aldosterone pathway, and inflammatory responses [176]. Hypoxia inducible factor-1 (HIF-1) controls cell proliferation, metabolism, and angiogenesis. It is released during immunological responses and plays crucial functions at the inflammation zone by encouraging the release of pro-inflammatory cytokines via immune cells [177]. HIF-1 also participates in the regulation of protein expression of key molecules of SARS-Cov-2 entrance, including ACE2 and TMPRSS2 on the cell surface [178]. Antioxidants have been suggested as a tissue barrier against ROS due to activation of immune cells, as well as suppressing HIF-1 driven cytokine secretion. Keeping in mind that the interaction of SARS-CoV-2 with endothelial cells, iron metabolism, and erythrocytes, as well as the resultant hypoxia, may lead to a number of coagulopathies, heparins are being commonly used for the treatment of COVID-19 patients. For example, a clinical trial in critically ill COVID-19 patients receiving a therapeutic-dose of heparin for anticoagulation did not improve survival rates [162]. In contrast, heparin treatment of non-critically ill COVID-19 patients increased survival and reduced the need of cardiovascular and respiratory organ support [163]. Concurrent inflammasome hyperactivation, especially in the context of hypoxia, is yet another prothrombotic mediator [164]. Melatonin has also been shown to prevent to some extent hypoxia, ferroptosis, and hemoglobin denaturation [164].
3.5 Calcium signaling
Calcium (Ca2+) is necessary for SARS-CoV fusion with host cells, suggesting that Ca2+ plays an important role in viral diseases [179]. SARS-CoV is also known to cause selective changes in Ca2+ signaling in host cells by activating Ca2+ channels and pumps and boosting intracellular Ca2+ load as part of reproduction, maturation, and survivability [180]. Changes in Ca2+ dynamics have been found to lead to alterations in numerous signaling pathways and gene functions. The voltage-gated calcium channels (VGCC) inhibitors, bepridil, amlodipine and nifedipine have been shown to diminish SARS-CoV-2 infection in vitro by preventing SARS-CoV-2 entry into host cells [165]. Vitamin D has been proposed to have a significant role in the control of autophagy or apoptosis through calcium signaling at the mitochondrial and ER levels during the COVID-19 pandemic. Vitamin D has also been demonstrated to down-regulate the toll-like receptors TLR2 and TLR4 in monocytes, resulting in reduced inflammatory reactions and stimulation of the synthesis of antimicrobial peptides (AMPs) such as defensin and cathelicidin, which may inhibit SARS-CoV-2. IROS production, oxidative stress, NADPH oxidase expression and DNA damage are also inhibited by vitamin D. Vitamin D stimulates the expression of antioxidant enzymes by upregulating a nuclear factor called erythroid-2(Nf-E2)-related factor 2 (Nrf2) [181].
3.6 Other pathways
3.6.1 Adaptor-associated kinase 1 (AAK1) and cyclin G-associated kinase (GAK)
The ACE2 receptor has several regulators among which are two cellular kinases from the serine–threonine protein-protein kinase family, AP2-associated protein kinase-1 (AAK1) and cyclin G-associated kinase (GAK), which mediate clathrin-dependent endocytosis [182]. Both AAK1 and GAK, have been linked to viral entry, assembly, and release [183]. AAK and GAK function as key regulators of the clathrin-associated host adaptor proteins and regulate the intracellular trafficking and clathrin-mediated endocytoses of multiple unrelated RNA viruses. Baricitinib was identified to possess a particularly high affinity for AAK1 and GAK, decreasing acute respiratory distress syndrome in patients and preventing SARS-CoV-2 from target cell entry and assembling intracellular assembly [184]. Baricitinib is also capable of dampening the inflammation through JAK1/2 inhibition [185], and along with fedratiniband ruxolitinib, has been suggested to be effective against elevated levels of IFN-γ [186]. Although baricitinib, sunitinib and erlotinib possess similar JAK inhibitor potency, the high affinity of baricitinib for AAK1 suggests it to be superior in the group, especially given its once-daily oral dosing and acceptable side-effect profile [186]. As a result, it is advised that baricitinib should be tested on COVID-19 patients in order to minimize viral entrance and inflammation (NCT04321993). Other GAK kinase inhibitors include sunitib, and erlotinib, which also interact with AAK1, AXL, JAK1 and KIT. The interaction takes place with tyrosine kinase in the case of sunitib and for erlotinib with Abl1 [177]. However, sunitinib and erlotinib would be difficult for patients to tolerate at doses required for inhibition of AAK1 and GAK [187].
3.6.2 Phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) and two-Pore Channel (TPC2)
Since endocytosis is an alternative mode of viral entry into host cells, phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) is required during SARS-CoV-2 infection through the endocytic pathway [188]. This initiates phosphoinositide synthesis to regulate the formation of early endosomes. Apilimod, a PIKfyve inhibitor, is currently undergoing clinical trials (NCT04446377) for management of COVID-19 [166]. Though apilimod may reduce viral infiltration by suppressing host cell proteases, these enzymes are required for antigen presentation and T cell activation, and it has been suggested that apilimod might inhibit antiviral immune responses [189]. Furthermore, a two-pore segment channel (TPC2) activated by phosphoinositides in membranes of lysosomes is essential for endocytosis [190]. Two-Pore Channels have been recognized as a specific targeting potential for preventing SARS-CoV-2 entry into host cells and inhibition of virus replication by impairing the fusogenic potential of the endo-lysosomal system and altering the normal trafficking [167]. Accordingly, a clinical trial is underway to evaluate the efficacy of the TPC2 antagonist tetrandrine in COVID-19 treatment (NCT04308317) [168]. The flavonoid naringenin, found in fruits, has also been discovered as an inhibitor of TPCs [190]. Furthermore, TPC2 antagonists ned-19 and tetrandine were proposed as putative lysosomal activity antagonists, resulting in additional suppression of autophagy at the breakdown stage. Keeping in mind that lysosomal Ca2+ dynamics, especially lysosomal Ca2+ efflux channel TPC2, plays a critical role in viral entry, TPC2 inhibition has been shown to prevent entry of SARS-CoV-2 [167].
4 Conclusions
Despite encouraging success in tackling the COVID-19 pandemic, especially by developing and applying efficient and safe vaccines for global mass vaccinations, there is a continuous demand on further development. Although some success has been seen for repurposed antiviral drugs such as RDV and FPV, drugs like HCQ and ivermectin have proven disappointing with hardly any difference to placebo in large well-designed clinical trials [54,55]. In contrast, monoclonal antibodies have demonstrated efficacy in treatment of COVID-19 patients [90], but the high costs have been discouraging for supporting mass distribution especially in developing countries. Oral administration of molnupiravir seemed initially like a major breakthrough in COVID-19 treatment, but more thorough clinical evaluation suggested that the reduced risk of hospitalization was only 30% [50]. On the other, an 89% reduced risk of hospitalization and death has been highly encouraging for paxlovid [56].
In the context of vaccines, initially more than 90% vaccine efficacy was achieved for both adenovirus- [102,105,109] and mRNA-based [121,126] COVID-19 vaccines against the original SARS-CoV-2 Wuhan strain. However, with the advent of several emerging SARS-CoV-2 S variants, there has been serious concerns about reduced vaccine efficacy. Booster vaccinations have provided a quick short-term solution, but obviously re-engineering of vaccines targeting the novel variants/mutants has been seen as one solution. Current vaccine development has almost uniquely focused on the SARS-CoV-2 S protein, which due to its surface location is a key target for novel mutations aiming at circumventing the vaccine protection. Therefore, future COVID-19 vaccine development should profit from engineering vaccines based on other SARS-CoV-2 targets and also aiming at several target simultaneously providing types of pan-vaccines.
Similarly, there is also a genuine need to expand the spectrum of COVID-19 drug targets. In this context, we review signaling pathways which are affected by SARS-CoV-2 infections. The biologically essential RAS presents interesting therapeutic possibilities for targeting COVID-19, especially related to viral entry and manipulation of ACE2 and TMPRSS2. The impact of protein transport by ER and Golgi trafficking can be highlighted by existing FDA-approved cathepsin L inhibitors, which can be repurposed for SARS.CoV-2, but also the potential discovery of novel drug targets. Immune pathways represent a rich source for identifying inhibitors, which can reduce inflammation and diminish cytokine storm events. In the context of hypoxia, therapeutic anticoagulation therapy with heparin has been conducted in both critically and non-critically ill COVID-19 patients to investigate its effect on survival rates. Moreover, drugs affecting calcium and other pathways have been studied in search for novel drugs capable of reducing entry and replication of SARS-CoV-2.
In summary, major progress has been achieved. However, intensive research and development is required to keep up with the evolution of new SARS-CoV-2 variants and to be prepared for future emerging outbreaks.
Funding
This research received no external funding.
Institutional review board statement
Not applicable.
Informed consent statement
Not applicable.
Data availability statement
Not applicable.
CRediT authorship contribution statement
Kenneth Lundstrom: Writing – original draft, Writing – review & editing. Altijana Hromić-Jahjefendić: Conceptualization, Writing – original draft, Writing – review & editing. Esma Bilajac: Writing – original draft. Alaa A.A. Aljabali: Writing – original draft. Katarina Baralić: Writing – original draft. Nagwa A. Sabri: Writing – original draft. Eslam M. Shehata: Writing – original draft. Mohamed Raslan: Writing – original draft. Sara A. Raslan: Writing – original draft. Ana Cláudia B.H. Ferreira: Writing – original draft. Lidiane Orlandi: Writing – original draft. Ángel Serrano-Aroca: Writing – original draft. Vladimir N. Uversky: Writing – original draft. Sk. Sarif Hassan: Writing – original draft. Elrashdy M. Redwan: Writing – original draft. Vasco Azevedo: Writing – original draft. Khalid J. Alzahrani: Writing – original draft. Khalaf F. Alsharif: Writing – original draft. Ibrahim F. Halawani: Writing – original draft. Fuad M. Alzahrani: Writing – original draft. Murtaza M. Tambuwala: Writing – original draft. Debmalya Barh: Conceptualization, Writing – review & editing, Supervision, Project administration.
Uncited reference
[36]
Declaration of Competing Interest
The authors declare no conflict of interest.
Data availability
No data was used for the research described in the article.
Acknowledgments
Not applicable.
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| 36521656 | PMC9744501 | NO-CC CODE | 2022-12-15 00:01:49 | no | Cell Signal. 2022 Dec 13;:110559 | utf-8 | Cell Signal | 2,022 | 10.1016/j.cellsig.2022.110559 | oa_other |
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Clin Infect Pract
Clin Infect Pract
Clinical Infection in Practice
2590-1702
The Authors. Published by Elsevier Ltd on behalf of British Infection Association.
S2590-1702(22)00082-6
10.1016/j.clinpr.2022.100214
100214
Case Reports and Series
Third dose of an mRNA COVID-19 vaccine for patients with multiple myeloma
Goldwater Marissa-Skye a
Stampfer Samuel D. b
Sean Regidor Bernard c
Bujarski Sean a
Jew Scott a
Chen Haiming a
Xu Ning a
Kim Clara d
Kim Susanna d
Berenson James R. acd⁎
a Institute for Myeloma and Bone Cancer Research, West Hollywood, CA
b Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
c Berenson Cancer Center, West Hollywood, CA
d ONCOtherapeutics, West Hollywood, CA
⁎ Corresponding author at: Institute for Myeloma and Bone Cancer Research, 9201 W. Sunset Blvd., Ste. 300, West Hollywood, CA 90069
13 12 2022
13 12 2022
1002145 7 2022
29 11 2022
9 12 2022
© 2022 The Authors. Published by Elsevier Ltd on behalf of British Infection Association.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
We have reported that IgG antibody responses following two mRNA COVID-19 vaccinations are impaired among patients with multiple myeloma (MM). In the current study, sixty-seven patients with MM were tested for anti-spike IgG antibodies 0-60 days prior to their first vaccination, 14-28 days following the second dose, and both before and 14-28 days after their third dose of the mRNA-1273 or BNT162b2 vaccines. After the first two doses, most patients' (93%) antibody levels declined to ineffective levels (<250 BAU/mL) prior to their third dose (D3). D3 elicited responses in 84% of patients (61% full response and 22% partial response). The third vaccination increased antibody levels (average = 370.4 BAU/mL; range, 1.0-8977.3 BAU/mL) relative to just prior to D3 (average = 25.0 BAU/mL; range, 1.0-683.8 BAU/mL) and achieved higher levels than peak levels after the first two doses (average = 144.8 BAU/mL; range, 1.0-4,284.1 BAU/mL). D3 response positively correlated with mRNA-1273, a >10-fold change from baseline for the two-dose series, switching from BNT162b2 to mRNA-1273 for D3, and treatment with elotuzumab and an immunomodulatory agent. Lower antibody levels prior to D3, poorer overall response to first two doses, and ruxolitinib or anti-CD38 monoclonal antibody treatment negatively correlated with D3 response. Our results show encouraging activity of the third vaccine, even among patients who failed to respond to the first two vaccinations. The finding of specific factors that predict COVID-19 antibody levels will help advise patients and healthcare professionals on the likelihood of responses to further vaccinations.
Keywords
COVID-19
SARS-CoV-2
Infectious Disease
Multiple Myeloma
vaccine booster dose
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pmcIntroduction
SARS-CoV-2 has infected over 500 million people and caused over 6 million deaths since its discovery in 2019. (Dong et al., 2020) Clinical trials have shown that mRNA vaccination for COVID-19 dramatically reduces the risk of severe disease and hospitalization among healthy individuals. (Polack et al., 2020, Baden et al., 2021) However, immunocompromised individuals, such as those with multiple myeloma (MM), are less likely to derive protective humoral and cell-mediated immunity from these vaccines (Clem, 2011, Ehmsen et al., 2021) and are at risk for more significant complications from COVID-19. (Baek et al., 2021)Table 1. Table 1 Patient demographics
Demographics
Total number of patients (N) 67
Sex n (%)
Male 38 (57%)
Female 29 (43%)
Age (Years)
Median (Range) 70 (40-86)
Race n (%)
Caucasian 54 (81%)
AA 5 (7%)
Hispanic 2 (3%)
Asian 2 (3%)
ME 4 (6%)
Disease Status n (%)
CR 27 (40%)
PR 12 (18%)
PD 10 (15%)
SD 9 (13%)
N/A 6 (9%)
MR 3 (4%)
Prior lines of therapy n
Median (Range) 2 (0-15)
Current line of therapy n (%)
Salvage 50 (75%)
Frontline 10 (15%)
Untreated 7 (10%)
Prior regimens based on drug class n (%)
Steroids 59 (88%)
IMiDs 30 (45%)
PI 23 (34%)
Antibody 23 (34%)
Other Chemotherapy 19 (28%)
Anti-CD38 15 (22%)
RUX 9 (13%)
ELO 8 (12%)
Alkylating Agent 2 (3%)
MM is a hematological malignancy characterized by the presence of clonal plasma cells in the bone marrow that produce monoclonal antibodies. (Liu et al., 2020) It is associated with a functional reduction in immune responses which results in a significantly increased risk of infection (Alemu et al., 2016, Tete et al., 2014) and less robust responses to vaccines. (Ludwig et al., 2021) We and other groups have found that MM patients show lower anti-spike IgG antibody responses to COVID-19 mRNA vaccinations than healthy controls, (Stampfer et al., 2021, Agha et al., 2019) leaving these patients at significant risk of experiencing symptomatic breakthrough infections. (Stampfer et al., 2022) This finding emphasizes the importance of regular serological monitoring of anti-spike IgG antibody levels for these patients following their ongoing COVID-19 vaccinations, which are likely to correlate with neutralizing antibody levels and T-cell responses. (Sui et al., 2021, Earle et al., 2021)
In our first report, (Stampfer et al., 2021) we stratified patients into clinical response categories based on studies showing mRNA vaccination achieving 94–95% efficacy against mild COVID-19 cases in the context of the original strain. (Polack et al., 2020, Baden et al., 2021) The spike antibody level of 250 BAU/mL was selected as the clinically relevant cutoff level as it was exceeded by 94% of the control samples in our previous study. Consistent with the clinical relevance of this cutoff, a longitudinal study of 246 dental professionals who had COVID-19 showed that spike antibody levels of ≥147 IU/mL conferred complete protection against reinfection during a six-month follow-up. (Shields et al., 2021) Specifically, patients were categorized into clinically relevant responders (>250 BAU/mL), partial responders (50-250 BAU/mL), and non-responders (<50 BAU/mL). Only 45% of MM patients achieved clinically relevant responses, and 22% fell into the partial responder category. We also identified specific characteristics that determined patients’ likelihood of responding to the first two vaccines which included both MM and vaccine related– factors, including mRNA vaccine type, age, and uninvolved immunoglobulin levels.
Although the first two doses of mRNA COVID-19 vaccines are highly effective in preventing infection for up to 6 months, both COVID-19 antibody levels; and, as a result, the effectiveness of these vaccinations decrease dramatically after that time point. (Goldberg et al., 2021, Levin et al., 2021, Rosenberg et al., 2021) As a result, booster vaccinations have been administered, and a recent large, placebo-controlled trial demonstrates the efficacy of a third dose of mRNA COVID19 vaccine in preventing this viral infection among adult volunteers. (Moreira et al., 2022) A recent paper shows that approximately half of patients with solid and hematologic malignancies lose neutralizing antibodies against the current variants of concern by the six-month mark post-vaccine, and that this drop in antibody level is faster than what is observed in healthy individuals. (Obeid et al., 2022) As a result, these patients likely need to receive booster vaccine doses more frequently than the general population. In the current study, we evaluated MM patients who received a third dose of a COVID-19 mRNA vaccine for anti-spike IgG antibodies. The purpose was to determine the response to a third vaccination and what factors might predict the level of response, including baseline levels prior to the third dose, response to the first two doses, mRNA vaccine type, and MM treatment regimen. Responses were categorized according to the three clinical response categories used in our previous study. (Stampfer et al., 2021)
Materials and Methods
Participants and eligibility
Subjects included MM patients treated at a single center specializing in the treatment of these patients who had received three doses of a COVID-19 mRNA vaccination. Patients with a history of COVID-19 infection confirmed by positive nucleic acid testing were excluded from this study.
Timepoints
Anti-spike IgG antibody levels were determined 0-60 days before (D3-baseline) and 14-28 days after their third dose (D3W2). These values were compared to post-two-dose series levels drawn 14-28 days following the second dose (D2W2), and pre-vaccination baseline values drawn 0-60 days prior to the first vaccine dose (D0).
Quantitative Anti-Spike IgG ELISA
The semiquantitative spike IgG ELISA assay [units in (BAU)/mL] used was the test described previously with 1000 BAU/mL matching the 20/136 NIBSC WHO convalescent plasma standard. (Stampfer et al., 2021)
Comparative Analysis
The reported measures of central tendency were median and geometric mean. Differences in antibody levels between time points for the same patient were analyzed using Wilcoxon signed rank test, while differences between patients were analyzed using Mann-Whitney U-tests. The difference in the percentage of patients that responded better to D3 than dose 2 (D2) was analyzed using a z-test of proportions.
To determine which variables were predictive of D3 response, we used a multivariate binary logistic regression model with stepwise AIC selection. Vaccine response was defined as >250 IU/mL. All statistical analysis was done using GraphPad Prism 9 and R (San Diego, CA) and R (version 4.1.2).
Results
There were 67 MM patients who received three doses of mRNA-based COVID-19 vaccines (BNT162b2 or mRNA-1273) found to be eligible based on sample availability at all of the time points that were part of the study. Thirty received three doses of mRNA-1273, 18 received three doses of BNT162b2, 19 received two doses of BNT162b2 followed by one dose of mRNA-1273, and the median number of days between the second and third vaccine was 185 (range, 99-247 days). The median age was 70 years (range, 40-86 years), 57% of patients were male, and 81% were Caucasian. Active MM patients were being treated with a variety of treatment regimens. For prior regimens based on drug class, 88%, 45%, 34%, 22%, 13%, and 12% were or had previously been on a steroid containing regimen, immunomodulatory agent (IMiD), proteasome inhibitor (PI), anti-CD38 antibody, ruxolitinib (RUX), and elotuzumab (ELO), respectively. At the time of D3, the median number of prior lines of therapy was 2 (range, 0-15), with 15% on frontline therapy, 75% on salvage therapy, and 10% untreated. With respect to disease status, 40%, 18%, 4%, 13%, 15%, and for 9% were in CR, PR, MR, SD, and PD, respectively, and 9% were not evaluable.
Antibody decline between second and prior to third dose of COVID-19 mRNA vaccination
Prior to their third vaccination, 80% (12/15) of patients who had a partial response (50–250 BAU/mL) to their first 2 doses and 42% (13/31) of patients who had a full response (>250 BAU/mL), fell below 50 BAU/mL. Twenty percent (3/15) of patients who had a partial response and 42% (13/31) of patients who had a full response showed partially protective levels between 50-250 BAU/mL at D3-baseline. Only 16% (5/31) of patients who had a full response remained at >250 BAU/mL at D3-baseline and only 20% (3/15) of patients who had a partial response remained at their 50-250 BAU/mL level. All patients who were non–responders (n = 21) remained <50 BAU/mL prior to their third vaccination (Figure 1 a). Longer duration between D2 and D3 was weakly associated with a greater drop in antibody levels from D2W2 to D3 baseline (spearman r = -0.3009; p = 0.0133).Figure 1 Percentage of patients in each D3-baseline category within each D2 response category. (A) Dose 3 baseline (D3-baseline antibody level just prior to booster dose) and (B) D3 (D3W2 antibody level) clinical response categories broken down by D2 (D2W2 antibody level) clinical response categories (no response = <50 BAU/mL, partial response = 50-250 BAU/mL, full response = >250 BAU/mL).
Third dose response
Among all patients, 61% (n = 41), 22% (n = 15), and 16% (n = 11) showed full response, partial response, and no response, respectively. For those who did not respond to the first two doses (n = 21), nearly half (10/21) of patients had no response to D3, whereas 38% (8/21) achieved a partial response, and 14% (3/21) a full response. One-third (5/15) of patients who had a partial response to the two-dose series had a similar partial response to D3, and the remaining 67% (10/15) achieved a full response. Ninety percent (28/31) of patients who had a full response to the two-dose series also had a full response to D3, with only 6% (2/31) showing a partial response and 3% (1/31) with no response (Figure 1b).
D3W2 antibody levels (average = 370.4 BAU/mL; range, 1.0-8977.3 BAU/mL) were higher than D3-baseline antibody levels (average = 25.03 BAU/mL; range, 1.0-683.8 BAU/mL; p < 0.0001) as well as D2W2 antibody levels (average = 144.8 BAU/mL; range, 1.0-4284.1 BAU/mL; p < 0.0001; Figure 2 ). The average D3-baseline antibody levels were higher than D0 levels (average = 7.6 BAU/mL; 1-71.7 BAU/mL; p < 0.0001).Figure 2 Average antibody levels across all time-points: D0, D2W2, D3-baseline, and D3W2. Statistical significance measured between average antibody levels at D0 and D2W2, as well as between D3-baseline and D3W2, among all patients.
A multivariate binary logistic regression model examined the effects of the following variables on D3 response: sex, age at D3, D2 and D3 mRNA vaccine types, treatment with ruxolitinib (RUX) or elotuzumab (ELO) with an immunomodulatory drug (IMiD) at D3, M-protein at D3-baseline, and D2 response. Only D2 response was found to be positively correlated with D3 response. Multivariate analysis was performed excluding D2 response and including the following variables: sex, days from D1 to D3W2, D2 mRNA vaccine type, and treatment with RUX or ELO with an IMiD at D3. This second analysis found that a longer time interval between D1 and D3W2 was positively correlated with D3 response, and treatment with RUX and receiving BNT162b2 for doses one and two were negatively correlated with D3 response (Supplemental Figure 1).
Vaccine response by mRNA vaccine type (mRNA-1273 vs. BNT162b2)
When categorized according to the original mRNA vaccine type that the patient received for their first two doses of vaccination, the mRNA-1273 group had higher antibody levels than the BNT162b2 group at D2W2 (p = 0.0002), D3-baseline (p = 0.0332), and D3W2 (p = 0.0069), despite no significant difference at D0 (Figure3 ). Notably, antibody levels at D3-baseline were higher among those who had received mRNA-1273 (average = 39.0 BAU/mL; range, 1-683.8 BAU/mL) than among those who had been treated with BNT162b2 (average = 17.5 BAU/mL; range, 1-289.2 BAU/mL; p = 0.0328; Figure 3). Based only on the type of mRNA vaccination patients received for their first two doses, including those who received BNT162b2 for their first two doses before switching to mRNA-1273, the median difference between average D3W2 and D2W2 levels among patients treated with the mRNA-1273 and BNT162b2 vaccines was 556.1 BAU/mL and 198.4 BAU/mL (p = 0.1767), respectively (Supplemental Figure 2).Figure 3 Antibody levels at each time-point across vaccine regimens based only on the first two doses. Patients were divided into those who received mRNA-1273 for their first two vaccine doses (n = 30) and those who received BNT162b2 (n = 37), to compare their antibody levels at D0, D2W2, D3-baseline, and D3W2.
Patients who received BNT162b2 for the first two doses were then divided into those who received another BNT162b2 (P-P-P) and those who switched to mRNA–1273 (P-P-M) for their third dose (Figure 4 ). P-P-M patients increased >4-fold above their D2W2 antibody levels (average = 42.6 BAU/mL to 172.1 BAU/mL) compared to P-P-P patients who only achieved an approximate 2.5–fold increase above their D2W2 antibody levels (average = 111.8 BAU/mL to 255.5 BAU/mL; Figure 5 ). For P-P-P patients, D3W2 antibody levels (average = 255.5 BAU/mL; range, 1 – 7931 BAU/mL) were higher than both D3-baseline antibody levels (average = 20.5 BAU/mL ; range, 1 – 489.2 BAU/mL; p < 0.0001) and D2W2 antibody levels (average = 111.8 BAU/mL ; range, 1 – 4284 BAU/mL; p = 0.0047 ; Supplemental Figure 3, Figure 4). This was also the case for P-P-M patients, who had D3W2 antibody levels (average = 172.1 BAU/mL; range, 1 – 7182 BAU/mL) that were significantly higher than their average D3-baseline and D2W2 antibody levels of 15.0 BAU/mL (range, 1 – 131.4 BAU/mL; p < 0.0001) and 42.6 BAU/mL (range, 1 – 423.9 BAU/mL; p < 0.0001), respectively. Patients who received mRNA-1273 for all three doses (M-M-M) achieved D2W2 antibody levels (average = 367.0 BAU/mL; range, 5.5-3163.0 BAU/mL) and D3W2 antibody levels (average = 751.9 BAU/mL; range, 7.3-8977.0 BAU/mL) that were higher than both the P-P-P and P-P-M groups (Figure 4). As was observed with the two BNT162b2 groups, these M-M-M patients exhibited significantly higher antibody levels at D3W2 (average = 751.9 BAU/mL; range, 7.3-8977.0 BAU/mL) than at D3-baseline (average = 39.0 BAU/mL; p < 0.0001) and D2W2 (average = 367.0 BAU/mL; range, 5.5-3163.0 BAU/mL; p = 0.0003; Supplemental Figure 3, Figure 4).Figure 4 Antibody levels at each time-point for all patients who received BNT162b2 for their initial two dose series were analyzed according to which vaccine they received for their third dose (BNT162b2 or mRNA-1273). Patients who received BNT162b2 were further broken down into those who again received BNT162b2 for their third dose (P-P-P) (n = 18) and those who switched to mRNA-1273 (P-P-M) (n = 19), to compare their antibody levels at D0, D2W2, D3 baseline, and D3W2.
Figure 5 D2 fold change from D0 broken down into <10 and >10 and analyzed by whether D3 response was greater than D2 response. Within each D2/D0 fold change category (<10 [n = 23] and >10 [n = 13]), there was a breakdown of the percentage of patients who achieved a D3 response that was greater than their D2 response and the percentage of patients who had a D3 response that was less than or equal to their D2 response.
Immunologic response among non-responders and partial responders
Next, we compared poor relative responders (<10-fold increase from baseline antibody levels to D2W2) to good relative responders (>10-fold increase from baseline antibody levels to D2W2) among patients whose D2W2 antibody levels were <250 BAU/mL. Most (85%; [11/15]) of those who responded to the two-dose series with a >10-fold change increase from pre-vaccination antibody levels to D2W2 antibody levels responded further to D3, whereas only 43% (10/23) of those who had a <10-fold change increase responded further (p = 0.0401) (Figure 5).
Myeloma treatment-related effects on COVID-19 antibody response
Patients were separated into five groups according to their current MM treatment: anti-CD38 monoclonal antibody (anti-CD38)-, RUX-, PI-, and ELO-containing therapies, and all other regimens not containing these drugs (no ELO, no RUX, no anti-CD38, no PI; Figure 6 ). Patients with overlapping treatments were excluded. Patients in the no ELO, no RUX, no anti-CD38, no PI group exhibited an approximately 2-fold increase in antibody levels from D2 to D3 (average D2W2 = 281.0 BAU/mL; average D3W2 = 578.2 BAU/mL). Similarly, the PI-treated group exhibited an approximately 3-fold increase in antibody levels (average D2W2 = 234.5 BAU/mL; average D3W2 = 762.9 BAU/mL). The ELO-treated group exhibited a 4.5-fold increase (average D2W2 = 258.1 BAU/mL; average D3W2 = 1357.0 BAU/mL). Those treated with anti–CD38-containing treatments showed the lowest D2 antibody levels (average D2W2 = 42.2 BAU/mL), and their average D3 response was only 165.2 BAU/mL. RUX-treated patients had an average D2 response of only 102.4 BAU/mL and an even lower average D3 response of 82.6 BAU/mL.Figure 6 Patient antibody levels broken down by myeloma drug type. Average patient antibody levels (BAU/mL) for each of four treatment containing subcategories: ELO (n = 7), RUX (n = 8 post-D2 ; n = 7 post-D3), anti CD38 (n = 15 post-D2 ; n = 16 post-D3), PI (n = 21), and all treatment regimens without these four drug types (no ELO/no RUX/no anti-CD38 antibody/no PI) (n = 15). Patients with overlapping treatments were excluded.
The same patients were then divided into three groups: ELO-containing therapies with an IMiD, IMiD without ELO, and IMiD without RUX, anti-CD38, or ELO (Figure 7 ). Patients with overlapping treatments were again excluded. Patients on PIs were not excluded from this third group as the previous data had already shown PIs to have little or no effect on vaccine response. The IMiD without ELO group had average D2 and D3 antibody levels of 118.4 BAU/mL and 292.3 BAU/mL, respectively. The IMiD without ELO, RUX, or anti-CD38, group had average D2 and D3 responses of 169.0 BAU/mL and 399.6 BAU/mL, respectively. The ELO with IMiD group had average D2 and D3 levels of 271.2 BAU/mL and 1201.0 BAU/mL, respectively. Median lines of treatment were 3 for all three groups.Figure 7 Patient antibody levels broken down by ELO and IMiD treatment subcategories. Average patient antibody levels (BAU/mL) for each of four treatment containing subcategories: ELO and IMiD (n = 6), IMiD and no ELO (n = 24), and IMiD and no ELO, no RUX, or no anti–CD38 antibody (n = 15). Patients with overlapping treatments were excluded.
Discussion
Previous studies have shown that only a minority of patients with active MM show full responses to the first two doses of COVID-19 vaccination. (Stampfer et al., 2021, Agha et al., 2019) Thus, it is important to determine the efficacy of a booster dose in this at-risk population and the factors that determine their response to this vaccination. Studies have recently shown that immunosuppressed populations demonstrate a marked decline in antibody levels in the months following the first two doses, and that administration of a third vaccination effectively boosts immunity. (Obeid et al., 2022, Kamar et al., 2021, Hall et al., 2021, Greenberger et al., 2021)This has been observed even among those who do not respond to the two–dose series. (Shapiro et al., 2022, Herishanu et al., 2022)
In this study of MM patients, we have shown that anti-spike IgG antibodies markedly decline between the peak level achieved following their second dose and just prior to the administration of their third dose with only a small minority (7% [5/67]) maintaining clinically effective antibody levels above 250 BAU/mL. Similarly, another study found the majority (78%) of patients with a variety of B-cell malignancies to be seronegative prior to a third dose of an COVID-19 mRNA vaccine. (Greenberger et al., 2021) Notably, nearly 2/3rds of patients in that study showed increased antibody levels following their third dose. In the current study, peak levels after the third vaccination were higher than following the second dose for most patients but varied widely between them. This may indicate that most patients could generate an anamnestic response. (Liu et al., 2022) Specifically, 61% (41/67), 22% (15/67), and 16% (11/67) showed a full, partial, and no relative response, respectively following the third vaccination. Thus, the majority of patients (84% [56/67]) derived some degree of protection from this third dose which was higher than after the first two doses. (Stampfer et al., 2021) This is also consistent with findings in other immunosuppressed populations, with one study in the context of solid organ transplants finding a third dose to significantly improve the immunogenicity of mRNA COVID-19 vaccines. (Kamar et al., 2021) Another study performed among transplant recipients found 71% to exhibit antibody responses to a third dose, with overall levels rising significantly relative to prior to this third dose. (Hall et al., 2021)
Among seronegative patients prior to their third dose of COVID-19 vaccine, 56% of cancer patients seroconverted following their third dose. (Shapiro et al., 2022) Another study found that CLL patients who did not respond to the first two doses of BNT162b2 responded in approximately one quarter of cases. (Herishanu et al., 2022) Similarly, in the current study, more than half (52% [11/21]) of patients who were below the 50 BAU/mL threshold defined as “non-responders” following their first two doses, displayed some degree of response to this third dose, though this was lower than the responses to the third dose among those who showed higher peak levels following the first two doses. This included the 22% (15/67) of patients in the 50-250 BAU/mL category and the 46% (31/67) of patients in the >250 category following the first two doses. Specifically, all of these patients except one (98% [60/61]) showed some degree of response to the third dose. This is particularly important as the magnitude of anti-spike IgG antibody response to vaccination correlates with other indicators of an immune response, as well as the degree of protection from COVID-19. (Hall et al., 2022, Salazar et al., 2020, Vályi-Nagy et al., 2021)
Factors related to these peak levels (D3W2) included the level of COVID-19 antibodies that was achieved following the first two vaccines, amounts of these antibodies just prior to the third vaccination, type of mRNA vaccination (mRNA-1273 versus BNT162b2), and type of myeloma treatment patients were receiving at the time of their third vaccination.
Consistent with our study and others following the first two vaccinations, (Stampfer et al., 2021, Naranbhai et al., 2022, Andrews et al., 2022) antibody levels among patients who received mRNA-1273 for all three doses were higher across all time points since receiving their second dose than the antibody levels of those who received BNT162b2 for all three doses (Figure 3). COVID-19 antibody levels drawn just prior to D3 were also higher among those who received mRNA-1273 than BNT162b2–treated patients. This suggests that mRNA-1273-treated patients may maintain effective levels of antibody longer; and, thus, may not need to be boosted as often as BNT162b2 patients. In fact, a recent study found that the magnitude and duration of neutralizing antibodies in response to the mRNA-1273 vaccine was substantially greater and longer than to the BNT162b2 vaccine among patients with solid and hematologic cancers, solid organ transplants, or autoimmune diseases, as well as among healthy controls. (Obeid et al., 2022)
Although some patients who received BNT162b2 for their two-dose series selected mRNA-1273 as their booster, it made no significant difference in overall antibody level compared with continuing with BNT162b2 vaccination (Figure 3, Figure 4). Individuals experiencing a more robust immune response to the two–dose series of mRNA-1273 may also have greater immunological memory, (Mairhofer et al., 2021) allowing for a more robust response to a third dose. (Liu et al., 2022) An alternative explanation is that patients in the P-P-M group showed lower responses following D2 than those in the P-P-P group, though this difference was not significant. This is likely due to patients who had poorer responses being the ones who chose to switch to mRNA-1273 for their third vaccination. Patients who received two doses of BNT162b2 followed by mRNA-1273 did, however, achieve a greater fold change above their D2W2 peak level compared to patients who only received BNT162b2. A notable finding given that the P–P–M group had markedly lower D2W2 responses than P-P-P and would have been expected to have poorer D3W2 responses. A technical briefing from the UK Health Security Agency showed that recipients of BNT162b2 have higher vaccine efficacy against Omicron if they switch to mRNA-1273 for their booster dose, (Health Security, 2021) further supporting a change to mRNA-1273 vaccination for those who had received BNT162b2 for their first two vaccinations.
MM treatment with PIs did not appear to affect vaccine response, as has been previously reported. (Herzog Tzarfati et al., 2021) However, treatment with the anti-CD38 monoclonal antibodies daratumumab and isatuximab, the Janus kinase 1/2 (JAK1/2) inhibitor RUX, and the signaling lymphocytic activation molecule F7 (SLAMF7) monoclonal antibody ELO did show differences in antibody responses.
Anti-CD38 antibody therapies such as daratumumab and isatuximab indiscriminately target the CD38 glycoprotein on both healthy and malignant plasma cells. (Frerichs et al., 2020) Consequently, the destruction of healthy plasma cells from these treatments likely results in the patients’ reduced response to COVID–19 vaccination due to decreased production of immunoglobulins. Consistent with the impaired antibody response to the third vaccine seen in our study, only a minority (42%) of patients with MM receiving anti-CD38 treatment achieved clinically significant neutralizing antibodies to vaccination. (Terpos et al., 2021) In another study, 13-30-fold lower ELISA binding titers were observed among vaccinated patients with MM receiving anti-CD38 treatments compared to their counterparts on other treatment regimens. (Shah et al., 2022)
In contrast, ELO-treated patients showed higher antibody levels. This monoclonal antibody targets SLAMF7 on both MM and NK cells. (Campbell et al., 2018) It activates NK cells, (Cox et al., 2021) which may explain the more robust antibody responses among ELO-treated patients. Similarly, IMiDs boost immune system activity via enhancement of T and NK cells, increased cytokine production, and enhancement of dendritic cells. (Terpos et al., 2021, Costa et al., 2017) However, IMiDs alone do not necessarily improve vaccine responses, (Avivi et al., 2021) which was also seen in our study. Instead, it was the combination of ELO and an IMiD that appeared to enhance antibody responses. This is consistent with findings that the combination of lenalidomide with ELO allowed the latter to enhance humoral immunity via mDCs through increasing the immunostimulatory effects of IMiDs. (Azuma et al., 2019)
Our inclusion of RUX-treated patients in this study stems from both preclinical, (Chen et al., 2021, Chen et al., 2020) and recent clinical studies demonstrating the efficacy of this JAK inhibitor for MM. (Berenson et al., 2020, Berenson et al., 2020) JAK inhibitors have been associated with impaired cellular responses. (McLornan et al., 2015) The impaired vaccine responses among RUX-treated MM patients are consistent with studies in myelofibrosis that found both reduced COVID-19 vaccine efficacy and reduced ability to respond promptly. (Ikeda et al., 2022) Coincidentally, RUX and other JAK inhibitors have been shown to be effective for treating severe COVID-19 infections, potentially as a result of the anti-inflammatory effects of these drugs. (Sarmiento et al., 2021)
These results certainly provide support for further studies of the impact and timing of specific myeloma treatments on antibody responses to these vaccinations. Whether drug holidays or vaccination during specific parts of the treatment cycle in different myeloma therapies will help improve impaired antibody responses to COVID-19 vaccination is unknown.
Conclusion
This data highlights that monitoring MM patients’ anti-spike IgG antibody levels before and after COVID-19 vaccinations can further our understanding of how to optimize the use of vaccines for this at-risk population. These results will help inform patients and healthcare professionals on the likelihood of responses to COVID-19 vaccinations, including boosters, and guide clinicians’ use of these vaccines to treat MM patients. In addition, our results demonstrate that a third dose of a mRNA COVID-19 vaccine achieves responses for most patients, including among those who failed to respond to the first two vaccinations, and that the magnitude of these responses surpass those achieved by the first two doses. A limitation of this and similar studies is that protection against COVID-19 infection and its severity based on antibody levels following vaccination is likely to vary depending on the COVID-19 variant to which the patient is exposed. Ongoing studies with likely different vaccines and antibody tests will be necessary to help establish protective antibody levels as this virus continues to evolve.
CRediT authorship contribution statement
Marissa-Skye Goldwater: Writing – original draft, Methodology, Validation, Visualization, Data curation, Project administration, Investigation, Formal analysis. Samuel D. Stampfer: Conceptualization, Methodology, Validation, Visualization, Writing – original draft, Supervision, Project administration, Resources, Funding acquisition, Formal analysis. Bernard Sean Regidor: . Sean Bujarski: Data curation, Software, Formal analysis, Investigation. Scott Jew: Data curation, Software, Formal analysis, Investigation. Haiming Chen: Investigation, Methodology, Supervision. Ning Xu: Investigation, Methodology, Supervision. Clara Kim: Writing – review & editing. Susanna Kim: Writing – review & editing. James R. Berenson: Conceptualization, Validation, Methodology, Resources, Writing – original draft, Visualization, Supervision, Project administration, Funding acquisition.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This publication was supported by the Institute for Myeloma & Bone Cancer Research and by the National Institute of Allergy and Infectious Diseases under award T32AI074492. The authors would like to thank the patients for their contributions to the study and all healthcare professional staff involved in collecting clinical specimens.
Data Sharing Statement
For original data, please contact the corresponding author.
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| 0 | PMC9744558 | NO-CC CODE | 2022-12-15 00:01:49 | no | Clin Infect Pract. 2022 Dec 13;:100214 | utf-8 | Clin Infect Pract | 2,022 | 10.1016/j.clinpr.2022.100214 | oa_other |
==== Front
J Franklin Inst
J Franklin Inst
Journal of the Franklin Institute
0016-0032
0016-0032
The Franklin Institute. Published by Elsevier Ltd.
S0016-0032(22)00879-1
10.1016/j.jfranklin.2022.12.009
Article
Dynamical analysis of a stochastic delayed epidemic model with Lévy jumps and regime switching
Đorđević Jasmina ab
Jovanović Bojana ⁎b
a The Faculty of Mathematics and Natural Sciences, University of Oslo, Blindern 0316 Oslo, Norway
b Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, Niš 18000, Serbia
⁎ Corresponding author.
13 12 2022
13 12 2022
19 1 2022
27 10 2022
4 12 2022
© 2022 The Franklin Institute. Published by Elsevier Ltd. All rights reserved.
2022
The Franklin Institute
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In this paper a delayed stochastic SLVIQR epidemic model, which can be applied for modeling the new coronavirus COVID-19 after a calibration, is derived. Model is constructed by assuming that transmission rate satisfies the mean-reverting Ornstain-Uhlenbeck process and, besides a standard Brownian motion, another two driving processes are considered: a stationary Poisson point process and a continuous finite-state Markov chain. For the constructed model, the existence and uniqueness of positive global solution is proven. Also, sufficient conditions under which the disease would lead to extinction or be persistent in the mean are established and it is shown that constructed model has a richer dynamic analysis compared to existing models. In addition, numerical simulations are given to illustrate the theoretical results.
Keywords
SARS-CoV-2 virus
epidemic model
extinction
persistence
stochastic differential equation
Brownian motion
numerical simulations
2010 MSC
34F05
60H10
92D30
==== Body
pmc1 Introduction
The current rampant Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) infection in human population, commonly known as COVID-19, has been declared a global pandemic by the World Health Organization [1]. A SARS-Cov-2 infection that may cause mortality in humans had spread very rapidly worldwide (see [2], [3]). The most common symptoms of the disease are lower respiratory tract infection, pneumonia, dry cough, fever, shortness of breath, dyspnea, and myalgia (see [4], [5]). The disease may be transmitted by either COVID-19-positive individuals or from a contaminated environment. Based on the published report, it is concluded that COVID-19 is primarily transmitted human-to-human via oral and respiratory aerosols and droplets with the virus-contaminated environment play a lesser role in the propagation of disease (see [6]).
To curb the spread of the virus, some preventive and control measures were outlined by the World Health Organization. Some of the control measures that have been identified to curb the spread of SARS-CoV-2 include lockdowns, vaccination, and quarantine while preventive measures include social distancing and wearing masks. The implementation of these measures depends on the severity of the infection and the policies which different countries choose in order to prevent, or minimize the spread of the virus.
The aim of mathematical models in epidemics in general is to describe the spread of a particular disease in the best possible way, and to suggest possible guidance for policy makers. A number of mathematical models of SIR, SEIR and refined version of SEIR type, have been constructed to describe the spread of SARS-CoV-2 virus in the human population. In the paper [7], the authors seek to formulate diverse models consisting of ordinary differential equations to explain the dynamics of SARS-CoV-2 virus, taking into account control measures such as quarantine, lockdown and vaccine interventions. Torres et al. in [8] defined the deterministic model of SEIR type in which they introduced the classes of asymptomatic individuals A, hospitalized individuals H and superspreaders P (SEIPHAR model). In [9], the authors propose a compartmental mathematical model for the spread of the COVID-19 disease that allows to describe the spread of COVID-19 in Portugal, fitting simultaneously not only the number of active infected individuals but also the number of hospitalized individuals. Viguerie at al. in [10] present an early version of a Susceptible–Exposed–Infected–Recovered–Deceased (SEIRD) mathematical model based on partial differential equations in combination with a heterogeneous diffusion model.
In reality, the environment varies randomly, making the population subject to a continuous spectrum of disturbances. Environmental fluctuations may involve a number of factors such as climate, habitats, health habits, medical quality and so on, which may affect the natural birth rate, death rate and so on (see [11]). In particular, for human diseases, the nature of the epidemic spread is inherently random due to the unpredictability of person-to-person contacts and the effects of the disturbances on the population. This was the motivation for the transition of deterministic models to their stochastic counterparts.
There are many ways of introducing environmental uncertainty into epidemiological models. Most of them assume that random noise is introduced into the differential systems in proportion to the distances of the compartments from their steady state (see [12]) or by perturbation of a certain model parameter (e.g. the transmission rate, the death rate, etc.) by additive noise, which is in deterministic models either constant or given as a deterministic function of time t (see [13], [14]). In [15], the authors define stochastic version of the SEIPHAR model for modeling the spread of COVID-19 disease by perturbing transmission rates and established sufficient conditions for persistence and extinction of the disease. Babaei et al. in [16] investigated a stochastic SEIAQHR model for transmission of Coronavirus disease which contains three white noises added to three of the main parameters of the system to represent the impact of randomness in the environment on the considered model. In [17], the authors studied deterministic and stochastic epidemic model consists of four compartments for transmission of COVID-19 disease in order to capture the disease progression.
Another approach assumes that the model parameters satisfy mean-reverting stochastic processes. In the paper [11], the author investigated the relation between this approach and perturbation of a particular model parameter by additive noise and showed that the mean-reverting stochastic processes are a practical and biologically realistic way to incorporate the effects of environmental variability in parameters. In [18] and [19], the authors assumed that environmental fluctuations mainly affect model parameters resulting in modeling model parameters with an appropriate stochastic diffusion process, specifically, they assumed that death rate could be modeled using Ornstain-Uhlenbeck (OU) process.
Environmental noise may cause a change in the intensity of various phenomena that can be expressed as a switching from one environmental regime to another. In mathematics, this transition from one state to another is often described by telegraph noise, also known as colored noise. In the paper [20] and [21], the authors analyzed stochastic epidemic models which is disturbed by both white and telegraph noises. In [22], the authors examined the dynamics of the stochastic coronavirus (COVID-19) epidemic model incorporating general incidence rate under regime switching.
Lately, a new form of stochastic epidemic models with time delay became a new field to investigate, see for instance [23] and [24]. It represents a significant role in describing the temporary immunity period (see [25], [26], [27]) and the time for vaccine to operate (see [28], [29]). Moreover, the person does not become infected at the time of contact with the virus. The period between contact with the infection and the actual development of the virus is incubation period, and in stochastic epidemic models it is supposed to be described with a time delay process (see [12], [30]). Due to such delay nature of the biological processes, delay models that consist of delay differential equations, play a very important role in the analysis of the spread and control of infectious diseases in dynamic models.
It has been recognized that in reality, population systems may suffer from certain suddenly environmental catastrophes, such as earthquakes, floods, droughts etc. This factors may have significant consequences on ecological systems where random migration of the local population are very common. As a result, the systems become rather complicated and the sample paths are discontinuous. These phenomena cannot be exactly described by differential systems with Brownian motions. To explain these phenomena, authors have to take into account jump processes intervening in systems. The importance of the Levy noise in the investigation of the model dynamics is significant to the avoidance and the control of the epidemics (see, for instance, [31], [32], [33], [34], [35], [36], [37], [38] and references therein.).
In this paper, we introduce stochastic epidemic model which can be applied for modeling the spread of COVID-19 disease after a calibration, by improving the existing deterministic epidemic model in order to make it more realistic. First of all, we incorporated environmental fluctuations following the results of [11] and assumed that transmission rate satisfies the mean-reverting Ornstain-Uhlenbeck process, which differs from the papers [18] and [19] where it is assumed that the mortality rate satisfies the Ornstain-Uhlenbeck process. The second model improvement is in the introduction of a stationary Poisson process for modeling sudden environmental shocks. The third improvement which our model contains is the implementation of a continuous finite-state Markov chain with the aim of describing the switching of the model parameters values from one state to another. And finally, the disease incubation period is incorporated into the model through a constant time-delay.
Up to our knowledge, no results have been reported relative to the dynamics of the stochastic epidemic model for transmission of COVID-19 or any other infectious disease, that incorporate white noise, Lévy jump, telegraph noise and constant time-delay. In [31] and [32], authors analyze the persistence and extinction of a stochastic delayed SIR epidemic model with Lévy jumps, where delay represents the length of immunity period of the vaccinated or recovered, but without telegraph noise. By combining all the above mentioned improvements in this paper, a complex system of processes with a richer dynamic analysis compared to the existing models was obtained, which better describes the real phenomena in nature and epidemiological characteristics. Our aim is to study the epidemic model, which can be applied for describing SARS-CoV-2 virus transmission, in a stochastic framework and reveal how the combination of white noise, telegraph noise and Lévy jump with time delay affects the dynamics of the model. Nevertheless, this model can be applied to other types of infectious diseases which have similar characteristics and transmission modes.
The paper is structured in the following way: In next section we introduce the deterministic model for modeling the spread of COVID-19 disease given in [7] which will be stochastically improved in Section 3. Section 3 contains definition of stochastic model. In Section 4, we introduced some preliminary results used in the following sections. Section 5 is dedicated to proving the existence and uniqueness of the global positive solution of the constructed stochastic model. In sections 6 and 7, sufficient conditions under which the disease would lead to extinction and be persistent in the mean, respectively, are established. Section 8 provides numerical simulations that illustrate the theoretical results. Last section contains concluding remarks.
2 Deterministic epidemiological model
In [7] authors introduced several deterministic epidemic model of SIR and SEIR type for modeling progression of the new corona virus SARS-CoV-2. Here we will present one of them, SLIQR model, which is established due to several safety protocols, for instance social-distancing, mask and quarantine. The model is constructed by assuming that the human population is divided into five mutually exclusive compartments:• S - susceptible individuals,
• L - lockdown compartment (L) which contains only susceptible persons who have restricted movement in goal to control the possibilities for them to get in contact with the virus (such persons become prone to the infection once they move from their restricted zones (lockdown) to the susceptible compartment),
• I - infectious individuals,
• Q - persons who are found to have the virus are classified as quarantined and they are isolated physically (have restricted movement in order not to spread the virus),
• R - recovered individuals.
The dynamics of the SARS-CoV-2 virus spread is described by the following system of ordinary differential equations (ODE):(1) {dS(t)dt=ηN(t)−βI(t)S(t)−(μ+l)S(t)+l1L(t),dL(t)dt=lS(t)−(μ+l1)L(t),dI(t)dt=βI(t)S(t)−(μ+α+ρi)I(t),dQ(t)dt=αI(t)−(μ+ρq)Q(t),dR(t)dt=ρiI(t)+ρqQ(t)−μR(t).
In this formulation, η is used to represent the birth rate, the transmission coefficient describing the human-to-human transmission due to the regular infected individuals is denoted by β, while the natural death rate is represented by μ. Here, natural death rate include death resulting from the coronavirus disease. Parameters ρi and ρq denote the recovery rates for infected and quarantined individuals, respectively. Parameters l and l1 are the rates at which the susceptible individuals move to the lockdown compartment and vice versa, respectively. The rate at which infected individuals become quarantined is denoted by α.
Obviously, if we take l,l1=0 in the system (1), we will get a system without a lockdown compartment. When a certain percentage of the population is vaccinated, it is natural to observe a system with smaller percentage of individuals under lockdown.
3 Stochastic epidemiological model
In this section we introduce the stochastic model which can be applied for modeling the spread of the virus SARS-CoV-2 after a calibration in the framework of the model constructed in [7].
We slightly modified the epidemic model presented in the previous section. First, a new compartment for vaccinated persons (V) is introduced. The proportion of the susceptible individuals who have received the vaccine is denoted by v and the proportion of vaccinated individuals who lose the immunity is v1. Besides, we separated a natural and disease induced death rate denoting δ the rate that infected population dies from disease. Also, we replaced the birth proportion ηN(t) in the deterministic model with parameter Λ which represents the expected number of new susceptible individuals, observed in appropriate units (e.g. per year, per million people, etc.) and assumed that recovered individuals eventually lose the immunity with rate r1. All model parameters are assumed to be non-negative.
The stochastic model is constructed by assuming that transmission coefficient β=(β(t),t≥0) satisfy mean-reverting Ornstain-Uhlenbeck stochastic process (for more details see [39]) given by the stochastic differential equation (SDE)(2) dβ(t)=θ(βe−β(t))dt+ξdB(t),t≥0,
where βe is the mean of the stationary Gaussian distribution with variance ξ/2θ. Parameter θ>0 determines the speed of the mean reversion, while ξ is the intensity of volatility and Brownian motion B=(B(t),t≥0) is the driving process.
Let us recall on non-stationary Ornstein-Uhlenbeck process. According to [18], the explicit solution of the SDE (2) has the following form:(3) β(t)=βe+(β(0)−βe)e−θt+ξ∫0te−θ(t−s)dBs.
The expected value of β(t) is given by(4) E[β(t)]=βe+(β(0)−βe)e−θt,
and its variance by(5) Var(β(t))=ξ22θ(1−e−2θt).
From the explicit solution (3), combined with the results regarding the expectation (4) and the varinace (5) of β(t), it follows that(6) ξ∫0te−θ(t−s)dBs∼N(0,ξ22θ(1−e−2θt)).
Therefore,ξ∫0te−θ(t−s)dBs=ξ2θ1−e−2θtdB(t)dta.s..
Now it follows that the explicit solution (3) can be written in the following form:(7) β(t)=βe+(β(0)−βe)e−θt+σ(t)dB(t)dt,a.s.,
whereσ(t)=ξ2θ1−e−2θt.
On the other hand, sudden and severe environmental perturbations, such as tsunami, volcanoes, toxic pollutants, etc, may affect epidemic models. In case of virus COVID 19, severe environmental shocks such as notable weather changes, gatherings of people in large numbers, economical crises and others, would lead to jumps in population size. Inspired by this, in this paper, we will use a Poisson process as the driven jump process. Let N¯ denotes the Poisson counting process with characteristic measure λ which is defined on a finite measurable subset Y of (0,∞) with λ(Y)<+∞. Let N˜ denotes the compensated random measure defined by N˜(dt,du)=N¯(dt,du)−λ(du)dt.
In addition to the assumptions already introduced, we assumed that newly infected individuals in the population doesn’t become infectious in the moment of contact with infected person but after a certain time τ that denotes incubation period.
By perturbing the transmission coefficient β with OU process and adding jump, the resulting stochastic model have the following form:(8) {dS(t)=(Λ−βe+(β(0)−βe)e−θtN(t)I(t−τ)S(t)−(μ+l+v)S(t)+l1L(t)+v1V(t)+r1R(t))dt−σ(t)N(t)I(t−τ)S(t)dB(t)−S(t−)I((t−τ)−)N(t−)∫Yη(u)N˜(dt,du),dL(t)=(lS(t)−(μ+l1)L(t))dt,dV(t)=(vS(t)−(μ+v1)V(t))dt,dI(t)=(βe+(β(0)−βe)e−θtN(t)I(t−τ)S(t)−(μ+α+ρi+δ)I(t))dt+σ(t)N(t)I(t−τ)S(t)dB(t)+S(t−)I((t−τ)−)N(t−)∫Yη(u)N˜(dt,du),dQ(t)=(αI(t)−(μ+ρq)Q(t))dt,dR(t)=(ρiI(t)+ρqQ(t)−(μ+r1)R(t))dt,
where S(t−),I((t−τ)−) and N(t−) are the left limits of S(t),I(t−τ) and N(t), respectively, and η:Y×Ω→R is bounded and continuous with respect to λ and is B(Y)×Ft-measurable, where B(Y) is a σ-algebra with respect to the set Y.
The total population size at time t is given byN(t)=S(t)+V(t)+L(t)+I(t)+Q(t)+R(t),t≥−τ.
Besides, environmental noise may cause a change in the intensity of the manifestation of various phenomena. This can be expressed as a switching between two or more subregimes. In mathematics, this transition from one state to another is often described by telegraph noise, also known as colored noise. Per example, in terms of weather forecast it can describe change from the rainy season to the dry season, and vice versa, in production changing the settings of machine parameters, etc. Particularly, since the spread of disease COVID-19 is unpredictable because of the movement of people in different geographical areas, by using telegraph noise we can describe local and weather changes, among other phenomena. The switching usually has memoryless property and the waiting time for the next switching follows an exponential distribution (see [40]). Hence the regime switching can be modeled by a continuous time finite-state Markov chain (a(t),t≥0) with values in a finite state space A={1,…,n}. In this paper, we will assume that all coefficients of the model are states of the Markov chain. Thus system (8) with regime switching can be denoted by(9) {dS(t)=(Λ(a(t))−βe(a(t))+(β(0)−βe(a(t)))e−θ(a(t))tN(t)I(t−τ)S(t)−(l(a(t))+v(a(t)))S(t)−μ(a(t))S(t)+l1(a(t))L(t)+v1(a(t))V(t)+r1(a(t))R(t))dt−σ(a(t),t)N(t)I(t−τ)S(t)dB(t)−S(t−)I((t−τ)−)N(t−)∫Yη(a(t),u)N˜(dt,du),dL(t)=(l(a(t))S(t)−(μ(a(t))+l1(a(t)))L(t))dt,dV(t)=(v(a(t))S(t)−(μ(a(t))+v1(a(t)))V(t))dt,dI(t)=(βe(a(t))+(β(0)−βe(a(t)))e−θ(a(t))tN(t)I(t−τ)S(t)−(α(a(t))+ρi(a(t)))I(t)−(μ(a(t))+δ(a(t)))I(t))dt+σ(a(t),t)N(t)I(t−τ)S(t)dB(t)+S(t−)I((t−τ)−)N(t−)∫Yη(a(t),u)N˜(dt,du),dQ(t)=(α(a(t))I(t)−(μ(a(t))+ρq(a(t)))Q(t))dt,dR(t)=(ρi(a(t))I(t)+ρq(a(t))Q(t)−(μ(a(t))+r1(a(t)))R(t))dt,
with initial value(10) S(ζ)=φ1(ζ)≥0,L(ζ)=φ2(ζ)≥0,V(ζ)=φ3(ζ)≥0,I(ζ)=φ4(ζ)≥0,Q(ζ)=φ5(ζ)≥0,R(ζ)=φ6(ζ)≥0,ζ∈[−τ,0],φi(0)>0,i∈{1,4},
where (φ1(ζ),φ2(ζ),φ3(ζ),φ4(ζ),φ5(ζ),φ6(ζ))∈L1([−τ,0],R+6) is the family of Lebesgue integrable functions mapping the interval [−τ,0] into R+6={(x1,…,x6)∈R6:xi>0,i=1,…,6}. All parameters of the model (9), Λ(k),βe(k),l(k),v(k),μ(k),l1(k),v1(k),r1(k),α(k),ρi(k),ρq(k),δ(k) are positive constants for each k∈A and have the same meanings previously defined. Also, we assumed that the speed of the mean reversion θ(k), the intensity of volatility ξ(k) and noise intensity η(k) are constants for each k∈A. Besides, through this paper, we will use notationsg^:=mink∈A{g(k)}andgˇ:=maxk∈A{g(k)},
for any vector g=(g(1),…,g(n)).
Obviously, system (8) is a special case of system (9) with one environmental regime. Therefore, existence and uniqueness of a positive global solution of system (8) follows from existence and uniqueness of a positive global solution of system (9).
According to the phenomena observed in nature, such as bee colonies, we introduce assumption that the self-regulating competitions within the same species are strictly positive, that is,Assumption 1 There exist a positive constant 0<h<1 such that for t≥−τ following holds:• |η(a(t),u)|≤hsup0≤s≤tμ(a(s))inf0≤s≤tΛ(a(s)),
• a(t)∈A.
In addition, let us denoteΓ={(S,L,V,I,Q,R)∈R+6:Λ^μˇ+δˇ≤S(t)+L(t)+V(t)+I(t)+Q(t)+R(t)≤Λˇμ^,t≥−τ}.
4 Preliminaries
In this section, we shall introduce some needed results which will be used in the following sections.
Throughout this paper, let (Ω,F,{Ft}t≥0,P) be a complete probability space with a natural filtration {Ft}t≥0, which is right continuous and such that F contains all P-null sets.
Let a(t),t≥0 be a right-continuous Markov chain with values in a finite state space A={1,…,n}. Throughout this paper, we assume that Brownian motion B(t), Markov chain a(t) and Poisson process N¯(t,ω) are mutually independent and defined on the same complete probability space (Ω,F,{Ft}t≥0,P).
Assume that the generator matrix Υ=(γij)nxn of the Markov chain is given byP{a(t+Δt)=j|a(t)=i}={γijΔ+o(Δ),i≠j,1+γiiΔ+o(Δ),i=j,
where Δt>0 and γij≥0 is the transition rate from i to j if i≠j, γii≤0 such that ∑i=1nγij=0. Furthermore, we assume that γij>0 for i≠j, so all stages are reachable with positive probabilities. Besides, we assume that the Markov chain a(·) is irreducible, which shows that it has a unique stationary distribution π=(π1,…,πn) which can be determined by the equationπΥ=01×n,
subject to∑i=1nπi=1,πi>0,i∈A.
For convenience, in first subsection of this section we recall some results on the stochastic differential equations and stochastic differential equations with regime switching and Lévy jumps, as we will need it in the sequel of the paper. For more details, we refer to [41] and [42].
4.1 Stochastic differential equations with regime switching and Lévy jumps
For t≥0 let (x(t),a(t)) be the diffusion process described by the following stochastic differential equations with regime switching and Lévy jumps(11) {dx(t)=b(x(t),a(t))dt+σ(x(t),a(t))dB(t)+∫YH(a(t),u)dN˜(dt,du),x(0)=x0,a(0)=a.
Processes B(·) and a(·) are the d-dimensional Brownian motion and the right continuous Markov chain in the above discussion, respectively, H(·,·) is defined on A×Y→R, and it is right continuous function and its left limit exists. Furthermore, drift and diffusion coefficients are such that b(·,·):R+n×A→R+n,σ(·,·):R+n×A→R+n×d and σ(x,k)σT(x,k)=:(dij(x,k)),i,j∈{1,2,…,n}.
For each k∈A, let V(x,k) be any twice continuously differentiable function with respect to x, the operator L of system (11) is defined by(12) LV(x,k)=∑i=1nbi(x,k)∂V(x,k)∂xi+12∑i=1ndij(x,k)∂2V(x,k)∂xi∂xj+∑i=1nγliV(x,k)+∫Y(V(x+H(k,u))−V(x)+VxH(k,u))λ(du).
By virtue of the generalized Itô’s formula - Theorem 1.16 in [42] (page 8), if x(t)∈Rn, then(13) dV(x(t),a(t))=LV(x(t),a(t))dt+Vx(x(t),a(t))σ(x(t),a(t))dB(t)+∫Y(V(x(t)+H(a(t),u))−V(x(t)))N˜(dt,du).
Following lemma will be useful in our analysis, see Theorem 3.4 in [39] (page 12).Lemma 1 (Strong law of large numbers) LetMt={Mt}t≥0be a real-valued continuous local martingale vanishing att=0. Thenlimt→∞〈M,M〉t=∞,a.s.⇒limt→∞Mt〈M,M〉t=0,a.s.
and alsolim supt→∞〈M,M〉tt<∞,a.s.⇒limt→∞Mtt=0,a.s.
5 Existence and uniqueness of a positive global solution
In this subsection, we will prove existence and uniqueness of a positive global solution of the system of stochastic differential equations (9).Theorem 1 For any initial value(S(ζ),L(ζ),V(ζ),I(ζ),Q(ζ),R(ζ),a(ζ))∈L1([−τ,0],Γ×A), there is a unique solution(S(t),L(t),V(t),I(t),Q(t),R(t),a(t)),t≥−τ, to the SDEs(9)and the solution will remain inΓ×Awith probability one. Moreover,(14) Λ^μˇ+δˇ≤N(t)≤Λˇμ^,t≥−τ.
Proof Having in mind that N(t)=S(t)+L(t)+V(t)+I(t)+Q(t)+R(t),t≥−τ, if we sum equations from system (9), we will get the following differential equations dN(t)=(Λ(a(t))−μ(a(t))N(t)−δ(a(t))I(t))dt.
From this we can easily conclude(Λ(a(t))−(μ(a(t))+δ(a(t)))N(t))dt≤dN(t)≤(Λ(a(t))−μ(a(t))N(t))dt⇔(μ(a(t))+δ(a(t)))(Λ^μˇ+δˇ−N(t))dt≤dN(t)≤μ(a(t))(Λˇμ^−N(t))dt.
It than follows thatd(Λ^μˇ+δˇ−N(t))+(μ(a(t))+δ(a(t)))(Λ^μˇ+δˇ−N(t))dt≤0,d(Λˇμ^−N(t))+μ(a(t))(Λˇμ^−N(t))dt≥0.
By integration from 0 to t we obtain(Λ^μˇ+δˇ−N(t))≤(Λ^μˇ+δˇ−N(0))e−∫0t(μ(a(s))+δ(a(s)))ds,(Λˇμ^−N(t))≥(Λˇμ^−N(0))e−∫0tμ(a(s))ds.
By the condition of the theorem, since Λ^μˇ+δˇ≤N(0)≤Λˇμ^, it follows thatΛ^μˇ+δˇ≤N(t)≤Λˇμ^,t∈[0,∞).
By this (14) is proved. □
Since the coefficients of system (9) satisfy the local Lipschitz condition, then for any initial value (S(ζ),L(ζ),V(ζ),I(ζ),Q(ζ),R(ζ),a(ζ))∈L1([−τ,0],Γ×A) there is a unique local solution on [−τ,τe], where τe is known in the literature as the explosion time (see Theorem 1.19 (page 10) in [42] and Theorem 3.1 (page 156) in [39]). To prove this solution is global, we need to prove that τe=∞ almost surely (a.s., for brevity). Let us choose k0≥0 sufficiently large such that S(ζ),L(ζ),V(ζ),I(ζ), Q(ζ) and R(ζ) for ζ∈[−τ,0], all lie within the interval [1k0,k0]. For each integer k≥k0, define the stopping time as followsτk=inf{t∈[−τ,τe):min{S(t),L(t),V(t),I(t),Q(t),R(t)}≤1kor
max{S(t),L(t),V(t),I(t),Q(t),R(t)}≥k}.
It is easy to see that τk is increasing as k→∞. Note that inf∅=∞, where ∅ denotes the empty set. Let us define τ∞=limk→∞τk. Then, τ∞≤τe a.s. If we prove that τ∞=∞ a.s., then τe=∞ which means that (S(t),L(t),V(t),I(t),Q(t),R(t),a(t))∈Γ×A, a.s. for all t≥−τ. If this assertion is not true, then there exists a pair of constants T>0 and ϵ∈(0,1) such that P{τ∞≤T}>ϵ. Thus there is an integer k1≥k0 such thatP{τ∞≤T}≥ϵ
for all k≥k1.
Let us define a C2-function F:R+6→R+∪{0} in the following way:(15) F(t)=F(S(t),L(t),V(t),I(t),Q(t),R(t))=(S(t)−a1−a1lnS(t))+(L(t)−1−lnL(t))+(V(t)−1−lnV(t))+(I(t)−1−lnI(t))+(Q(t)−1−lnQ(t))+(R(t)−1−lnR(t))+a2∫t−τtI(s)ds+a3∫t−τtI2(s)ds,
where a1,a2 and a3 are positive constants to be determined. Obviously, u−1−lnu≥0 for any u>0 which implies the non-negativity of function F.
Let k≥k0 and T>0 be arbitrary. Applying generalized Itô’s formula (13), it follows that(16) dF(t)=LF(t)dt−σ(a(t),t)N(t)I(t−τ)(a1−S(t)I(t))dB(t)−∫Y(ln(1+S(t−)N(t−)I((t−τ)−)I(t)η(a(t),u))+a1ln(1−I((t−τ)−)η(a(t),u)N(t−)))N˜(dt,du)
where(17) LF(t)=(Λ(a(t))−βe(a(t))+(β(0)−βe(a(t)))e−θ(a(t))tN(t)I(t−τ)S(t)−μ(a(t))S(t))(1−a1S(t))+(l1(a(t))L(t)−(l(a(t))+v(a(t)))S(t)+v1(a(t))V(t)+r1(a(t))R(t))(1−a1S(t))−a1∫YI((t−τ)−)N(t−)η(a(t),u)+ln(1−I((t−τ)−)N(t−)η(a(t),u))λ(du)+(l(a(t))S(t)−(μ(a(t))+l1(a(t)))L(t))(1−1L(t))+(v(a(t))S(t)−(μ(a(t))+v1(a(t)))V(t))(1−1V(t))+βe(a(t))+(β(0)−βe(a(t)))e−θ(a(t))tN(t)I(t−τ)S(t)(1−1I(t))−(μ(a(t))+α(a(t))+ρi(a(t))+δ(a(t)))I(t)(1−1I(t))+∫Y(S(t−)N(t−)I((t−τ)−)I(t)η(a(t),u)−ln(1+S(t−)N(t−)I((t−τ)−)I(t)η(a(t),u)))λ(du)+(α(a(t))I(t)−(μ(a(t))+ρq(a(t)))Q(t))(1−1Q(t))+(ρi(a(t))I(t)+ρq(a(t))Q(t)−(μ(a(t))+r1(a(t)))R(t))(1−1R(t))+a2(I(t)−I(t−τ))+a3(I2(t)−I2(t−τ))+12σ2(a(t),t)N2(t)I2(t−τ)S2(t)a1S2(t)+12σ2(a(t),t)N2(t)I2(t−τ)S2(t)1I2(t)≤K1+(a2−δ^)I(t)−(a2−a1max{βeˇ,β(0)})I(t−τ)+(12ξˇ22θ^(a1+1)−a3)I2(t−τ)+a3I2(t)−a1Y1+Y2≤K1+a3Λˇ2μ^2−a1Y1+Y2,
and we chose a1=δ^max{βeˇ,β(0)},a2=δ^,a3=12ξˇ22θ^(δ^max{βeˇ,β(0)}+1) and denotedY1=∫Y(I((t−τ)−)N(t−)η(a(t),u)+ln(1−I((t−τ)−)N(t−)η(a(t),u)))λ(du)
andY2=∫Y(S(t−)N(t−)I((t−τ)−)I(t)η(a(t),u)−ln(1+S(t−)N(t−)I((t−τ)−)I(t)η(a(t),u)))λ(du).
Bearing in mind Assumption (1) and applying the Taylor formula to function ln(1−x) (where x=I(t−τ−)N(t−)η(a(t),u)), we obtain(18) Y1=∫Y(I((t−τ)−)N(t−)η(a(t),u)+ln(1−I((t−τ)−)N(t−)η(a(t),u)))λ(du)=∫Y(I((t−τ)−)N(t−)η(a(t),u)+(I((t−τ)−)N(t−)η(a(t),u))22(1−κ(I((t−τ)−)N(t−)η(a(t),u)))2−I((t−τ)−)N(t−)η(a(t),u))λ(du)≤∫Y(I((t−τ)−)N(t−)η(a(t),u))22(1−κ(I((t−τ)−)N(t−)η(a(t),u)))2λ(du)≤(I((t−τ)−)N(t−)η(a(t),u))22(1−κ(I((t−τ)−)N(t−)η(a(t),u)))2≤h22(1−h)2
where κ∈(0,1) is an arbitrary number. Similarly, we can obtain that(19) Y2=∫Y(S(t−)N(t−)I((t−τ)−)I(t)η(a(t),u)−ln(1+S(t−)N(t−)I((t−τ)−)I(t)η(a(t),u)))λ(du)≤∫Y(S(t−)N(t−)I((t−τ)−)I(t)η(a(t),u))22(1−κ(S(t−)N(t−)I((t−τ)−)I(t)η(a(t),u)))2λ(du)≤(S(t−)N(t−)I((t−τ)−)I(t)η(a(t),u))22(1−κ(S(t−)N(t−)I((t−τ)−)I(t)η(a(t),u)))2≤h22(1−h)2.
Then,LF(t)≤K1+a3Λˇ2μ^2+(1+a1)h22(1−h)2=:C,
Therefore, we havedF(t)≤Cdt−σ(a(t),t)N(t)I(t−τ)(a1−S(t)I(t))dB(t)−∫Y(ln(1+S(t−)N(t−)I((t−τ)−)I(t)η(a(t),u))+a1ln(1−I((t−τ)−)N(t−)η(a(t),u)))N˜(dt,du).
Integrating the last equation from 0 to τk∧T and then taking the expectation on both sides, we haveEF(τk∧T)≤F(0)+CE(τk∧T)≤F(0)+CT.
Set Ωk={τk≤T}. Then we obtain P(Ωk)≥ϵ. Note that for every ω∈Ωk, at least one of S(τk,ω), L(τk,ω), V(τk,ω), I(τk,ω), Q(τk,ω) or R(τk,ω) equals either k or 1k. Hence F(S(τk,ω),L(τk,ω), V(τk,ω),I(τk,ω),Q(τk,ω),R(τk,ω)) is no less than either k−1−lnk or 1k−1−ln1k. Consequently, we haveF(τk∧T)≥min{k−1−lnk,1k−1−ln1k}.
ThereforeF(0)+CT≥E[IΩkF(τk∧T)]≥ϵmin{k−1−lnk,1k−1−ln1k}.
where IΩk is the indicator function of Ωk. Letting k→∞, we have∞>F(0)+CT=∞,
which is in contradiction. So we conclude that τ∞=∞ a.s., which completes the proof. ▵ Remark 5.1 Note that the setΓ={(S,L,V,I,Q,R)∈R+6:Λ^μˇ+δˇ≤S(t)+L(t)+V(t)+I(t)+Q(t)+R(t)≤Λˇμ^}
is almost surely positive invariant of system (9) for every t≥−τ, i.e. if the system starts from Γ, it never leaves Γ. Therefore, in this paper we always assume that the initial value(S(ζ),L(ζ),V(ζ),I(ζ),Q(ζ),R(ζ),a(ζ))∈Γ×A,ζ∈[−τ,0].
6 Extinction
Analyzing the dynamical behavior of epidemics, one of the goal is to identify the conditions under which the epidemic will disappear or persist in the population. In this section, we will establish sufficient conditions for the extinction of the disease.
Let us introduce notationσ¯(k):=ξ(k)2θ(k),k∈A.
Then, σ(k,t)=σ¯(k)1−e−2θ(k)t,k∈A,t≥0. Obviously, it is satisfied σ(k,t)≤σ¯(k),k∈A,t≥0. Let σˇ=maxσ¯(k) and σ^=minσ¯(k),k∈A.
Furthermore, let us denote〈x(t)〉:=1t∫0tx(s)ds,t≥0.
Theorem 2 Let the Assumption (1) holds and let(S(t),L(t),V(t),I(t),Q(t),R(t),a(t)),t≥−τbe the solution of the system(9)with any initial value(S(ζ),L(ζ),V(ζ),I(ζ),Q(ζ),R(ζ),a(ζ))∈L1([−τ,0],Γ×A). If at least one of following conditions is satisfied:
1.(20) σ¯2(k)≤max{βe(k),β0}μ(k)Λ(k)foranyk∈AandR1*=θˇβˇeΛˇμ^+max{βˇe,β0}Λˇμ^−σ^2c22Λˇ2μ^2μ^+α^+ρ^i+δ^<1,
2.(21) R2*=(βˇeθˇ+max{βˇe,β0})Λˇμ^+δ^−σ^2c22μ^4Λˇ4(μ^+α^+ρ^i+δ^)<1,
wherecis the constant such thatc=1−e−2θ^zandz>0is the first moment observed, thenlimt→∞I(t)=0,a.s.,
i.e, the disease will go to extinction.
In addition, we havelimt→∞Q(t)=0,limt→∞R(t)=0,a.s.
andΛ^μˇ+δˇ≤limt→∞[S(t)+L(t)+V(t)]≤Λˇμ^,a.s.
Proof 1. Applying generalized Itô’s formula (13) on function lnI(t), it follows that(22) dlnI(t)=(−θ(k)(β0−βe(k))e−θ(k)tI(t−τ)S(t)N(t)−(μ(k)+α(k)+ρi(k)+δ(k))+(βe(k)+(β0−βe(k))e−θ(k)t)I(t−τ)S(t)I(t)N(t)−σ2(k,t)2I2(t−τ)S2(t)I2(t)N2(t))dt+∫Y(ln(1+η(k)I((t−τ)−)S(t−)I(t)N(t−))−η(k)I((t−τ)−)S(t−)I(t)N(t−))λ(du)+σ(k,t)I(t−τ)S(t)I(t)N(t)dB(t)+∫Y(ln(1+η(k)I((t−τ)−)S(t−)I(t)N(t−)))N˜(ds,du)≤(θˇβˇeΛˇμ^+max{βˇe,β0}Λˇμ^−(μ^+α^+ρ^i+δ^)−σ^2c22Λˇ2μ^2)dt+σ(k,t)I(t−τ)S(t)I(t)N(t)dB(t)+∫Y(ln(1+η(k)I((t−τ)−)S(t−)I(t)N(t−)))N˜(ds,du)≤(μ^+α^+ρ^i+δ^)(R1*−1)dt+σ(k,t)I(t−τ)S(t)I(t)N(t)dB(t)+∫Y(ln(1+η(k)I((t−τ)−)S(t−)I(t)N(t−)))N˜(ds,du),
where we used that S(t)N(t)≤1, S(t),L(t),V(t),I(t),Q(t),R(t)≤N(t)≤Λˇμ^, inequality ln(1+x)−x≤0, σ(k,t)≥σ^c and the fact that function f(x)=βx−σ22x2 is increasing on (0,βσ2), and denotedR1*=θˇβˇeΛˇμ^+max{βˇe,β0}Λˇμ^−σ^2c22Λˇ2μ^2μ^+α^+ρ^i+δ^.
Integrating the both sides of equation (22) from 0 to t and dividing with t, we obtain(23) lnI(t)−lnI(0)t=1t∫0t(μ^+α^+ρ^i+δ^)(R1*−1)dt+1tM1+1tM2,
where(24) M1=∫0tσ(k,s)I(s−τ)S(s)I(s)N(s)dB(s)
and(25) M2=∫0t∫Y(ln(1+η(k)I((s−τ)−)S(s−)I(s)N(s−)))N˜(ds,du).
According to Lemma (1), using the boundedness of σ(k,s),I(s),S(s) and N(s),s≥0 and Assumption (1) we getM1t→0andM2t→0,a.s.,ast→∞.
Taking the superior limit on the both sides of expression (23), we obtain(26) lim supt→∞lnI(t)t≤(μ^+α^+ρ^i+δ^)(θˇβˇeΛˇμ^+max{βˇe,β0}Λˇμ^−σ^2c22Λˇ2μ^2μ^+α^+ρ^i+δ^−1)<0,a.s.,
by the condition (20). Then,(27) limt→∞I(t)=0,a.s.
Furthermore, we have that(28) limt→∞Q(t)=0,limt→∞R(t)=0,a.s.
when I goes to zero. □
Having in mind that N(t)=S(t)+L(t)+V(t)+I(t)+Q(t)+R(t), Λ^μˇ+δˇ≤N(t)≤Λˇμ^,t≥−τ, and previously obtained relations (27) and (28), we getΛ^μˇ+δˇ≤limt→∞[S(t)+L(t)+V(t)]≤Λˇμ^,a.s.
This completes the first part of the proof.
2. Making use of the generalized Itô’s formula to lnI(t) gives(29) dlnI(t)=(−θ(k)(β0−βe(k))e−θ(k)tI(t−τ)S(t)N(t)−(μ(k)+α(k)+ρi(k)+δ(k))+(βe(k)+(β0−βe(k))e−θ(k)t)I(t−τ)S(t)I(t)N(t)−σ2(k,t)2I2(t−τ)S2(t)I2(t)N2(t))dt+∫Y(ln(1+η(k)I((t−τ)−)S(t−)I(t)N(t−))−η(k)I((t−τ)−)S(t−)I(t)N(t−))λ(du)+σ(k,t)I(t−τ)S(t)I(t)N(t)dB(t)+∫Y(ln(1+η(k)I((t−τ)−)S(t−)I(t)N(t−)))N˜(ds,du)
Integrating the both sides of the previous equation from 0 to t and dividing with t, by a similar consideration as in the first part we obtain(30) lnI(t)−lnI(0)t≤βˇeθˇ〈I(t−τ)〉+max{βˇe,β0}〈I(t−τ)〉−σ^2c22μ^4Λˇ4−(μ^+α^+ρ^i+δ^)+1tM1+1tM2≤(μ^+α^+ρ^i+δ^)(R2*−1)+1tM1+1tM2
whereR2*=(βˇeθˇ+max{βˇe,β0})Λˇμ^+δ^−σ^2c22μ^4Λˇ4(μ^+α^+ρ^i+δ^),
and M1 and M2 are defined with (24) and (25). According to the consideration in the first part, it is satisfiedM1t→0andM2t→0,a.s.,ast→∞.
Taking the superior limit on the both sides of expression (30), we obtain(31) lim supt→∞lnI(t)t≤(μ^+α^+ρ^i+δ^)((βˇeθˇ+max{βˇe,β0})Λˇμ^+δ^−σ^2c22μ^4Λˇ4(μ^+α^+ρ^i+δ^)−1)<0,a.s.,
by the condition (21). Then,limt→∞I(t)=0,a.s.
Furthermore, repeating the same consideration as in the first part of the proof we have thatlimt→∞Q(t)=0,limt→∞R(t)=0,a.s.
andΛ^μˇ+δˇ≤limt→∞[S(t)+L(t)+V(t)]≤Λˇμ^,a.s.
This completes the second part of the proof. ▵ Remark 6.1 Since lockdown represents a measure of control and suppression of disease whose introduction is decided by the state government depending on the current number of infected individuals, in the case of the extinction of the disease, the lockdown will be abolished. Thus, as a consequence of disease extinction, starting from some point, the coefficients that determine the lockdown will become zero, that is l=0.
Having in mind Remark (6.1), we can formulate the following corollary.Corollary 1 Let the Assumption (1) holds and let(S(t),L(t),V(t),I(t),Q(t),R(t),a(t)),t≥−τbe the solution of the system(9)with any initial value(S(ζ),L(ζ),V(ζ),I(ζ),Q(ζ),R(ζ),a(ζ))∈L1([−τ,0],Γ×A). Let at least one of the conditions of Theorem (2) be satisfied. Ifl(a(t))=0,t≥t1, for somet1≥0, then the solution of system(9)has the propertylimt→∞I(t)=0,limt→∞L(t)=0,limt→∞Q(t)=0,limt→∞R(t)=0,a.s.
andΛ^μˇ+δˇ≤limt→∞[S(t)+V(t)]≤Λˇμ^,a.s.
Proof Solving the second equation of system (9) explicitly, we getL(t)=e−(μ(a(t))+l1(a(t)))t[L(0)+∫0tl(a(t))S(s)e(μ(a(t))+l1(a(t)))sds].
Since l(a(t))=0,t≥t1, we obtainlimt→∞L(t)=0,a.s.
and consequentlyΛ^μˇ+δˇ≤limt→∞[S(t)+V(t)]≤Λˇμ^,a.s.
This completes the proof. ▵ □
7 Persistence in mean
In this section, we will establish sufficient conditions for the strong persistence in mean of the disease.Definition 1 System (9) is said to be strong persistent in mean iflim inft→∞〈I(t)〉=lim inft→∞1t∫0tI(s)ds>0,a.s.
Theorem 3 Let the Assumption (1) holds and let(S(t),L(t),V(t),I(t),Q(t),R(t),a(t)),t≥−τbe the solution of system(9)with any initial value(S(ζ),L(ζ),V(ζ),I(ζ),Q(ζ),R(ζ),a(ζ))∈L1([−τ,0],Γ×A). If
1.R0S=∑k=1nπ(k)(min{β(0),βe(k)}μ(k)Λ(k))∑k=1nπ(k)(μ(k)+α(k)+ρi(k)+δ(k)+σ¯2(k)2Λ2(k)μ2(k)+∫Y12η2(k,u)Λˇ2μ^2λ(du))>1,
thenlim inft→∞1t∫0tI(s)ds≥∑k=1nπ(k)(μ(k)+α(k)+ρi(k)+δ(k)+σ¯2(k)2Λ2(k)μ2(k)+∫Y12η2(k,u)Λˇ2μ^2λ(du))(R0S−1)θˇβ(0)+max{β(0),βˇe}>0,a.s,
lim inft→∞1t∫0tQ(s)ds≥α^∑k=1nπ(k)(μ(k)+α(k)+ρi(k)+δ(k)+σ¯2(k)2Λ2(k)μ2(k)+∫Y12η2(k,u)Λˇ2μ^2λ(du))(R0S−1)(μˇ+ρqˇ)(θˇβ(0)+max{β(0),βˇe})>0,a.s,
lim inft→∞1t∫0tR(s)ds≥(ρi^+ρq^α^μˇ+ρqˇ)∑k=1nπ(k)(μ(k)+α(k)+ρi(k)+δ(k)+σ¯2(k)2Λ2(k)μ2(k)+∫Y12η2(k,u)Λˇ2μ^2λ(du))(R0S−1)(μˇ+r1ˇ)(θˇβ(0)+max{β(0),βˇe})>0,a.s,
2.R0S*=min{β(0),β^e}μ^Λˇμˇ+αˇ+ρˇi+δˇ+σˇ22Λˇ2μ^2+∫Y12ηˇ2(u)Λˇ2μ^2λ(du)>1,
thenlim inft→∞1t∫0tI(s)ds≥(μˇ+αˇ+ρˇi+δˇ+σˇ22Λˇ2μ^2+∫Y12ηˇ2(u)Λˇ2μ^2λ(du))(R0S*−1)θˇβ(0)+max{β(0),βˇe}>0,a.s,
lim inft→∞1t∫0tQ(s)ds≥α^(μˇ+αˇ+ρˇi+δˇ+σˇ22Λˇ2μ^2+∫Y12ηˇ2(u)Λˇ2μ^2λ(du))(R0S*−1)(μˇ+ρqˇ)(θˇβ(0)+max{β(0),βˇe})>0,a.s.,
lim inft→∞1t∫0tR(s)ds≥(ρi^+ρq^α^μˇ+ρqˇ)(μˇ+αˇ+ρˇi+δˇ+σˇ22Λˇ2μ^2+∫Y12ηˇ2(u)Λˇ2μ^2λ(du))(R0S*−1)(μˇ+r1ˇ)(θˇβ(0)+max{β(0),βˇe})>0,a.s.,
that is, the disease is strong persistent in mean.
Proof 1. The proof of the first part of theorem is derived following the idea from [21]. Applying the generalized Ito’s formula to the function −lnI(t), we obtain that(32) L(−lnI(t))=(θ(k)(β(0)−βe(k))e−θ(k)tI(t−τ)S(t)N(t)−(βe(k)+(β(0)−βe(k))e−θ(k)t)I(t−τ)(N(t)−L(t)−V(t)−I(t)−Q(t)−R(t))I(t)N(t)+μ(k)+α(k)+ρi(k)+δ(k)+σ2(t,k)2I2(t−τ)S2(t)I2(t)N2(t))dt+∫Y(−ln(1+η(k,u)I((t−τ)−)S(t−)I(t)N(t−))+η(k,u)I((t−τ)−)S(t−)I(t)N(t−))λ(du)≤(θ(k)β(0)e−θ(k)tI(t−τ)S(t)N(t)−(βe(k)+(β(0)−βe(k))e−θ(k)t)I(t−τ)I(t)+(βe(k)+(β(0)−βe(k))e−θ(k)t)I(t−τ)I(t)+μ(k)+α(k)+ρi(k)+δ(k)+σ2(t,k)2I2(t−τ)I2(t))dt+∫Y12(η(k,u)I((t−τ)−)S(t−)I(t)N(t−))2λ(du)≤((θˇβ(0)+max{β(0),βˇe})I(t−τ)−min{β(0),βe(k)}μ(k)Λ(k)+μ(k)+α(k)+ρi(k)+δ(k)+σ¯2(k)2Λ2(k)μ2(k))dt+∫Y12η2(k,u)Λˇ2μ^2λ(du).
where we applied Taylor formula to the function ln(1+x).
Let us define a Lyapunov function U:Γ×A⇒R as follows:U(S,L,V,I,Q,R,k)=−lnI(t)+(θˇβ(0)+max{β(0),βˇe})∫t−τtI(s)ds+ω(k).
where ω(k)=(ω(1),…,ω(n))T(k),k∈A will be determined in the sequel. Applying the generalized Itô’s formula to U leads to(33) LU(S,L,V,I,Q,R,k)=L(−lnI(t))+(θˇβ(0)+max{β(0),βˇe})∫t−τtI(s)ds−∑j=1nγijω(j)≤((θˇβ(0)+max{β(0),βˇe})I(t−τ)−min{β(0),βe(k)}μ(k)Λ(k)+μ(k)+α(k)+ρi(k)+δ(k)+σ¯2(k)2Λ2(k)μ2(k))+∫Y12η2(k,u)Λˇ2μ^2λ(du)+(θˇβ(0)+max{β(0),βˇe})(I(t)−I(t−τ))−∑j=1nγijω(j)≤−R*(k)+(θˇβ(0)+max{β(0),βˇe})I(t)−∑j=1nγijω(j),
where R*(k)=min{β(0),βe(k)}μ(k)Λ(k)−(μ(k)+α(k)+ρi(k)+δ(k)+σ¯2(k)2Λ2(k)μ2(k))−∫Y12η2(k,u)Λˇ2μ^2λ(du). Since the generator matrix Υ is irreducible, hence for R*=(R*(1),⋯,R*(n))T, there exists ω=(ω(1),⋯,ω(n))T satisfying the following Poisson systemΥω=∑i=1nπ(i)R*(i)(1,1,⋯,1)T−R*,
which implies that−∑j=1nγ(kj)ω(j)−R*(k)=−∑j=1nπ(j)R*(j),k∈{1,2,…,n}.
Substituting this equality into (33), we getLU(S,L,V,I,Q,R,k)≤−∑k=1nπ(k)R*(k)+(θˇβ(0)+max{β(0),βˇe})I(t)≤−∑k=1nπ(k)(min{β(0),βe(k)}μ(k)Λ(k)−μ(k)−α(k)−ρi(k)−δ(k)−σ¯2(k)2Λ2(k)μ2(k)−∫Y12η2(k,u)Λˇ2μ^2λ(du))+(θˇβ(0)+max{β(0),βˇe})I(t)=−∑k=1nπ(k)(μ(k)+α(k)+ρi(k)+δ(k)+σ¯2(k)2Λ2(k)μ2(k)+∫Y12η2(k,u)Λˇ2μ^2λ(du))(R0S−1)+(θˇβ(0)+max{β(0),βˇe})I(t)
where R0S=∑k=1nπ(k)(min{β(0),βe(k)}μ(k)Λ(k))∑k=1nπ(k)(μ(k)+α(k)+ρi(k)+δ(k)+σ¯2(k)2Λ2(k)μ2(k)+∫Y12η2(k)Λˇ2μ^2λ(du)). □
An integration of the above equality from 0 to t and then dividing by t on both sides give(34) U(t)−U(0)t≤−1t∑k=1nπ(k)(μ(k)+α(k)+ρi(k)+δ(k)+σ¯2(k)2Λ2(k)μ2(k)+∫Y12η2(k,u)Λˇ2μ^2λ(du))(R0S−1)+(θˇβ(0)+max{β(0),βˇe})〈I(t)〉−1t∫0tσ(k,s)I(s−τ)S(s)I(s)N(s)dB(s)−1t∫0t∫Y(ln(1+η(k,u)I((s−τ)−)S(s−)I(s)N(s−)))N˜(ds,du)
According to Lemma (1), using the boundedness of σ(k,t),I(t),S(t) and N(t) for t≥0, for k∈A and under Assumption (1) we get1t∫0tσ(k,s)I(s−τ)S(s)I(s)N(s)dB(s)→0
and1t∫0t∫Y(ln(1+η(k,u)I((s−τ)−)S(s−)I(s)N(s−)))N˜(ds,du)→0,a.s.,ast→∞.
Since Λ^μˇ+δˇ≤S(t)+L(t)+V(t)+I(t)+Q(t)+R(t)≤Λˇμ^, t≥−τ, we getU(S,L,V,I,Q,R,k)=−lnI(t)+(θˇβ(0)+max{β(0),βˇe})∫t−τtI(s)ds−ω(k)≥−lnΛˇμ^−ωˇ:=M>−∞.
Taking the inferior limit on the both sides of relation (34) and using the previous relation, we have(35) lim inft→∞1t∫0tI(s)ds≥∑k=1nπ(k)(μ(k)+α(k)+ρi(k)+δ(k)+σ¯2(k)2Λ2(k)μ2(k)+∫Y12η2(k)Λˇ2μ^2λ(du))(R0S−1)θˇβ(0)+max{β(0),βˇe},a.s.
Therefore, by the condition R0S>1, we can easily obtain that required assertionlim inft→∞1t∫0tI(s)ds>0a.s.
On the other hand, by integrating the fifth equation of system (9) and then dividing by t on both sides, one can obtain thatQ(t)−Q(0)t=1t∫0tα(k)I(s)ds−1t∫0t(μ(k)+ρq(k))Q(s)ds
Taking the inferior limit on the both sides of previous equality and combining with (35) and the boundedness of Q(t),Q(0), we get(36) lim inft→∞1t∫0tQ(s)ds≥lim inft→∞1(μˇ+ρqˇ)t∫0t(μ(k)+ρq(k))Q(s)ds=lim inft→∞1(μˇ+ρqˇ)t∫0tα(k)I(s)ds≥α^(μˇ+ρqˇ)tlim inft→∞∫0tI(s)ds≥α^∑k=1nπ(k)(μ(k)+α(k)+ρi(k)+δ(k)+σ¯2(k)2Λ2(k)μ2(k)+∫Y12η2(k)Λˇ2μ^2λ(du))(R0S−1)(μˇ+ρqˇ)(θˇβ(0)+max{β(0),βˇe})>0,a.s.
Similarly, when the populations I and Q are persistent in the mean a.s., then the population R will be also persistent in the mean a.s. Indeed, by integrating the sixth equation of system (9) and then dividing by t on both sides, one can obtain thatR(t)−R(0)t=1t∫0tρi(k)I(s)ds+1t∫0tρq(k)Q(s)ds−1t∫0t(μ(k)+r1(k))R(s)ds.
Taking the inferior limit on the both sides of previous equality and combining with (35) and (36) and the boundedness of R(t),R(0), we getlim inft→∞1t∫0tR(s)ds≥lim inft→∞1(μˇ+r1ˇ)t∫0t(μ(k)+r1(k))R(s)ds≥1(μˇ+r1ˇ)t(ρi^lim inft→∞∫0tI(s)ds+ρq^lim inft→∞∫0tQ(s)ds)≥(ρi^+ρq^α^μˇ+ρqˇ)∑k=1nπ(k)(μ(k)+α(k)+ρi(k)+δ(k)+σ¯2(k)2Λ2(k)μ2(k)+∫Y12η2(k)Λˇ2μ^2λ(du))(R0S−1)(μˇ+r1ˇ)(θˇβ(0)+max{β(0),βˇe})>0,
a.s. which completes the proof.
2. The proof of the second part of theorem is similar to the proof of the first part so is omitted. ▵ Remark 7.1 From Theorem (3), we obtain that if R0S>1, then the solution (S(t),L(t),V(t),I(t), Q(t),R(t),a(t)),t≥−τ of system (9) with any initial value (S(ζ),L(ζ),V(ζ),I(ζ),Q(ζ),R(ζ),a(ζ))∈L1([−τ,0],Γ×A) is persistent in the mean. Moreover, sincelim supt→∞1t∫0tI(s)ds≤Λˇμ^,lim supt→∞1t∫0tQ(s)ds≤Λˇμ^,lim supt→∞1t∫0tR(s)ds≤Λˇμ^,a.s,
along with the results of Theorem (3), we can conclude that the system (9) is stochastic permanent.
8 Numerical simulations
In this section, we give some numerical simulations in order to illustrate the results of Theorems (2) and (3). Complex dynamic of the spread of the disease is described by SDE model (9) and its trajectories, as well as the trajectories of its deterministic counterpart are illustrated via graphics. All simulations were done assuming daily scale and population size given in millions.
In the Table 1 are given realistic parameters space values for the spread of the SARS-CoV-2 virus and their appropriate units, taken from the prior studies where they were estimated using different statistical methods, derived on the basis of World Health Organization data or rationally assumed.Table 1 Parameters space involved in the SARS-Cov-2 stochastic model
Table 1Symbol Description Range Units References
Λ Recruitment rate (0,∞) day−1 [1]
β Transmission coefficient (0.2,1.5) day−1 [43], [44], [45], [46], [47]
θ speed of the mean reversion (0,∞) day−1 assumed
l movement from susceptible to lockdown (0,1) day−1 assumed
l1 movement from lockdown to susceptible (0,1) day−1 assumed
v movement from susceptible to vaccinated (0,0.24) day−1 [1]
v1 movement from vaccinated to susceptible (1/1825,1/90) day−1 [1], assumed
r1 movement from recovered to susceptible (1/1825,1/90) day−1 [1], assumed
α movement from infected to quarantined (0,1) day−1 assumed
ρi Recovery rate for infected population (1/30,1/3) day−1 [43], [44], [47], [48], [49], [50]
ρq Recovery rate for quarantined population (1/30,1/3) day−1 [43], [44], [47], [48], [49], [50]
δ Disease induced death rate (0.0001,0.1) day−1 [1], [43], [47]
μ Natural death rate (0.033,0.77) day−1 [1]
τ Incubation period (2,14) day [1], [46],[47], [51], [52], [53]
The results proven in Theorems (2) and (3) are illustrated for starting values given in Table 2 . We focus on the transmission rate βe of model (9) supposing that is disturbed by a random switching because in reality it is more sensitive to environmental fluctuations than other parameters. In simulations, we assumed that all model parameters except transmission coefficient have the same values in all subregimes, which are given in Table 2.Table 2 Parameter and starting values taken in extinction and persistence simulation
Table 2 Λ θ μ l l1 v v1 r1 α ρi ρq δ
Extinction 0.05 0.01 0.045 0.8 0.015 0.007 0.005 0.55 0.025 0.025 0.005
Persistence 0.05 0.01 0.05 0.02 0.8 0.015 0.011 0.011 0.3 0.03 0.03 0.0005
S(0) L(0) V(0) I(0) Q(0) R(0) β(0) c
Extinction 0.7 0.025 0.05 0.1 0.07 0.055 0.48 0.0002
Persistence 1 0.0002 0.2 0.003 0.001 0.3 0.7 -
In Figure 1 we illustrate the extinction result proved in Theorem (2) with model parameters and initial conditions given in table 2. Here we assumed that a(t) is a right-continuous Markov chain taking values in a finite state space A={1,2,3,4,5} with the generatorΥ=[−440000−330000−330000−444000−4]
Fig. 1 Extinction of disease - Deterministic (blue) and stochastic (red) trajectories of epidemic models.
Fig. 1
We assumed that transmission rate βe, coefficient l and noises intensities are switching between five regimes as follows:1. βe(1)=0.4,σ¯(1)=0.1,η(1)=0.2,l(1)=0.8
2. βe(2)=0.5,σ¯(2)=0.25,η(2)=0.45,l(2)=0.1
3. βe(3)=0.5,σ¯(3)=0.25,η(3)=0.2,l(3)=0.08
4. βe(4)=0.45,σ¯(4)=0.15,η(4)=0.25,l(4)=0.04
5. βe(5)=0.45,σ¯(5)=0.2,η(5)=0.15,l(5)=0.
Such a choice of model parameters satisfies the second condition of Theorem (2). Thus, from the results in the Theorem (2), we can conclude that the disease will die out with probability one. From the numerical simulation results in Figure 1, we can see that the stochastic paths fluctuate around deterministic paths and solution I(t) of the SDE model (9) goes to extinction (and consequently Q(t) and R(t) also go to extinction).
In Figure 2 we illustrated persistence result proved in Theorem (3) with the model parameters and initial conditions given in table 2. As in first example, we assumed that a(t) is a right-continuous Markov chain taking values in a finite state space A={1,2,3,4,5} with the generatorΥ=[−220000−330000−330000−443000−3]
We assumed that transmission rate βe and noises intensities are switching between five regimes as follows:1. βe(1)=0.75,σ¯(1)=0.3,η(1)=0.1,
2. βe(2)=0.9,σ¯(2)=0.2,η(2)=0.05,
3. βe(3)=0.5,σ¯(3)=0.15,η(3)=0.025,
4. βe(4)=0.68,σ¯(4)=0.12,η(4)=0.03,
5. βe(5)=0.8,σ¯(5)=0.1,η(5)=0.01.
Fig. 2 Persistence of disease - Deterministic (blue) and stochastic (red) trajectories of epidemic models.
Fig. 2
Such a choice of model parameters satisfies the first condition of Theorem (3). According to Theorem (3), the system (9) is strong persistent in mean, which is confirmed by the numerical results shown in Figure 2. The figure illustrates that the stochastic trajectories fluctuated slightly around deterministic ones and that the disease persists.
9 Conclusion
In this paper, we introduced a stochastic delayed SLVIQR epidemic model (9) which can be applied for modeling the spread of the new strain coronavirus COVID-19 after a calibration. We incorporated environmental fluctuations in the transmission rate assuming that transmission rate satisfied the mean-reverting Ornstain-Uhlenbeck process. Besides a standard Brownian motion, another two driving processes are considered: a stationary Poisson point process and a continuous finite-state Markov chain. We proved the existence of the global positive solution of the stochastic epidemic model and established some sufficient conditions for extinction and persistence in the mean of the disease. It has been proved that the disease dies out if the coefficient R1*<1 for small values of the white noise intensity or if R2*<1. On the other hand, if R0S>1 or R0S*>1, the disease persists in the population.
From the expressions of R1*,R2*,R0S and R0S*, we can conclude that the white noise and Lévy jump have a positive effect in controlling the progression of the disease. That is, higher intensities of white noise σ and Lévy jump η guarantee the extinction of the disease. By substituting the expression σ¯(k)=ξ(k)2θ(k),k∈A, into the R1*,R2*,R0S and R0S*, one can find that R1*,R2*,R0S and R0S* are increasing per ξ and decreasing functions per θ which implies that the smaller intensity of volatility or the higher speed of reversion can enhance the outbreak of the disease. However, the telegraph noise has the negative effect. This means that, even if the disease persists only in one regime, eventually it will have the opportunity to persist.
This stochastic SLVIQR model better describes epidemiological characteristics and spread of epidemics comparing to existing ones. The model provides new insights into epidemiological situations when different types of the environmental noises (perturbations) are considered. The combination of white noise, telegraph noise and Lévy jump with time delay in the epidemic model, has a considerable impact on the persistence and extinction of the infection and enriches the dynamics of the model. Nevertheless, this model can be applied to all infectious diseases with the characteristics and mode of transmission described in the paper.
In order to show the added value of the model (9), we compare dynamic outcomes of the following versions of the model:• First model is a deterministic model in which the transmission coefficient is constant and the model parameters can switch the regime, that is, β→βe(a(t)) (the model does not contain white noise or Lévy jump):{dS(t)=(Λ(a(t))−βe(a(t))N(t)I(t−τ)S(t)−(l(a(t))+v(a(t)))S(t)−μ(a(t))S(t)+l1(a(t))L(t)+v1(a(t))V(t)+r1(a(t))R(t))dt,dL(t)=(l(a(t))S(t)−(μ(a(t))+l1(a(t)))L(t))dt,dV(t)=(v(a(t))S(t)−(μ(a(t))+v1(a(t)))V(t))dt,dI(t)=(βe(a(t))N(t)I(t−τ)S(t)−(α(a(t))+ρi(a(t))+μ(a(t))+δ(a(t)))I(t))dt,dQ(t)=(α(a(t))I(t)−(μ(a(t))+ρq(a(t)))Q(t))dt,dR(t)=(ρi(a(t))I(t)+ρq(a(t))Q(t)−(μ(a(t))+r1(a(t)))R(t))dt,
The trajectories of this model are illustrated by the orange color in the Figures 3 and 4 .Fig. 3 Comparison of dynamic outcomes of different versions of model (9).
Fig. 3
Fig. 4 Comparison of dynamic outcomes for compartment I(t) of different versions of model (9).
Fig. 4
• In order to better describe the epidemiological characteristics of COVID-19, in the second model, we chose that transmission coefficient beta is deterministic function of the form β→βe(a(t))+(β(0)−βe(a(t)))e−θ(a(t))t, and the model parameters can switch the regime. Then model becomes:{dS(t)=(Λ(a(t))−βe(a(t))+(β(0)−βe(a(t)))e−θ(a(t))tN(t)I(t−τ)S(t)−(l(a(t))+v(a(t)))S(t)−μ(a(t))S(t)+l1(a(t))L(t)+v1(a(t))V(t)+r1(a(t))R(t))dt,dL(t)=(l(a(t))S(t)−(μ(a(t))+l1(a(t)))L(t))dt,dV(t)=(v(a(t))S(t)−(μ(a(t))+v1(a(t)))V(t))dt,dI(t)=(βe(a(t))+(β(0)−βe(a(t)))e−θ(a(t))tN(t)I(t−τ)S(t)−(α(a(t))+ρi(a(t)))I(t)−(μ(a(t))+δ(a(t)))I(t))dt,dQ(t)=(α(a(t))I(t)−(μ(a(t))+ρq(a(t)))Q(t))dt,dR(t)=(ρi(a(t))I(t)+ρq(a(t))Q(t)−(μ(a(t))+r1(a(t)))R(t))dt,
The trajectories of this model are illustrated by the blue color in the Figures 3 and 4.
• Third model is a stochastic model in which the transmission coefficient beta is OU process, and the model parameters can switch the regime. Thus the model becomes more general but still simpler then model considered in the paper (does not contain Lévy jump):{dS(t)=(Λ(a(t))−βe(a(t))+(β(0)−βe(a(t)))e−θ(a(t))tN(t)I(t−τ)S(t)−(l(a(t))+v(a(t)))S(t)−μ(a(t))S(t)+l1(a(t))L(t)+v1(a(t))V(t)+r1(a(t))R(t))dt−σ(a(t),t)N(t)I(t−τ)S(t)dB(t),dL(t)=(l(a(t))S(t)−(μ(a(t))+l1(a(t)))L(t))dt,dV(t)=(v(a(t))S(t)−(μ(a(t))+v1(a(t)))V(t))dt,dI(t)=(βe(a(t))+(β(0)−βe(a(t)))e−θ(a(t))tN(t)I(t−τ)S(t)−(α(a(t))+ρi(a(t)))I(t)−(μ(a(t))+δ(a(t)))I(t))dt+σ(a(t),t)N(t)I(t−τ)S(t)dB(t),dQ(t)=(α(a(t))I(t)−(μ(a(t))+ρq(a(t)))Q(t))dt,dR(t)=(ρi(a(t))I(t)+ρq(a(t))Q(t)−(μ(a(t))+r1(a(t)))R(t))dt,
The trajectories of this model are illustrated by the purple color in the Figures 3 and 4.
• Fourth model is (9), considered in the paper, and the trajectories of this model are illustrated by the red color in the Figures 3 and 4.
The trajectories of the model versions shown in the Figures 3 and 4 were obtained using the same parameter values and underlying regime process for all model versions with the aim of comparing them. The parameter values, starting values, white noise intensity and generator matrix used in the simulations of different versions of model (9) illustrated in Figures 3 and 4 are the same one used in illustration of persistence result in the section Numerical simulations. Here we assumed that Lévy noise intensity is switching between five regimes as follows: η(1)=0.1, η(2)=0.05, η(3)=−0.025, η(4)=0.03, and η(5)=0.01.
In order to better illustrate the comparison of these models, Figure (4) shows infected compartment.
The trajectories of the second model, which has the property of mean reverting by definition, are quite similar to the trajectories of the first model. However, this is not a sufficient improvement since this model cannot catch the random effect of the environment, so we introduced perturbations into the model.
The trajectories of the third model fluctuate around the trajectories of the second (blue) one and have continuous environmental perturbations incorporated which makes the third model more realistic compared to the second one.
The advantages of the fourth model are reflected in the fact that with fourth model, sudden and severe jumps can be explained with Lévy jumps, while this is not possible with third model which contains only the white noise. On the Figure 4, comparing trajectories of the third and fourth model, in the third regime we can see the impact of the jump that leads to an increase in the number of infected people, which may be the consequence of a larger gathering of individuals (events, concerts, matches,...). While in the fourth regime the impact of the jump leads to a decrease in the number of infected population, which may be the impact of introduction of (anti-covid) government policy measures per example.
The disadvantage of the model is the assumption that the switching between two or more subregimes is modeled by a finite-state Markov chain. A more realistic assumption would be to model the transition from one subregime to another by a non-Markov process. Thus, the model may be improved by introduction of non-Markov chain for modeling the switching between subregimes with some distribution function for the waiting time until the next switching. Another improvement of the model is by introducing the assumption that the probability of transition between subregimes depends on the number of infected individuals. Besides, complexity of the model, that is, a large number of the model parameters can lead to over-fitting or weird results in calibration of the model and estimation of the model parameters. For that reason, special attention should be paid when evaluating model parameters. Also, time delay could be modeled by certain deterministic function or random variable rather than constant. In the future work we will try to overcome this disadventages.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknoledgements
Authors acknowledge financial support through the Ministry of Science, Technological Development and Innovation of Republic of Serbia, agreement no. 451-03-9/2021-14/200124 and through the project ”Application of short-range and long-range dependent stochastic models” - bilateral project of J.J. Strossmayer University of Osijek - Department of Mathematics, Croatia, and University of Niš, Faculty of Sciences and Mathematics - Department of Mathematics, Serbia (funded by the Ministry of Science and Education of the Republic of Croatia and Ministry of Science, Technological Development and Innovation of the Republic of Serbia).
Jasmina Đorđević is supported by STORM- Stochastics for Time-Space Risk Models, granted by Research Council of Norway - Independent projects: ToppForsk. Project nr. 274410.
Furthermore, we thank the Editor, the Associate Editor and three anonymous Referees for their constructive suggestions that led to substantial improvement of the paper.
==== Refs
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| 0 | PMC9744559 | NO-CC CODE | 2022-12-15 00:01:50 | no | J Franklin Inst. 2022 Dec 13; doi: 10.1016/j.jfranklin.2022.12.009 | utf-8 | J Franklin Inst | 2,022 | 10.1016/j.jfranklin.2022.12.009 | oa_other |
==== Front
Appl Soft Comput
Appl Soft Comput
Applied Soft Computing
1568-4946
1872-9681
Elsevier B.V.
S1568-4946(22)00974-7
10.1016/j.asoc.2022.109925
109925
Article
Design of multimodal hub-and-spoke transportation network for emergency relief under COVID-19 pandemic: A meta-heuristic approach
Li Chi a
Han Peixiu b⁎
Zhou Min a
Gu Ming a
a School of Software, Tsinghua University, Beijing, China
b College of Transportation Engineering, Dalian Maritime University, Dalian, China
⁎ Corresponding author.
12 12 2022
12 12 2022
10992512 1 2022
10 9 2022
8 12 2022
© 2022 Elsevier B.V. All rights reserved.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
When COVID-19 suddenly broke out, the epidemic areas are short of basic emergency relief which need to be transported from surrounding areas. To make transportation both time-efficient and cost-effective, we consider a multimodal hub-and-spoke transportation network for emergency relief schedules. Firstly, we establish a mixed integer nonlinear programming (MINLP) model considering multi-type emergency relief and multimodal transportation. The model is a bi-objective one that aims at minimizing both transportation time consumption and transportation costs. Due to its NP-hardness, devising an efficient algorithm to cope with such a problem is challenging. This study thus employs and redesigns Grey Wolf Optimizer (GWO) to tackle it. To benchmark our algorithm, a real-world case is tested with three solution methods which include other two state-of-the-art meta-heuristics. Results indicate that the customized GWO can solve such a problem in a reasonable time with higher accuracy. The research could provide significant practical management insights for related government departments and transportation companies on designing an effective transportation network for emergency relief schedules when faced with the unexpected COVID-19 pandemic.
Keywords
COVID-19 pandemic
Emergency relief schedules
Multimodal hub-and-spoke transportation network
Bi-objective MINLP model
Customized Grey Wolf Optimizer
Meta-heuristics
==== Body
pmc1 Introduction
The COVID-19 virus, characterized with fast-speed spread, easy infection and long-time duration among people, has been described as a pandemic by the World Health Organization (WHO) [1]. Data published by WHO as of November 9, 2020, informed that the epidemic has spread to more than 210 countries [2]. Due to the suddenness of COVID-19 pandemic outbreak, the epidemic districts and their adjacent areas are always caught unprepared [3]. The local reserve of basic materials is usually not sufficient when COVID-19 suddenly comes [4].
In such situation, people in disaster areas are in shortage of multi-type relief, such as basic living materials (food) and personal medical protection equipment (mask). Therefore, the scheduling of food and mask from other areas with adequate inventory for aid is of great importance. An optimal transportation network for food and mask scheduling depends on proper network structures. The hub-and-spoke structure is well-used in a comprehensive transportation network with scale of economies [5], [6], [7], [8]. In a hub-and-spoke transportation network, freights are firstly picked up from supply nodes and transited to proper hubs functioned as huge transshipment centers. After sorting, labeling and packaging operations inside hubs, such freights are then delivered to demand nodes (shown in Fig. 1). In the hub-and-spoke emergency relief transportation network, different types of relief may have particular transportation requirements. For instance, medical products are urgent relief with high value which should be transported within a relative short time. In reality, they are usually transported by air mode. Generally, different transportation modes have their specific advantages in aspects with capacity, unit freight and transportation time. Therefore, not only the scheduling of multi-type relief, but also multimodal transportation should be taken into considerations in the hub-and-spoke transportation network for satisfying various transportation requirements.
As is known for all, time is life, particularly faced with such cruel pandemic. The time efficiency of basic living supplies transition should always be taken in the first place. While considering transportation time consuming, the transportation cost should not be ignored since the economic expenditure is tighter than usual. Thus a proper transportation network for transporting emergency relief with both time efficiency and economic superiority is of essential necessity. Namely, in this research, minimizing both transportation time and transportation cost of the hub-and-spoke network should be considered.
Undoubtedly, the problem becomes much more complicated when we take all the mentioned aspects (multi-type relief, multimodal transportation, minimize both transportation time and transportation cost) into account. Based on considerations of two objectives mentioned in last paragraph, such a complex problem can be formulated as a bi-objective mixed integer nonlinear programming (MINLP) model which could not be directly solved by an MIP solver [9], [10]. In addition, due to its NP-hardness, the problem cannot be solved optimally by exact algorithms within a reasonable computational time, particularly for large-scale instances [11]. Therefore, it is essential to design efficient meta-heuristic approach to solve such problems. Among the existing meta-heuristic algorithms, Grey Wolf Optimizer (GWO) is a population-based nature-inspired algorithm recently proposed by Mirjalili in 2014 [12]. It simulates the social behavior of grey wolf for hunting prey which is a swarm intelligence algorithm based on leadership hierarchy. The application of GWO has been greatly active in the literature and related engineering fields [13], [14], [15], [16], [17], [18]. In this study, customized GWO is designed to cope with problems in pickup (from supply nodes to hubs) and delivery processes (from hubs to demand nodes) within a hub-and-spoke transportation network. To validate the correctness of model and the proposed algorithm, a real-world case is introduced for tests. Two other state-of-the-art algorithms: Firefly Algorithm (FA) [19] and Particle Swarm Optimization (PSO) [20] are also presented to make comparisons with customized GWO for algorithm efficiency verification.
From the aspects of transportation network design, tailored model establishment, customized GWO algorithm design, and important management insights for related authorities, the main contributions of this study are concluded and given as follows:
• We are dedicated to designing and optimizing a comprehensive emergency relief supply transportation network with hub-and-spoke structure with high efficiency. In the network, multi-type relief and multimodal transportation are both considered.
• A bi-objective MINLP model is established for the specific network which considers not only transportation time consumption but also transportation cost. In reality, transportation time consuming has greater priority than transportation cost with higher weights in the calculation.
• To solve the model with efficiency, a customized GWO is designed and applied to solve a real-world case. The other two heuristic approaches are then introduced to make comparisons. The experimental results validate the superiorities of customized GWO.
• The research can provide practical management insights for both related government departments and transportation companies. For government departments, the effective transportation network provides basic safeguards for medical aid and life order guarantee. For transportation companies undertaking transportation tasks, this study will guarantee both transportation capacities and economic benefits.
The remainder of the paper is organized as follows. In Section 2, a literature review of existing researches for solving emergency relies supply transportation problem and current applications for routing problems solved by GWO are given. In Section 3, we establish a bi-objective MINLP model minimizing both transportation time and cost to optimize the whole emergency relief transportation network. The basic GWO and customized GWO are presented in details in Section 4. In Section 5, to benchmark our algorithm, a real-world case are tested with three solution methods which include other two state-of-the-art heuristics. From the industrial case, practical management insights are summarized in Section 6. Finally, conclusion is given in Section 7.
Fig. 1 The structure of hub-and-spoke transportation network.
2 Literature review
In this study, we aim at designing an efficient transportation network for emergency relief under COVID-19 pandemic. To effectively solve such a complex problem, a tailored GWO was designed. As a newly proposed meta-heuristic algorithm, GWO has wide applications in routing problems. Therefore, in this section, we first summarize typical emergency relief transportation research. Subsequently, the classical research on solving routing problems with GWO are reviewed and summarized.
2.1 Researches on emergency relief transportation
The emergency relief transportation, also called as emergency relief logistics, has long been researched by related scholars. Pettit et al. [21] present a refined model for logistics requirements in emergency conditions. The model takes the existing military and non-military response models into consideration. Sheu [22] presents a hybrid fuzzy clustering-optimization approach for emergency relief logistics in the crucial rescue period. Two recursive mechanisms containing disaster-affected area grouping and relief co-distribution are involved in a three-layer emergency logistics co-distribution framework. Numerical experiments are conducted based on earthquake disaster occurring in Taiwan and the corresponding results validate the superiority of the proposed method. Lei [23] proposes a novel decision support system for relief logistics in natural disasters. Capacity limitations, priority of commodities and dynamic demand requirements are considered in the system. An interactive solution approach is then introduced for solving dynamic and goal programming model. Altay [24] gives a detailed presentation about existing modeling approaches that relate to disaster relief. Also, some challenging directions that cannot be easily incorporated into mathematical models have also been presented. Customer service is then considered in the international emergency relief chains by Oloruntoba and Gray [25]. Inspired by the immune system, Hu [26] models container multimodal transportation emergency relief system as an affinity network. To solve such problem, an integer linear programming model is then proposed. Afterwards, the simulation results of case studies verify the promising effects of model. It is known that humanitarian relief logistics is one of the most important elements of emergency relief logistics management. For reality, Ali et al. [27] develop a multi-objective robust stochastic programming approach for disaster emergency relief logistics under uncertainty. It is worth mentioning that the uncertain parameters contain demand uncertainty, supplies uncertainty and procurement and transportation cost uncertainty. Malek and Moghaddam [28] present a bi-objective mixed integer mathematical model for Humanitarian Relief Logistics (HRL) which determines optimal warehouse locations, emergency relief amounts of warehouse, and transportation plans. Then a Reservation Level Tchebycheff Procedure (RLTP) method is proposed to solve the bi-objective model. Liu et al. [29] propose a stochastic model for post-disaster relief logistics considering the particular environmental conditions after a catastrophic earthquake in mountainous areas. A robust optimization approach is introduced to tackle with uncertainties of the proposed stochastic model. Considering the post-disaster road network repair work scheduling and relief logistics, Li and Teo [30] establish a multi-period bi-level programming model for the problem. To work it out, a maximum relative satisfaction degree based steady-state parallel genetic algorithm is proposed. From the new aspect of minimizing the late arrival of relief vehicles, Davoodi and Goli [31] proposed an integrated model for relief operations in critical situations. It is worth mentioning that the covering tour approach is applied for vehicle routing part in the model which can speed up the disaster logistics system systems. To work out the model, a hybrid benders decomposition and variable neighborhood search approach is designed and introduced whose applications in the case study are proved to be highly efficient.Boostani et al. [32] present a three-level relief chain problem in pre- and postdisaster duration. The objective functions contain three aspects: (1) minimizing total costs of the humanitarian relief supply chain, (2) maximizing the social welfare and (3) minimizing the environmental impacts. A multi-objective mixed integer stochastic programming model is established to decide facility locations, procurement and resource allocation.
2.2 Applications for GWO solving routing problems
The applications of GWO for solving routing problems are in a quite few amount. While there are still some researchers dedicated to introducing GWO to solving complex routing problems. A ‘K-GWO’ algorithm is designed by [33] combining GWO with the traditional K-means clustering algorithm to solve CVRP. The results tested on benchmark datasets validate the efficiency of ‘K-GWO’. A new technique to solve TSP based on standard GWO is proposed and verified among several numerical experiments [34]. Furthermore, swap operator and swap sequence are also considered to adapt GWO for TSP. A novel D-GWO [35] is recently presented for solving symmetric TSP, with which 2-opt algorithm also is combined. D-GWO is then verified by comparing the results with several hybrid algorithms among 17 instances from TSPLIB. More researches related to GWO and its applications can be found in [36]. Although GWO is a relative fresh algorithm compared with other classical ones, its superiorities on solving routing problems can be clearly observed from related researches. In this study, while enhancing the solution efficiency, we continue employing and redesigning a customized GWO for solving such emergency relief supply routing problem under COVID-19 pandemic.
3 Model establishment
In this section, we first present a formal description of the multi-type relief and multimodal transportation network design problem. Some necessary assumptions and notations are given in details subsequently. We then introduce a tailored bi-objective mixed integer linear programming (MILP) model established for the specific problem.
3.1 Problem description
Basic living and medical emergency relief (like food and mask) in the epidemic areas are always in critical shortage status at the initial stage of COVID-19 pandemic outbreak [3], [4]. Thus filling the basic supply shortage as soon as possible by scheduling emergency relief from other nearer regions is of great significance. While transportation cost should also be taken into considerations even though transportation time is more prioritized. Taking fully consideration of improving transportation time efficiency and minimizing transportation cost, a bi-objective MINLP model with reasonable constraints is proposed.
In reality, emergency supplies come in all directions from other regions functioned with sufficient material storage and relative optimal distance [37]. However, it would easily lead to high time consuming and cost waste if all the supply areas connect directly to each demand region. Thus hub-and-spoke transportation network is adopted in this research due to scale of economies. In the designed hub-and-spoke network, different transportation modes are also introduced since particular transportation mode has its own characteristics which caters for the specific transportation requirements. For instance, railway mode has advantages in freight volumes and unit transportation cost, but it cannot guarantee transportation time. While air mode is quite the contrary.
Based on what has mentioned above, a multi-type relief and multimodal transportation network with hub-and-spoke structure is designed in this study. Given supply and demand nodes, candidate hub nodes, demand quantities and other related parameters, the following terms can be determined:
• which hub(s) is/are selected
• which supply nodes and demand nodes are allocated to hub(s)
• which transportation modes are selected to deliver the specific type of relief supplies
• how many particular-type supplies are transported en-route
3.2 Assumptions and notations
For convenience to establish tailored model, some necessary assumptions and notations need to be given here. The assumptions are listed as bellows and notation explanations are given in Table 1.
• The reserve in supply nodes are comprised of original reserve, social donation and other supply channels.
• All the candidate hubs are established ones whose construction cost will not be reconsidered.
• The areas where hubs are located have already been sufficiently supplied and do not need extra relief from supply nodes.
• The direct connections between hubs are not allowed.
Table 1 Notations explanation.
Set
I The set of supply nodes, i ∈ I
O The set of candidate hubs, o ∈ O
J The set of demand nodes, j ∈ J
K The set of transportation modes, k ∈ K
W The set of emergency relief types, w ∈ W
Parameter
mw The unit weight of the w-type emergency relief
tiokw The transportation time of the w-type emergency relief picked up by the k-type vehicle from supply node i∈I to hub o∈O
tojkw The transportation time of the w-type emergency relief delivered by the k-type vehicle from hub o∈O to demand node j∈J
tow The transshipment time of the w-type emergency relief at hub o∈O
Mk The maximum capacity of the k-type vehicle
ciokw The unit transportation cost of the w-type emergency relief picked up by the k-type vehicle from supply node i∈I to hub o∈O
cojkw The unit transportation cost of the w-type emergency relief delivered by the k-type vehicle from hub o∈O to demand node j∈J
cow The transshipment cost of the w-type emergency relief at hub o∈O
diok The distance between supply node i∈I and hub o∈O when emergency relief is picked up by the k-type vehicle
dojk The distance between hub o∈O and demand node j∈J when emergency relief is delivered by the k-type vehicle
Siw The reserve of the w-type emergency relief at supply node i∈I
Cow The maximum capacity of hub o∈O
Djw The demand of the w-type emergency relief at demand node j∈J
Qiok The maximum available vehicle number transported from supply node i∈I to hub o∈O
Qojk The maximum available vehicle number transported from hub o∈O to demand node j∈J
φjw The minimum demand ratio of the w-type emergency relief at demand node j∈J
Decision Variables
xiokw xiokw is 1 if the w-type emergency relief is transported by the k-type vehicle from supply node i∈I to hub o∈O, is 0 otherwise
xojkw xojkw is 1 if the w-type emergency relief is transported by the k-type vehicle from hub o∈O to demand node j∈J, is 0 otherwise
xoo xoo is 1 if node o is selected to be a hub, is 0 otherwise
hiokw The amount of the w-type emergency relief picked up by the k-type vehicle from supply node i∈I to hub o∈O
hojkw The amount of the w-type emergency relief delivered by the k-type vehicle from hub o∈O to demand node j∈J
3.3 Mathematical model
Based on problem assumptions and necessary notation explanations, the model for emergency relief hub-and-spoke transportation network under COVID-19 pandemic can be detailed given in this subsection.
3.3.1 Objective function
Objective function contains two parts: (1) minimizing transportation time and (2) minimizing the total transportation cost.
COVID-19 pandemic is undoubtedly a serious emergency event and the pandemic will rapidly expand as time passes for the sake of high-infectious characteristics and COVID-19 variant [37], [38]. To some extent, time is life. Therefore, the scheduling of emergency relief should always take transportation time efficiency as the first place. The transportation time contains three parts: transportation time from supply nodes to hubs, transshipment time inside hubs and transportation time from hubs to corresponding demand nodes (Eq. (1)). (1) F1=min∑i∈I∑o∈O∑k∈K∑w∈Whiokw⋅mwMk⋅tiokwxiokw
+∑i∈I∑o∈O∑w∈Whiokwtowxoo
+∑o∈O∑j∈J∑k∈K∑w∈Whojkw⋅mwMk⋅tojkwxojkw
Secondly, the consideration of transportation cost should also be taken after transportation time consuming. Once the transportation started from supply nodes, corresponding transportation cost will generate. Particularly, more urgent the supplies are, more expensive the transportation cost will be. It can be explained that the most urgent relief will be transported by air mode to assure the time efficiency whose transportation cost is much more higher than that of other modes (road and railway mode). As is known to all that the economy is rather tense during the COVID-19 pandemic due to distribution of regular social work and life. Therefore, optimizing total transportation cost should also be considered as the second objective which contains three aspects: Transportation cost from supply node to hub, transshipment cost in hub and transportation cost from hub to demand node (Eq. (2)). (2) F2=min∑i∈I∑o∈O∑k∈K∑w∈Wciokwdiokwhiokwmwxiokw
+∑i∈I∑o∈O∑w∈Wcowhiokwmwxoo
+∑o∈O∑j∈J∑k∈K∑w∈Wcojkwdojkwhojkwmwxojkw
3.3.2 Constraints
Reasonable constraints are essential components of a model since they can restrict the model and make the solutions accurate. Firstly, the hub location and allocation should be constrained as follows:
For hub nodes, each hub node can be connected with more than one supply nodes: (3) ∑i∈Ixiokw≥1∀o∈O,k∈K,w∈W
For demand nodes, each demand node can be served by more than one hub: (4) ∑o∈Oxojkw≥1∀j∈J,k∈K,w∈W
Only if the hub is established and selected can the arcs between supply nodes and hub (or between hub and demand nodes) exist (5) xiokw≤xoo∀i∈I,o∈O,k∈K,w∈W
(6) xojkw≤xoo∀o∈O,j∈J,k∈K,w∈W
Each supply node has their own reserve limitation, the amount of relief supplies transported from the supply nodes should not exceed the corresponding reserve limitation. Similarly, each hub has its own capacity limitation for the specific relief, the amount of relief arrived and shortly stored at hubs should be within the limitation respectively: (7) ∑o∈Ohiokw≤Siw∀i∈I,k∈K,w∈W
(8) ∑i∈Ihiokw≤Cow∀o∈O,k∈K,w∈W
The flow balance principal should always be obey, that is, the amount of relief flowing into the hub equals to the amount flowing out of the hub whatever the types: (9) ∑o∈Oxojkw=1∀j∈J,k∈K,w∈W
The demand requirements should be satisfied as much as possible. In fact, the emergency relief may not be quite adequate when COVID-19 pandemic suddenly breaks out, but the minimum demand must be fulfilled: (10) ∑j∈Jhojkw≤Djw∀o∈O,k∈K,w∈W
(11) ∑j∈Jhojkw≥φjwDjw∀o∈O,k∈K,w∈W
For the transportation modes, the relief supplies with specific type can only be delivered by one transportation mode on the corresponding arc: (12) ∑k∈Kxiokw=1∀i∈I,o∈O,w∈W
(13) ∑k∈Kxojkw=1∀o∈O,j∈J,w∈W
The available vehicle number of each transportation mode is different at each supply node and hub. The vehicles put into use should not exceed the corresponding transport capacity of each node: (14) hiokwmwMk≤Qiok∀i∈I,o∈O,k∈K,w∈W
(15) hojkwmwMk≤Qojk∀o∈O,j∈J,k∈K,w∈W
All the decision variables domains are defined as follows: (16) xiokw∈{0,1}∀i∈I,o∈O,k∈K,w∈W
(17) xojkw∈{0,1}∀o∈O,j∈J,k∈K,w∈W
(18) xoo∈{0,1}∀o∈O
(19) hiokw≥0∀i∈I,o∈O,k∈K,w∈W
(20) hojkw≥0∀o∈O,j∈J,k∈K,w∈W
4 Meta-heuristic approach
In this section, we first give a brief introduction to basic GWO. Subsequently, our customized GWO is described at length in four parts: construction stage, fitness calculation, improvement stage, and the customized GWO. To make it a clear and vivid readership, we finally depict the whole model solution framework.
4.1 Basic GWO
Grey Wolf Optimizer (GWO) is a population-based meta-heuristics algorithm inspired by the hunting and social behavior of the grey wolf pack. Grey wolf maintains a hierarchy of their society. Specifically, α represents the leader wolf, β represents the second-hierarchy wolf and δ is the third-hierarchy wolf. The rest wolves are called ω. Tracking, pursuing, and attacking are the main phases of grey wolf hunting. For vivid readership, detailed introduction of basic GWO is presented in Algorithm 1.
In order to model the social hierarchy of grey wolves, the first three best wolves (α, β, δ) will instruct other wolves rushing to the target. The rest wolves (ω) always update their locations according to α, β and δ.
In the process of hunting, encircling action can be defined as following: (21) D→=|C→⋅X→p(t)−X→(t)|
(22) X⃗(t+1)=Xp⃗(t)−A⋅⃗D⃗
where t indicates the current iteration, A⃗ and C⃗ are coefficient vectors, Xp⃗(t) is the position vector of the prey, and X⃗(t) indicates the position vector of a grey wolf.
The vectors A⃗ and C⃗ are calculated as follows: (23) A⃗=2a⃗⋅r1⃗−a⃗
(24) C⃗=2⋅r2⃗
where components of a⃗ are linearly decreased from 2 to 0 over the course of iterations and r1⃗, r2⃗ are random vectors in [0,1].
Each wolf uses the potential of α, β and δ wolves in hunting strategy as they are best in pack. The wolves update their position with the help of α, β and δ as follows: (25) X1⃗=Xα⃗−A1⋅(Dα⃗)X2⃗=Xβ⃗−A2⋅(Dβ⃗)X3⃗=Xδ⃗−A3⋅(Dδ⃗)
(26) X⃗(t+1)=X1⃗+X2⃗+X3⃗3
where Xα⃗, Xβ⃗ and Xδ⃗ are the approximated positions of α, β and δ wolves. X⃗(t+1) represents the updated position of wolf.
4.2 Customized GWO
The model given in Section 3 is a nonlinear one which could not be directly solved by MIP solver. In addition, due to its NP-hardness, the model cannot be solved optimally by exact algorithms within a reasonable computational time particularly for large-scale instances. Therefore, we design a meta-heuristic approach based on GWO structure. The proposed algorithm is comprised of two stages: construction stage and improvement stage. In construction stage, some initial operations are conducted and respective constraints are checked for validation. In improvement stage, we design a HD move strategy to update GWO solutions.
Our model can be simply described as Fig. 2. As is shown in Fig. 2, the designed transportation network is divided into three processes: (1) pickup process (from supply nodes to hubs), (2) transshipment process (transshipment operations inside hubs) and (3) delivery process (from hubs to demand nodes). The transportation planning of pickup process shares the same logic with that of delivery process. Thus we only introduce detailed solutions of pickup process. The solutions of delivery process can be obtained according to the same method used in pickup process. Now we proceed to design and introduce customized GWO for solving transportation problems in pickup process.
Fig. 2 The diagram of the proposed transportation network.
4.2.1 Construction stage
In construction stage, we firstly initialize the pickup amount of food and mask. Specifically, initialize and generate a transportation-amount matrix with the scale of N(numberofsupplynodes)×M(numberofhubs). For instance, if the number of supply nodes and hubs is both two, then we generate a 2 × 2 matrix formed as [[A1, A2], [B1, B2]]. During construction of transportation-amount matrix, it should be guaranteed that the sum of A1 and A2 is no more than the reserve of current first supply node. Similarly, the total of B1 and B2 should not exceed the reserve of current second supply node. Each item in the matrix represents detailed supply amount which is always non-negative. For instance, A1 denotes the transportation quantity from the first supply node to the first hub. Two sets of N×M transportation-amount matrices are generated to represent the transportation amount of food and mask respectively. According to the model described in Section 3.3, constraint examinations should be conducted to initial transportation-amount matrices. Here, only the constraint related to hub capacity need to be checked. Take the first hub (hub1) for example, the current capacity of hub1 is the sum of A1 and B1, then we need to check whether the current capacity is within the limitation of hub1’s capacity. If all the capacity constraints of hubs are satisfied, then a transportation-amount matrix [[A1, A2], [B1, B2]] is successfully obtained. The initialization operations for transportation amounts then end up. Otherwise, regenerate transportation-amount matrix until all the hub constraints are satisfied.
Two matrices of transportation amount for food and mask could be obtained based on steps mentioned above. For the two transportation-amount matrices, we need to generate two respective transportation-mode matrices. For instance, given ‘road mode = 1, railway mode = 2 and air mode = 3’, the transportation-mode matrix can be initialized as [[2, 3], [1, 2]]. Then it can be described as: railway mode is selected to transit freights from the first supply node to the first hub. We generate transportation-mode matrices respectively against food and mask. Thus two specific transportation-mode matrices are obtained. Now we proceed to check constraints of vehicle number in each supply node. Namely, it should be examined that whether the available vehicle number can cater for current vehicle demand based on above-mentioned transportation mode. If the constraints are violated, then we regenerate transportation-mode matrices until the vehicle number constraints are satisfied.
Finally, we obtain a solution of pickup process which contains transportation-amount matrices of food and mask (food_amount, mask_amount) and corresponding matrices of transportation mode (food_trans, mask_trans). In summary, an initial solution of customized GWO will be formed as (food_amount, mask_amount, food_trans, mask_trans).
4.2.2 Fitness calculation
Each solution can be regarded as a wolf in GWO structure. After construction stage, qualified wolves are obtained. Then we proceed to calculate the fitness of each wolf according to Eq. (27): (27) fitness=w1⋅ftime−minftimeminftime+w2⋅ftrans−minftransminftrans
where ftime is the whole time consuming and ftrans denotes the total transportation cost for one solution. ftime and ftrans of pickup process can be calculated respectively by the first item of Eqs. (1), (2). w1 and w2 are particular weights of transportation time and transportation cost. The sum of w1 and w2 equals to 1 whereas w1 is set to be more than 0.5 due to the priority of time efficiency under COVID-19 pandemic. It is worth mentioning that the solutions obtained will be better when w1 = 0.6 and w2 = 0.4. minftime and minftrans are obtained by ordering the time and transportation cost among all the solutions.
4.2.3 Improvement stage
According to the fitness calculation, the first three optimal solutions are selected to be α, β, δ wolf mentioned in basic GWO. In our proposed algorithm, improvement part is focus on enhancing transportation modes, that is, the value within food_trans and mask_trans.
In improvement stage, Hamming distance (HD) concept [39] is introduced to update each ordinary wolf. In informatics, between two strings with equal length, the number of different characters in the corresponding positions is called hamming distance. For instance, the two binary strings S1= [0 1 0 1] and S2= [1 0 1 1], the first, second and third place are different between S1 and S2, then HD is 3. Now we define the transportation-mode matrix needed to improve as X and the target transportation-mode matrix is L (matrix in α, β or δ). Then, the moving distance of X attracted by L is defined as follows (Eq. (28)), that is, the random number between 0 and HD. New solutions are obtained after such HD move, as shown in Algorithm 2. After each HD move, we need to examine the constraints of vehicle number. If the new transportation mode cannot cater for the vehicle number, we will keep the original one. Otherwise, update current transportation mode. (28) Random[0,HD(X,L)]
4.2.4 The customized GWO
The design of customized GWO is given in Algorithm 2. At first, we initialize the transportation amount of food and mask by the methods introduced in Section 4.2.1, after which initial transportation-amount solutions food_amount and mask_amount are obtained. Then, based on the food_amount and mask_amount, we proceed to get transportation-mode solutions food_trans and mask_trans. A wolf in customized GWO is defined as (food_amount, mask_amount, food_trans, mask_trans).
In Algorithm 3, for the food_amount and mask_amount, there are ten different transportation modes food_trans and mask_trans being constructed respectively. Thus we form a wolf population with ten wolves. Afterwards, improvement stage introduced in Section 4.2.3 is conducted to update the wolf population. We firstly calculate fitness of wolf groups and then select the first three wolves with minimum fitness as α, β and δ. Carrying out HD move to enhance food_trans and mask_trans for obtaining better results. Continually repeat the above steps until it reaches iteration time settings. Finally we output wolf α (food_amount, mask_amount, food_trans, mask_trans) as the solution of customized GWO where food_trans and mask_trans are the optimal transportation mode against food_amount and mask_amount via customized GWO.
4.3 The whole model solution framework
The whole model solution framework is given in Algorithm 4. As is mentioned above, the transportation process contains three parts: pickup process, transshipment process and delivery process. Firstly, we conduct customized GWO (Algorithm 3) to the pickup process. Solutions of pickup process are then obtained which contain transportation amount of food and mask (food_amount and mask_amount) and their respective transportation mode (food_trans and mask_trans) from supply nodes to hubs. Secondly, calculate transshipment time and cost of food and mask in transshipment process. After that, we proceed to solve delivery process using Algorithm 3 since the solution logic is the same of both pickup and delivery process. Solutions of delivery process can also be obtained which are comprised of transportation amount of food and mask, and their respective transportation mode from hubs to demand nodes. Above all, we get solutions of pickup process, transshipment process and delivery process. According to solutions of each process, the model transportation time consuming and transportation cost can be calculated respectively by Eqs. (1), (2). Whilst solving the model, repeat the above solving process until iteration time N reaches. Meanwhile, the number of N results are obtained, from which we choose the result with minimum fitness as the final output result. By conducting the Algorithm 4, solutions of pickup process, transshipment process and delivery process are finally obtained which also give answers to Section 3.1.
5 Numerical experiments and analysis
In this section, we conduct the customized GWO to solve a real-world case of Hubei Province in China. To verify the efficiency of proposed algorithm, FA [19] and PSO [20] are also conducted and compared with customized GWO. The proposed algorithm is coded in Python and computational tests are performed on the computer with Intel(R) Core (TM) i7-5200U, CPU 2.20 GHz with 8 GB RAM. For statistical reliability, all the conducted algorithms take the same 20 independent runs.
5.1 Data collection
We use the real-life case of emergency relief (food and mask) transportation under COVID-19 pandemic in Hubei Province. The whole transportation network contains five supply nodes (Shijiazhuang, Xian, Chengdu, Guiyang and Nanning), three candidate hubs (Wuhan, Ezhou and Xiantao) and five demand nodes (Xiaogan, Huanggang, Huangshi, Tianmen and Xianning). The geographical locations of 13 nodes are shown in Fig. 3. The data comes from Gaode map, related offices and communities in Hubei province. It includes GIS (shown in Fig. 3) and parameter-related data (shown in Table 2). In Table 2, the food and mask amount are presented in the form of ‘(food-amount/ton,mask-amount/unit)’.
Fig. 3 The geographical locations of 13 nodes.
Table 2 Information of supply, hub capacity and demand.
Supply Hub capacity Demand
Shijiazhuang (3000,1700k) Wuhan (15000,10000k) Xiaogan (4900,1000k)
Xian (3800,1500k) Ezhou (8000,8000k) Huanggang (6300,2100k)
Chengdu (5650,1500k) Xiantao (9000,8500k) Huangshi (2500,1900k)
Guiyang (2650,1400k) Tianmen (1300,810k)
Nanning (1900,1000k) Xianing (2000,2000k)
5.2 Result of real-world case
Fig. 4 and Fig. 5 visualize the results of food and mask transportation in the hub-and-spoke network solving by customized GWO. The more detailed route results are listed in Table 3 and Table 4. In two tables, pickup or delivery amount and transportation mode are given in the form of ‘(amount, transportation mode)’ whereas 1 represents road mode, 2 represents railway mode and 3 represents air mode. In addition, respective transportation time consuming cost and transportation cost of food and mask are given in Table 5.
Fig. 4 The transportation network of food.
Fig. 5 The transportation network of mask.
Table 3 Pickup and delivery processes of food transportation.
Process Supply/Demand nodes Hub nodes
Wuhan Enzhou Xiantao
Pickup Shijiazhuang (0,0) (2600,2) (0,0)
Xian (3400,2) (0,0) (0,0)
Chengdu (0,0) (214,2) (5036,2)
Guiyang (2250,2) (0,0) (0,0)
Nanning (1500,2) (0,0) (0,0)
Delivery Xiaogan (0,0) (0,0) (4126,2)
Huanggang (6300,2) (0,0) (0,0)
Huangshi (0,0) (1750,2) (0,0)
Tianmen (0,0) (0,0) (910,2)
Xianning (850,2) (1064,2) (0,0)
Table 4 Pickup and delivery processes of mask transportation.
Process Supply/Demand nodes Hub nodes
Wuhan Enzhou Xiantao
Pickup Shijiazhuang (0,0) (1200k,2) (0,0)
Xian (207.9k,3) (643.9k,3) (208.1k,3)
Chengdu (0,0) (1978k,2) (0,0)
Guiyang (0,0) (0,0) (847k,3)
Nanning (565k,3) (0,0) (0,0)
Delivery Xiaogan (0,0) (0,0) (700k,2)
Huanggang (0,0) (1470k,1) (0,0)
Huangshi (0,0) (1330k,2) (0,0)
Tianmen (0,0) (567k,2) (0,0)
Xianning (772.9k,2) (454.9k,1) (355.1k,2)
Table 5 Time cost and transportation cost of real-world case.
Relief supplies Time cost (h) Transportation cost (CNY)
Pickup Transshipment Delivery Pickup Transshipment Delivery
Food 131.00 65.60 9.73 2906644.16 7287850.00 191696.00
Mask 82.97 10.40 36.83 3626481.24 1959192.42 77730.53
Total cost 336.53 16049594.34
5.3 Comparative analysis of numerical results
To further verify the efficiency of proposed algorithm, comparisons with FA [19] and PSO [20] are conducted to solve the same case. The reason for choosing PSO and FA is that they both belong to Swarm Intelligent algorithm and they exhibit great performances on solving such combinatorial problems. The comparative results are given in Table 6 which are the best ones obtained by respective algorithms in 20 runs. From the table, it can be concluded that customized GWO makes better performance on solving the problem within a reasonable time. It is worth mentioning that running time of customized GWO is not the best, but it is in a reasonable range.
Table 6 Comparisons among Customized GWO, FA and PSO.
Algorithm Cost Running time (s)
Time cost (h) Transportation cost (CNY)
Customized GWO 336.53 16049594.34 27.32
FA 374.80 16276706.55 29.13
PSO 433.79 17057410.01 26.55
6 Management insights from the industrial case
As a sudden and fast-spread disease, COVID-19 pandemic caught related epidemic areas unawares. In the real-world case given in Section 5, when COVID-19 pandemic seriously breaks out, residents in epidemic areas need to stop working and keep themselves stay at home. Thus the production and economic activities in epidemic areas need to be suspended for weeks or even months until the epidemic is basically controlled. However, during this closure period, residents’ normal medical protection equipment and basic daily necessities need to be guaranteed in quantity and quality. Local reserves are often difficult to cover basic needs, so emergency supplies need to be transported from neighboring regions with sufficient supplies. For the epidemic areas, transportation time for basic emergency relief is in the first place since time means life. Besides, transportation is accompanied by a cost. Therefore, on the basis of meeting the transportation time and demand, the economy of transportation also needs to be considered. Therefore, in this study, we make efforts to design a practically time-efficient and cost-effective transportation network when faced with COVID-19. The results of the real-world case prove the efficiency of our methods and can provide significantly practical suggestions for related authorities. From such an industrial case, some practical management insights can be extracted and concluded for related government departments and transportation companies that undertake transportation tasks.
For relevant government departments, when COVID-19 pandemic suddenly broke out, it is of paramount importance to quickly control COVID-19 pandemic situation and ensure the stability of residents’ living order during the epidemic. The first aspect needing to consider is the isolation and medical measures for infected people and the medical protection for other residents, which requires timely transportation and guarantee of medical materials. The good living order of residents is based on enough food, so the basic food demand must be satisfied, which requires the timely guarantee of basic living materials. Therefore, the transportation network designed in this study is important for delivering necessary materials on time and on-demand, which also provides the basic safeguard of management for relevant government departments.
For related transportation companies which undertake such important transportation tasks, what they need to consider is transportation capacity and economic benefits. First of all, the transportation means (trucks, trains, and airplanes) should be sufficiently used and the transportation capacity should not exceed the limited standard, which requires that the balance between demand and capacity should be fully considered when designing the transportation network. In addition, transportation companies have economic costs. Minimizing total transportation cost on the basis of meeting transportation capacity is also an essential aspect of company operation. Therefore, the transportation network designed in this study also takes the transportation cost into account. In a word, the method proposed in our study can minimize the transportation cost for transportation company meanwhile catering to the transportation capacity, which has certain practical significance for related companies undertaking transportation tasks.
7 Conclusion
COVID-19 pandemic, a world-wide hazard disease, has spread over 210 countries with unbelievable speed. The suddenness of COVID-19 outbreak will lead to great shortage of basic living materials and medical protection products in the disaster-affected areas. Therefore, it is urgent to schedule aided materials from other nearer districts to injured areas. In this study, we make efforts to design a comprehensive multimodal transportation network with hub-and-spoke structure for transporting food and mask. Considering both transportation time efficiency and transportation cost, a bi-objective MINLP model is established. Due to its nonlinearity, related MIP solver can not directly cope with it. In addition, as a NP-hard problem, it cannot be solved by exact algorithms with efficiency as the problem scales expand. Therefore, to solve such complex problem with efficiency, a meta-heuristic algorithm called customized GWO is designed and proposed in detail. Two stages are contained in proposed algorithm. In construction stage, transportation amount and transportation mode are well initialized. In improvement stage, HD move concept is introduced to further enhance solution accuracy. Taking the actual cases of Hubei Province as research background, the model is verified with real-world example. To prove that customized GWO is a promising approximation method to solve such problem, its performance is compared with other two state-of-the-art algorithms. The simulation results support the fact that our proposed algorithm can solve such problem with higher accuracy within a reasonable time.
The research has strong practical guiding significance for emergency relief supply transportation network design under COVID-19 pandemic. And some important management insights can be extracted and summarized for related government departments and transportation companies. For related government departments, this study can provide basic safeguards for medical aid and life order guarantee. For transportation companies undertaking transportation tasks, this study will guarantee both transportation capacities and economic benefits.
CRediT authorship contribution statement
Chi Li: Conceptualization, Programming, Validation. Peixiu Han: Conceptualization, Visualization, Writing – original draft. Min Zhou: Responsible for gathering information. Ming Gu: Writing – review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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| 0 | PMC9744580 | NO-CC CODE | 2022-12-15 00:01:50 | no | Appl Soft Comput. 2022 Dec 12;:109925 | utf-8 | Appl Soft Comput | 2,022 | 10.1016/j.asoc.2022.109925 | oa_other |
==== Front
Appl Soft Comput
Appl Soft Comput
Applied Soft Computing
1568-4946
1872-9681
Elsevier B.V.
S1568-4946(22)00974-7
10.1016/j.asoc.2022.109925
109925
Article
Design of multimodal hub-and-spoke transportation network for emergency relief under COVID-19 pandemic: A meta-heuristic approach
Li Chi a
Han Peixiu b⁎
Zhou Min a
Gu Ming a
a School of Software, Tsinghua University, Beijing, China
b College of Transportation Engineering, Dalian Maritime University, Dalian, China
⁎ Corresponding author.
12 12 2022
12 12 2022
10992512 1 2022
10 9 2022
8 12 2022
© 2022 Elsevier B.V. All rights reserved.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
When COVID-19 suddenly broke out, the epidemic areas are short of basic emergency relief which need to be transported from surrounding areas. To make transportation both time-efficient and cost-effective, we consider a multimodal hub-and-spoke transportation network for emergency relief schedules. Firstly, we establish a mixed integer nonlinear programming (MINLP) model considering multi-type emergency relief and multimodal transportation. The model is a bi-objective one that aims at minimizing both transportation time consumption and transportation costs. Due to its NP-hardness, devising an efficient algorithm to cope with such a problem is challenging. This study thus employs and redesigns Grey Wolf Optimizer (GWO) to tackle it. To benchmark our algorithm, a real-world case is tested with three solution methods which include other two state-of-the-art meta-heuristics. Results indicate that the customized GWO can solve such a problem in a reasonable time with higher accuracy. The research could provide significant practical management insights for related government departments and transportation companies on designing an effective transportation network for emergency relief schedules when faced with the unexpected COVID-19 pandemic.
Keywords
COVID-19 pandemic
Emergency relief schedules
Multimodal hub-and-spoke transportation network
Bi-objective MINLP model
Customized Grey Wolf Optimizer
Meta-heuristics
==== Body
pmc1 Introduction
The COVID-19 virus, characterized with fast-speed spread, easy infection and long-time duration among people, has been described as a pandemic by the World Health Organization (WHO) [1]. Data published by WHO as of November 9, 2020, informed that the epidemic has spread to more than 210 countries [2]. Due to the suddenness of COVID-19 pandemic outbreak, the epidemic districts and their adjacent areas are always caught unprepared [3]. The local reserve of basic materials is usually not sufficient when COVID-19 suddenly comes [4].
In such situation, people in disaster areas are in shortage of multi-type relief, such as basic living materials (food) and personal medical protection equipment (mask). Therefore, the scheduling of food and mask from other areas with adequate inventory for aid is of great importance. An optimal transportation network for food and mask scheduling depends on proper network structures. The hub-and-spoke structure is well-used in a comprehensive transportation network with scale of economies [5], [6], [7], [8]. In a hub-and-spoke transportation network, freights are firstly picked up from supply nodes and transited to proper hubs functioned as huge transshipment centers. After sorting, labeling and packaging operations inside hubs, such freights are then delivered to demand nodes (shown in Fig. 1). In the hub-and-spoke emergency relief transportation network, different types of relief may have particular transportation requirements. For instance, medical products are urgent relief with high value which should be transported within a relative short time. In reality, they are usually transported by air mode. Generally, different transportation modes have their specific advantages in aspects with capacity, unit freight and transportation time. Therefore, not only the scheduling of multi-type relief, but also multimodal transportation should be taken into considerations in the hub-and-spoke transportation network for satisfying various transportation requirements.
As is known for all, time is life, particularly faced with such cruel pandemic. The time efficiency of basic living supplies transition should always be taken in the first place. While considering transportation time consuming, the transportation cost should not be ignored since the economic expenditure is tighter than usual. Thus a proper transportation network for transporting emergency relief with both time efficiency and economic superiority is of essential necessity. Namely, in this research, minimizing both transportation time and transportation cost of the hub-and-spoke network should be considered.
Undoubtedly, the problem becomes much more complicated when we take all the mentioned aspects (multi-type relief, multimodal transportation, minimize both transportation time and transportation cost) into account. Based on considerations of two objectives mentioned in last paragraph, such a complex problem can be formulated as a bi-objective mixed integer nonlinear programming (MINLP) model which could not be directly solved by an MIP solver [9], [10]. In addition, due to its NP-hardness, the problem cannot be solved optimally by exact algorithms within a reasonable computational time, particularly for large-scale instances [11]. Therefore, it is essential to design efficient meta-heuristic approach to solve such problems. Among the existing meta-heuristic algorithms, Grey Wolf Optimizer (GWO) is a population-based nature-inspired algorithm recently proposed by Mirjalili in 2014 [12]. It simulates the social behavior of grey wolf for hunting prey which is a swarm intelligence algorithm based on leadership hierarchy. The application of GWO has been greatly active in the literature and related engineering fields [13], [14], [15], [16], [17], [18]. In this study, customized GWO is designed to cope with problems in pickup (from supply nodes to hubs) and delivery processes (from hubs to demand nodes) within a hub-and-spoke transportation network. To validate the correctness of model and the proposed algorithm, a real-world case is introduced for tests. Two other state-of-the-art algorithms: Firefly Algorithm (FA) [19] and Particle Swarm Optimization (PSO) [20] are also presented to make comparisons with customized GWO for algorithm efficiency verification.
From the aspects of transportation network design, tailored model establishment, customized GWO algorithm design, and important management insights for related authorities, the main contributions of this study are concluded and given as follows:
• We are dedicated to designing and optimizing a comprehensive emergency relief supply transportation network with hub-and-spoke structure with high efficiency. In the network, multi-type relief and multimodal transportation are both considered.
• A bi-objective MINLP model is established for the specific network which considers not only transportation time consumption but also transportation cost. In reality, transportation time consuming has greater priority than transportation cost with higher weights in the calculation.
• To solve the model with efficiency, a customized GWO is designed and applied to solve a real-world case. The other two heuristic approaches are then introduced to make comparisons. The experimental results validate the superiorities of customized GWO.
• The research can provide practical management insights for both related government departments and transportation companies. For government departments, the effective transportation network provides basic safeguards for medical aid and life order guarantee. For transportation companies undertaking transportation tasks, this study will guarantee both transportation capacities and economic benefits.
The remainder of the paper is organized as follows. In Section 2, a literature review of existing researches for solving emergency relies supply transportation problem and current applications for routing problems solved by GWO are given. In Section 3, we establish a bi-objective MINLP model minimizing both transportation time and cost to optimize the whole emergency relief transportation network. The basic GWO and customized GWO are presented in details in Section 4. In Section 5, to benchmark our algorithm, a real-world case are tested with three solution methods which include other two state-of-the-art heuristics. From the industrial case, practical management insights are summarized in Section 6. Finally, conclusion is given in Section 7.
Fig. 1 The structure of hub-and-spoke transportation network.
2 Literature review
In this study, we aim at designing an efficient transportation network for emergency relief under COVID-19 pandemic. To effectively solve such a complex problem, a tailored GWO was designed. As a newly proposed meta-heuristic algorithm, GWO has wide applications in routing problems. Therefore, in this section, we first summarize typical emergency relief transportation research. Subsequently, the classical research on solving routing problems with GWO are reviewed and summarized.
2.1 Researches on emergency relief transportation
The emergency relief transportation, also called as emergency relief logistics, has long been researched by related scholars. Pettit et al. [21] present a refined model for logistics requirements in emergency conditions. The model takes the existing military and non-military response models into consideration. Sheu [22] presents a hybrid fuzzy clustering-optimization approach for emergency relief logistics in the crucial rescue period. Two recursive mechanisms containing disaster-affected area grouping and relief co-distribution are involved in a three-layer emergency logistics co-distribution framework. Numerical experiments are conducted based on earthquake disaster occurring in Taiwan and the corresponding results validate the superiority of the proposed method. Lei [23] proposes a novel decision support system for relief logistics in natural disasters. Capacity limitations, priority of commodities and dynamic demand requirements are considered in the system. An interactive solution approach is then introduced for solving dynamic and goal programming model. Altay [24] gives a detailed presentation about existing modeling approaches that relate to disaster relief. Also, some challenging directions that cannot be easily incorporated into mathematical models have also been presented. Customer service is then considered in the international emergency relief chains by Oloruntoba and Gray [25]. Inspired by the immune system, Hu [26] models container multimodal transportation emergency relief system as an affinity network. To solve such problem, an integer linear programming model is then proposed. Afterwards, the simulation results of case studies verify the promising effects of model. It is known that humanitarian relief logistics is one of the most important elements of emergency relief logistics management. For reality, Ali et al. [27] develop a multi-objective robust stochastic programming approach for disaster emergency relief logistics under uncertainty. It is worth mentioning that the uncertain parameters contain demand uncertainty, supplies uncertainty and procurement and transportation cost uncertainty. Malek and Moghaddam [28] present a bi-objective mixed integer mathematical model for Humanitarian Relief Logistics (HRL) which determines optimal warehouse locations, emergency relief amounts of warehouse, and transportation plans. Then a Reservation Level Tchebycheff Procedure (RLTP) method is proposed to solve the bi-objective model. Liu et al. [29] propose a stochastic model for post-disaster relief logistics considering the particular environmental conditions after a catastrophic earthquake in mountainous areas. A robust optimization approach is introduced to tackle with uncertainties of the proposed stochastic model. Considering the post-disaster road network repair work scheduling and relief logistics, Li and Teo [30] establish a multi-period bi-level programming model for the problem. To work it out, a maximum relative satisfaction degree based steady-state parallel genetic algorithm is proposed. From the new aspect of minimizing the late arrival of relief vehicles, Davoodi and Goli [31] proposed an integrated model for relief operations in critical situations. It is worth mentioning that the covering tour approach is applied for vehicle routing part in the model which can speed up the disaster logistics system systems. To work out the model, a hybrid benders decomposition and variable neighborhood search approach is designed and introduced whose applications in the case study are proved to be highly efficient.Boostani et al. [32] present a three-level relief chain problem in pre- and postdisaster duration. The objective functions contain three aspects: (1) minimizing total costs of the humanitarian relief supply chain, (2) maximizing the social welfare and (3) minimizing the environmental impacts. A multi-objective mixed integer stochastic programming model is established to decide facility locations, procurement and resource allocation.
2.2 Applications for GWO solving routing problems
The applications of GWO for solving routing problems are in a quite few amount. While there are still some researchers dedicated to introducing GWO to solving complex routing problems. A ‘K-GWO’ algorithm is designed by [33] combining GWO with the traditional K-means clustering algorithm to solve CVRP. The results tested on benchmark datasets validate the efficiency of ‘K-GWO’. A new technique to solve TSP based on standard GWO is proposed and verified among several numerical experiments [34]. Furthermore, swap operator and swap sequence are also considered to adapt GWO for TSP. A novel D-GWO [35] is recently presented for solving symmetric TSP, with which 2-opt algorithm also is combined. D-GWO is then verified by comparing the results with several hybrid algorithms among 17 instances from TSPLIB. More researches related to GWO and its applications can be found in [36]. Although GWO is a relative fresh algorithm compared with other classical ones, its superiorities on solving routing problems can be clearly observed from related researches. In this study, while enhancing the solution efficiency, we continue employing and redesigning a customized GWO for solving such emergency relief supply routing problem under COVID-19 pandemic.
3 Model establishment
In this section, we first present a formal description of the multi-type relief and multimodal transportation network design problem. Some necessary assumptions and notations are given in details subsequently. We then introduce a tailored bi-objective mixed integer linear programming (MILP) model established for the specific problem.
3.1 Problem description
Basic living and medical emergency relief (like food and mask) in the epidemic areas are always in critical shortage status at the initial stage of COVID-19 pandemic outbreak [3], [4]. Thus filling the basic supply shortage as soon as possible by scheduling emergency relief from other nearer regions is of great significance. While transportation cost should also be taken into considerations even though transportation time is more prioritized. Taking fully consideration of improving transportation time efficiency and minimizing transportation cost, a bi-objective MINLP model with reasonable constraints is proposed.
In reality, emergency supplies come in all directions from other regions functioned with sufficient material storage and relative optimal distance [37]. However, it would easily lead to high time consuming and cost waste if all the supply areas connect directly to each demand region. Thus hub-and-spoke transportation network is adopted in this research due to scale of economies. In the designed hub-and-spoke network, different transportation modes are also introduced since particular transportation mode has its own characteristics which caters for the specific transportation requirements. For instance, railway mode has advantages in freight volumes and unit transportation cost, but it cannot guarantee transportation time. While air mode is quite the contrary.
Based on what has mentioned above, a multi-type relief and multimodal transportation network with hub-and-spoke structure is designed in this study. Given supply and demand nodes, candidate hub nodes, demand quantities and other related parameters, the following terms can be determined:
• which hub(s) is/are selected
• which supply nodes and demand nodes are allocated to hub(s)
• which transportation modes are selected to deliver the specific type of relief supplies
• how many particular-type supplies are transported en-route
3.2 Assumptions and notations
For convenience to establish tailored model, some necessary assumptions and notations need to be given here. The assumptions are listed as bellows and notation explanations are given in Table 1.
• The reserve in supply nodes are comprised of original reserve, social donation and other supply channels.
• All the candidate hubs are established ones whose construction cost will not be reconsidered.
• The areas where hubs are located have already been sufficiently supplied and do not need extra relief from supply nodes.
• The direct connections between hubs are not allowed.
Table 1 Notations explanation.
Set
I The set of supply nodes, i ∈ I
O The set of candidate hubs, o ∈ O
J The set of demand nodes, j ∈ J
K The set of transportation modes, k ∈ K
W The set of emergency relief types, w ∈ W
Parameter
mw The unit weight of the w-type emergency relief
tiokw The transportation time of the w-type emergency relief picked up by the k-type vehicle from supply node i∈I to hub o∈O
tojkw The transportation time of the w-type emergency relief delivered by the k-type vehicle from hub o∈O to demand node j∈J
tow The transshipment time of the w-type emergency relief at hub o∈O
Mk The maximum capacity of the k-type vehicle
ciokw The unit transportation cost of the w-type emergency relief picked up by the k-type vehicle from supply node i∈I to hub o∈O
cojkw The unit transportation cost of the w-type emergency relief delivered by the k-type vehicle from hub o∈O to demand node j∈J
cow The transshipment cost of the w-type emergency relief at hub o∈O
diok The distance between supply node i∈I and hub o∈O when emergency relief is picked up by the k-type vehicle
dojk The distance between hub o∈O and demand node j∈J when emergency relief is delivered by the k-type vehicle
Siw The reserve of the w-type emergency relief at supply node i∈I
Cow The maximum capacity of hub o∈O
Djw The demand of the w-type emergency relief at demand node j∈J
Qiok The maximum available vehicle number transported from supply node i∈I to hub o∈O
Qojk The maximum available vehicle number transported from hub o∈O to demand node j∈J
φjw The minimum demand ratio of the w-type emergency relief at demand node j∈J
Decision Variables
xiokw xiokw is 1 if the w-type emergency relief is transported by the k-type vehicle from supply node i∈I to hub o∈O, is 0 otherwise
xojkw xojkw is 1 if the w-type emergency relief is transported by the k-type vehicle from hub o∈O to demand node j∈J, is 0 otherwise
xoo xoo is 1 if node o is selected to be a hub, is 0 otherwise
hiokw The amount of the w-type emergency relief picked up by the k-type vehicle from supply node i∈I to hub o∈O
hojkw The amount of the w-type emergency relief delivered by the k-type vehicle from hub o∈O to demand node j∈J
3.3 Mathematical model
Based on problem assumptions and necessary notation explanations, the model for emergency relief hub-and-spoke transportation network under COVID-19 pandemic can be detailed given in this subsection.
3.3.1 Objective function
Objective function contains two parts: (1) minimizing transportation time and (2) minimizing the total transportation cost.
COVID-19 pandemic is undoubtedly a serious emergency event and the pandemic will rapidly expand as time passes for the sake of high-infectious characteristics and COVID-19 variant [37], [38]. To some extent, time is life. Therefore, the scheduling of emergency relief should always take transportation time efficiency as the first place. The transportation time contains three parts: transportation time from supply nodes to hubs, transshipment time inside hubs and transportation time from hubs to corresponding demand nodes (Eq. (1)). (1) F1=min∑i∈I∑o∈O∑k∈K∑w∈Whiokw⋅mwMk⋅tiokwxiokw
+∑i∈I∑o∈O∑w∈Whiokwtowxoo
+∑o∈O∑j∈J∑k∈K∑w∈Whojkw⋅mwMk⋅tojkwxojkw
Secondly, the consideration of transportation cost should also be taken after transportation time consuming. Once the transportation started from supply nodes, corresponding transportation cost will generate. Particularly, more urgent the supplies are, more expensive the transportation cost will be. It can be explained that the most urgent relief will be transported by air mode to assure the time efficiency whose transportation cost is much more higher than that of other modes (road and railway mode). As is known to all that the economy is rather tense during the COVID-19 pandemic due to distribution of regular social work and life. Therefore, optimizing total transportation cost should also be considered as the second objective which contains three aspects: Transportation cost from supply node to hub, transshipment cost in hub and transportation cost from hub to demand node (Eq. (2)). (2) F2=min∑i∈I∑o∈O∑k∈K∑w∈Wciokwdiokwhiokwmwxiokw
+∑i∈I∑o∈O∑w∈Wcowhiokwmwxoo
+∑o∈O∑j∈J∑k∈K∑w∈Wcojkwdojkwhojkwmwxojkw
3.3.2 Constraints
Reasonable constraints are essential components of a model since they can restrict the model and make the solutions accurate. Firstly, the hub location and allocation should be constrained as follows:
For hub nodes, each hub node can be connected with more than one supply nodes: (3) ∑i∈Ixiokw≥1∀o∈O,k∈K,w∈W
For demand nodes, each demand node can be served by more than one hub: (4) ∑o∈Oxojkw≥1∀j∈J,k∈K,w∈W
Only if the hub is established and selected can the arcs between supply nodes and hub (or between hub and demand nodes) exist (5) xiokw≤xoo∀i∈I,o∈O,k∈K,w∈W
(6) xojkw≤xoo∀o∈O,j∈J,k∈K,w∈W
Each supply node has their own reserve limitation, the amount of relief supplies transported from the supply nodes should not exceed the corresponding reserve limitation. Similarly, each hub has its own capacity limitation for the specific relief, the amount of relief arrived and shortly stored at hubs should be within the limitation respectively: (7) ∑o∈Ohiokw≤Siw∀i∈I,k∈K,w∈W
(8) ∑i∈Ihiokw≤Cow∀o∈O,k∈K,w∈W
The flow balance principal should always be obey, that is, the amount of relief flowing into the hub equals to the amount flowing out of the hub whatever the types: (9) ∑o∈Oxojkw=1∀j∈J,k∈K,w∈W
The demand requirements should be satisfied as much as possible. In fact, the emergency relief may not be quite adequate when COVID-19 pandemic suddenly breaks out, but the minimum demand must be fulfilled: (10) ∑j∈Jhojkw≤Djw∀o∈O,k∈K,w∈W
(11) ∑j∈Jhojkw≥φjwDjw∀o∈O,k∈K,w∈W
For the transportation modes, the relief supplies with specific type can only be delivered by one transportation mode on the corresponding arc: (12) ∑k∈Kxiokw=1∀i∈I,o∈O,w∈W
(13) ∑k∈Kxojkw=1∀o∈O,j∈J,w∈W
The available vehicle number of each transportation mode is different at each supply node and hub. The vehicles put into use should not exceed the corresponding transport capacity of each node: (14) hiokwmwMk≤Qiok∀i∈I,o∈O,k∈K,w∈W
(15) hojkwmwMk≤Qojk∀o∈O,j∈J,k∈K,w∈W
All the decision variables domains are defined as follows: (16) xiokw∈{0,1}∀i∈I,o∈O,k∈K,w∈W
(17) xojkw∈{0,1}∀o∈O,j∈J,k∈K,w∈W
(18) xoo∈{0,1}∀o∈O
(19) hiokw≥0∀i∈I,o∈O,k∈K,w∈W
(20) hojkw≥0∀o∈O,j∈J,k∈K,w∈W
4 Meta-heuristic approach
In this section, we first give a brief introduction to basic GWO. Subsequently, our customized GWO is described at length in four parts: construction stage, fitness calculation, improvement stage, and the customized GWO. To make it a clear and vivid readership, we finally depict the whole model solution framework.
4.1 Basic GWO
Grey Wolf Optimizer (GWO) is a population-based meta-heuristics algorithm inspired by the hunting and social behavior of the grey wolf pack. Grey wolf maintains a hierarchy of their society. Specifically, α represents the leader wolf, β represents the second-hierarchy wolf and δ is the third-hierarchy wolf. The rest wolves are called ω. Tracking, pursuing, and attacking are the main phases of grey wolf hunting. For vivid readership, detailed introduction of basic GWO is presented in Algorithm 1.
In order to model the social hierarchy of grey wolves, the first three best wolves (α, β, δ) will instruct other wolves rushing to the target. The rest wolves (ω) always update their locations according to α, β and δ.
In the process of hunting, encircling action can be defined as following: (21) D→=|C→⋅X→p(t)−X→(t)|
(22) X⃗(t+1)=Xp⃗(t)−A⋅⃗D⃗
where t indicates the current iteration, A⃗ and C⃗ are coefficient vectors, Xp⃗(t) is the position vector of the prey, and X⃗(t) indicates the position vector of a grey wolf.
The vectors A⃗ and C⃗ are calculated as follows: (23) A⃗=2a⃗⋅r1⃗−a⃗
(24) C⃗=2⋅r2⃗
where components of a⃗ are linearly decreased from 2 to 0 over the course of iterations and r1⃗, r2⃗ are random vectors in [0,1].
Each wolf uses the potential of α, β and δ wolves in hunting strategy as they are best in pack. The wolves update their position with the help of α, β and δ as follows: (25) X1⃗=Xα⃗−A1⋅(Dα⃗)X2⃗=Xβ⃗−A2⋅(Dβ⃗)X3⃗=Xδ⃗−A3⋅(Dδ⃗)
(26) X⃗(t+1)=X1⃗+X2⃗+X3⃗3
where Xα⃗, Xβ⃗ and Xδ⃗ are the approximated positions of α, β and δ wolves. X⃗(t+1) represents the updated position of wolf.
4.2 Customized GWO
The model given in Section 3 is a nonlinear one which could not be directly solved by MIP solver. In addition, due to its NP-hardness, the model cannot be solved optimally by exact algorithms within a reasonable computational time particularly for large-scale instances. Therefore, we design a meta-heuristic approach based on GWO structure. The proposed algorithm is comprised of two stages: construction stage and improvement stage. In construction stage, some initial operations are conducted and respective constraints are checked for validation. In improvement stage, we design a HD move strategy to update GWO solutions.
Our model can be simply described as Fig. 2. As is shown in Fig. 2, the designed transportation network is divided into three processes: (1) pickup process (from supply nodes to hubs), (2) transshipment process (transshipment operations inside hubs) and (3) delivery process (from hubs to demand nodes). The transportation planning of pickup process shares the same logic with that of delivery process. Thus we only introduce detailed solutions of pickup process. The solutions of delivery process can be obtained according to the same method used in pickup process. Now we proceed to design and introduce customized GWO for solving transportation problems in pickup process.
Fig. 2 The diagram of the proposed transportation network.
4.2.1 Construction stage
In construction stage, we firstly initialize the pickup amount of food and mask. Specifically, initialize and generate a transportation-amount matrix with the scale of N(numberofsupplynodes)×M(numberofhubs). For instance, if the number of supply nodes and hubs is both two, then we generate a 2 × 2 matrix formed as [[A1, A2], [B1, B2]]. During construction of transportation-amount matrix, it should be guaranteed that the sum of A1 and A2 is no more than the reserve of current first supply node. Similarly, the total of B1 and B2 should not exceed the reserve of current second supply node. Each item in the matrix represents detailed supply amount which is always non-negative. For instance, A1 denotes the transportation quantity from the first supply node to the first hub. Two sets of N×M transportation-amount matrices are generated to represent the transportation amount of food and mask respectively. According to the model described in Section 3.3, constraint examinations should be conducted to initial transportation-amount matrices. Here, only the constraint related to hub capacity need to be checked. Take the first hub (hub1) for example, the current capacity of hub1 is the sum of A1 and B1, then we need to check whether the current capacity is within the limitation of hub1’s capacity. If all the capacity constraints of hubs are satisfied, then a transportation-amount matrix [[A1, A2], [B1, B2]] is successfully obtained. The initialization operations for transportation amounts then end up. Otherwise, regenerate transportation-amount matrix until all the hub constraints are satisfied.
Two matrices of transportation amount for food and mask could be obtained based on steps mentioned above. For the two transportation-amount matrices, we need to generate two respective transportation-mode matrices. For instance, given ‘road mode = 1, railway mode = 2 and air mode = 3’, the transportation-mode matrix can be initialized as [[2, 3], [1, 2]]. Then it can be described as: railway mode is selected to transit freights from the first supply node to the first hub. We generate transportation-mode matrices respectively against food and mask. Thus two specific transportation-mode matrices are obtained. Now we proceed to check constraints of vehicle number in each supply node. Namely, it should be examined that whether the available vehicle number can cater for current vehicle demand based on above-mentioned transportation mode. If the constraints are violated, then we regenerate transportation-mode matrices until the vehicle number constraints are satisfied.
Finally, we obtain a solution of pickup process which contains transportation-amount matrices of food and mask (food_amount, mask_amount) and corresponding matrices of transportation mode (food_trans, mask_trans). In summary, an initial solution of customized GWO will be formed as (food_amount, mask_amount, food_trans, mask_trans).
4.2.2 Fitness calculation
Each solution can be regarded as a wolf in GWO structure. After construction stage, qualified wolves are obtained. Then we proceed to calculate the fitness of each wolf according to Eq. (27): (27) fitness=w1⋅ftime−minftimeminftime+w2⋅ftrans−minftransminftrans
where ftime is the whole time consuming and ftrans denotes the total transportation cost for one solution. ftime and ftrans of pickup process can be calculated respectively by the first item of Eqs. (1), (2). w1 and w2 are particular weights of transportation time and transportation cost. The sum of w1 and w2 equals to 1 whereas w1 is set to be more than 0.5 due to the priority of time efficiency under COVID-19 pandemic. It is worth mentioning that the solutions obtained will be better when w1 = 0.6 and w2 = 0.4. minftime and minftrans are obtained by ordering the time and transportation cost among all the solutions.
4.2.3 Improvement stage
According to the fitness calculation, the first three optimal solutions are selected to be α, β, δ wolf mentioned in basic GWO. In our proposed algorithm, improvement part is focus on enhancing transportation modes, that is, the value within food_trans and mask_trans.
In improvement stage, Hamming distance (HD) concept [39] is introduced to update each ordinary wolf. In informatics, between two strings with equal length, the number of different characters in the corresponding positions is called hamming distance. For instance, the two binary strings S1= [0 1 0 1] and S2= [1 0 1 1], the first, second and third place are different between S1 and S2, then HD is 3. Now we define the transportation-mode matrix needed to improve as X and the target transportation-mode matrix is L (matrix in α, β or δ). Then, the moving distance of X attracted by L is defined as follows (Eq. (28)), that is, the random number between 0 and HD. New solutions are obtained after such HD move, as shown in Algorithm 2. After each HD move, we need to examine the constraints of vehicle number. If the new transportation mode cannot cater for the vehicle number, we will keep the original one. Otherwise, update current transportation mode. (28) Random[0,HD(X,L)]
4.2.4 The customized GWO
The design of customized GWO is given in Algorithm 2. At first, we initialize the transportation amount of food and mask by the methods introduced in Section 4.2.1, after which initial transportation-amount solutions food_amount and mask_amount are obtained. Then, based on the food_amount and mask_amount, we proceed to get transportation-mode solutions food_trans and mask_trans. A wolf in customized GWO is defined as (food_amount, mask_amount, food_trans, mask_trans).
In Algorithm 3, for the food_amount and mask_amount, there are ten different transportation modes food_trans and mask_trans being constructed respectively. Thus we form a wolf population with ten wolves. Afterwards, improvement stage introduced in Section 4.2.3 is conducted to update the wolf population. We firstly calculate fitness of wolf groups and then select the first three wolves with minimum fitness as α, β and δ. Carrying out HD move to enhance food_trans and mask_trans for obtaining better results. Continually repeat the above steps until it reaches iteration time settings. Finally we output wolf α (food_amount, mask_amount, food_trans, mask_trans) as the solution of customized GWO where food_trans and mask_trans are the optimal transportation mode against food_amount and mask_amount via customized GWO.
4.3 The whole model solution framework
The whole model solution framework is given in Algorithm 4. As is mentioned above, the transportation process contains three parts: pickup process, transshipment process and delivery process. Firstly, we conduct customized GWO (Algorithm 3) to the pickup process. Solutions of pickup process are then obtained which contain transportation amount of food and mask (food_amount and mask_amount) and their respective transportation mode (food_trans and mask_trans) from supply nodes to hubs. Secondly, calculate transshipment time and cost of food and mask in transshipment process. After that, we proceed to solve delivery process using Algorithm 3 since the solution logic is the same of both pickup and delivery process. Solutions of delivery process can also be obtained which are comprised of transportation amount of food and mask, and their respective transportation mode from hubs to demand nodes. Above all, we get solutions of pickup process, transshipment process and delivery process. According to solutions of each process, the model transportation time consuming and transportation cost can be calculated respectively by Eqs. (1), (2). Whilst solving the model, repeat the above solving process until iteration time N reaches. Meanwhile, the number of N results are obtained, from which we choose the result with minimum fitness as the final output result. By conducting the Algorithm 4, solutions of pickup process, transshipment process and delivery process are finally obtained which also give answers to Section 3.1.
5 Numerical experiments and analysis
In this section, we conduct the customized GWO to solve a real-world case of Hubei Province in China. To verify the efficiency of proposed algorithm, FA [19] and PSO [20] are also conducted and compared with customized GWO. The proposed algorithm is coded in Python and computational tests are performed on the computer with Intel(R) Core (TM) i7-5200U, CPU 2.20 GHz with 8 GB RAM. For statistical reliability, all the conducted algorithms take the same 20 independent runs.
5.1 Data collection
We use the real-life case of emergency relief (food and mask) transportation under COVID-19 pandemic in Hubei Province. The whole transportation network contains five supply nodes (Shijiazhuang, Xian, Chengdu, Guiyang and Nanning), three candidate hubs (Wuhan, Ezhou and Xiantao) and five demand nodes (Xiaogan, Huanggang, Huangshi, Tianmen and Xianning). The geographical locations of 13 nodes are shown in Fig. 3. The data comes from Gaode map, related offices and communities in Hubei province. It includes GIS (shown in Fig. 3) and parameter-related data (shown in Table 2). In Table 2, the food and mask amount are presented in the form of ‘(food-amount/ton,mask-amount/unit)’.
Fig. 3 The geographical locations of 13 nodes.
Table 2 Information of supply, hub capacity and demand.
Supply Hub capacity Demand
Shijiazhuang (3000,1700k) Wuhan (15000,10000k) Xiaogan (4900,1000k)
Xian (3800,1500k) Ezhou (8000,8000k) Huanggang (6300,2100k)
Chengdu (5650,1500k) Xiantao (9000,8500k) Huangshi (2500,1900k)
Guiyang (2650,1400k) Tianmen (1300,810k)
Nanning (1900,1000k) Xianing (2000,2000k)
5.2 Result of real-world case
Fig. 4 and Fig. 5 visualize the results of food and mask transportation in the hub-and-spoke network solving by customized GWO. The more detailed route results are listed in Table 3 and Table 4. In two tables, pickup or delivery amount and transportation mode are given in the form of ‘(amount, transportation mode)’ whereas 1 represents road mode, 2 represents railway mode and 3 represents air mode. In addition, respective transportation time consuming cost and transportation cost of food and mask are given in Table 5.
Fig. 4 The transportation network of food.
Fig. 5 The transportation network of mask.
Table 3 Pickup and delivery processes of food transportation.
Process Supply/Demand nodes Hub nodes
Wuhan Enzhou Xiantao
Pickup Shijiazhuang (0,0) (2600,2) (0,0)
Xian (3400,2) (0,0) (0,0)
Chengdu (0,0) (214,2) (5036,2)
Guiyang (2250,2) (0,0) (0,0)
Nanning (1500,2) (0,0) (0,0)
Delivery Xiaogan (0,0) (0,0) (4126,2)
Huanggang (6300,2) (0,0) (0,0)
Huangshi (0,0) (1750,2) (0,0)
Tianmen (0,0) (0,0) (910,2)
Xianning (850,2) (1064,2) (0,0)
Table 4 Pickup and delivery processes of mask transportation.
Process Supply/Demand nodes Hub nodes
Wuhan Enzhou Xiantao
Pickup Shijiazhuang (0,0) (1200k,2) (0,0)
Xian (207.9k,3) (643.9k,3) (208.1k,3)
Chengdu (0,0) (1978k,2) (0,0)
Guiyang (0,0) (0,0) (847k,3)
Nanning (565k,3) (0,0) (0,0)
Delivery Xiaogan (0,0) (0,0) (700k,2)
Huanggang (0,0) (1470k,1) (0,0)
Huangshi (0,0) (1330k,2) (0,0)
Tianmen (0,0) (567k,2) (0,0)
Xianning (772.9k,2) (454.9k,1) (355.1k,2)
Table 5 Time cost and transportation cost of real-world case.
Relief supplies Time cost (h) Transportation cost (CNY)
Pickup Transshipment Delivery Pickup Transshipment Delivery
Food 131.00 65.60 9.73 2906644.16 7287850.00 191696.00
Mask 82.97 10.40 36.83 3626481.24 1959192.42 77730.53
Total cost 336.53 16049594.34
5.3 Comparative analysis of numerical results
To further verify the efficiency of proposed algorithm, comparisons with FA [19] and PSO [20] are conducted to solve the same case. The reason for choosing PSO and FA is that they both belong to Swarm Intelligent algorithm and they exhibit great performances on solving such combinatorial problems. The comparative results are given in Table 6 which are the best ones obtained by respective algorithms in 20 runs. From the table, it can be concluded that customized GWO makes better performance on solving the problem within a reasonable time. It is worth mentioning that running time of customized GWO is not the best, but it is in a reasonable range.
Table 6 Comparisons among Customized GWO, FA and PSO.
Algorithm Cost Running time (s)
Time cost (h) Transportation cost (CNY)
Customized GWO 336.53 16049594.34 27.32
FA 374.80 16276706.55 29.13
PSO 433.79 17057410.01 26.55
6 Management insights from the industrial case
As a sudden and fast-spread disease, COVID-19 pandemic caught related epidemic areas unawares. In the real-world case given in Section 5, when COVID-19 pandemic seriously breaks out, residents in epidemic areas need to stop working and keep themselves stay at home. Thus the production and economic activities in epidemic areas need to be suspended for weeks or even months until the epidemic is basically controlled. However, during this closure period, residents’ normal medical protection equipment and basic daily necessities need to be guaranteed in quantity and quality. Local reserves are often difficult to cover basic needs, so emergency supplies need to be transported from neighboring regions with sufficient supplies. For the epidemic areas, transportation time for basic emergency relief is in the first place since time means life. Besides, transportation is accompanied by a cost. Therefore, on the basis of meeting the transportation time and demand, the economy of transportation also needs to be considered. Therefore, in this study, we make efforts to design a practically time-efficient and cost-effective transportation network when faced with COVID-19. The results of the real-world case prove the efficiency of our methods and can provide significantly practical suggestions for related authorities. From such an industrial case, some practical management insights can be extracted and concluded for related government departments and transportation companies that undertake transportation tasks.
For relevant government departments, when COVID-19 pandemic suddenly broke out, it is of paramount importance to quickly control COVID-19 pandemic situation and ensure the stability of residents’ living order during the epidemic. The first aspect needing to consider is the isolation and medical measures for infected people and the medical protection for other residents, which requires timely transportation and guarantee of medical materials. The good living order of residents is based on enough food, so the basic food demand must be satisfied, which requires the timely guarantee of basic living materials. Therefore, the transportation network designed in this study is important for delivering necessary materials on time and on-demand, which also provides the basic safeguard of management for relevant government departments.
For related transportation companies which undertake such important transportation tasks, what they need to consider is transportation capacity and economic benefits. First of all, the transportation means (trucks, trains, and airplanes) should be sufficiently used and the transportation capacity should not exceed the limited standard, which requires that the balance between demand and capacity should be fully considered when designing the transportation network. In addition, transportation companies have economic costs. Minimizing total transportation cost on the basis of meeting transportation capacity is also an essential aspect of company operation. Therefore, the transportation network designed in this study also takes the transportation cost into account. In a word, the method proposed in our study can minimize the transportation cost for transportation company meanwhile catering to the transportation capacity, which has certain practical significance for related companies undertaking transportation tasks.
7 Conclusion
COVID-19 pandemic, a world-wide hazard disease, has spread over 210 countries with unbelievable speed. The suddenness of COVID-19 outbreak will lead to great shortage of basic living materials and medical protection products in the disaster-affected areas. Therefore, it is urgent to schedule aided materials from other nearer districts to injured areas. In this study, we make efforts to design a comprehensive multimodal transportation network with hub-and-spoke structure for transporting food and mask. Considering both transportation time efficiency and transportation cost, a bi-objective MINLP model is established. Due to its nonlinearity, related MIP solver can not directly cope with it. In addition, as a NP-hard problem, it cannot be solved by exact algorithms with efficiency as the problem scales expand. Therefore, to solve such complex problem with efficiency, a meta-heuristic algorithm called customized GWO is designed and proposed in detail. Two stages are contained in proposed algorithm. In construction stage, transportation amount and transportation mode are well initialized. In improvement stage, HD move concept is introduced to further enhance solution accuracy. Taking the actual cases of Hubei Province as research background, the model is verified with real-world example. To prove that customized GWO is a promising approximation method to solve such problem, its performance is compared with other two state-of-the-art algorithms. The simulation results support the fact that our proposed algorithm can solve such problem with higher accuracy within a reasonable time.
The research has strong practical guiding significance for emergency relief supply transportation network design under COVID-19 pandemic. And some important management insights can be extracted and summarized for related government departments and transportation companies. For related government departments, this study can provide basic safeguards for medical aid and life order guarantee. For transportation companies undertaking transportation tasks, this study will guarantee both transportation capacities and economic benefits.
CRediT authorship contribution statement
Chi Li: Conceptualization, Programming, Validation. Peixiu Han: Conceptualization, Visualization, Writing – original draft. Min Zhou: Responsible for gathering information. Ming Gu: Writing – review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
==== Refs
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| 36510043 | PMC9744581 | NO-CC CODE | 2022-12-15 00:01:50 | no | MMW Fortschr Med. 2022 Dec 13; 164(21-22):3 | latin-1 | MMW Fortschr Med | 2,022 | 10.1007/s15006-022-2083-5 | oa_other |
==== Front
Appl Soft Comput
Appl Soft Comput
Applied Soft Computing
1568-4946
1872-9681
Elsevier B.V.
S1568-4946(22)00974-7
10.1016/j.asoc.2022.109925
109925
Article
Design of multimodal hub-and-spoke transportation network for emergency relief under COVID-19 pandemic: A meta-heuristic approach
Li Chi a
Han Peixiu b⁎
Zhou Min a
Gu Ming a
a School of Software, Tsinghua University, Beijing, China
b College of Transportation Engineering, Dalian Maritime University, Dalian, China
⁎ Corresponding author.
12 12 2022
12 12 2022
10992512 1 2022
10 9 2022
8 12 2022
© 2022 Elsevier B.V. All rights reserved.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
When COVID-19 suddenly broke out, the epidemic areas are short of basic emergency relief which need to be transported from surrounding areas. To make transportation both time-efficient and cost-effective, we consider a multimodal hub-and-spoke transportation network for emergency relief schedules. Firstly, we establish a mixed integer nonlinear programming (MINLP) model considering multi-type emergency relief and multimodal transportation. The model is a bi-objective one that aims at minimizing both transportation time consumption and transportation costs. Due to its NP-hardness, devising an efficient algorithm to cope with such a problem is challenging. This study thus employs and redesigns Grey Wolf Optimizer (GWO) to tackle it. To benchmark our algorithm, a real-world case is tested with three solution methods which include other two state-of-the-art meta-heuristics. Results indicate that the customized GWO can solve such a problem in a reasonable time with higher accuracy. The research could provide significant practical management insights for related government departments and transportation companies on designing an effective transportation network for emergency relief schedules when faced with the unexpected COVID-19 pandemic.
Keywords
COVID-19 pandemic
Emergency relief schedules
Multimodal hub-and-spoke transportation network
Bi-objective MINLP model
Customized Grey Wolf Optimizer
Meta-heuristics
==== Body
pmc1 Introduction
The COVID-19 virus, characterized with fast-speed spread, easy infection and long-time duration among people, has been described as a pandemic by the World Health Organization (WHO) [1]. Data published by WHO as of November 9, 2020, informed that the epidemic has spread to more than 210 countries [2]. Due to the suddenness of COVID-19 pandemic outbreak, the epidemic districts and their adjacent areas are always caught unprepared [3]. The local reserve of basic materials is usually not sufficient when COVID-19 suddenly comes [4].
In such situation, people in disaster areas are in shortage of multi-type relief, such as basic living materials (food) and personal medical protection equipment (mask). Therefore, the scheduling of food and mask from other areas with adequate inventory for aid is of great importance. An optimal transportation network for food and mask scheduling depends on proper network structures. The hub-and-spoke structure is well-used in a comprehensive transportation network with scale of economies [5], [6], [7], [8]. In a hub-and-spoke transportation network, freights are firstly picked up from supply nodes and transited to proper hubs functioned as huge transshipment centers. After sorting, labeling and packaging operations inside hubs, such freights are then delivered to demand nodes (shown in Fig. 1). In the hub-and-spoke emergency relief transportation network, different types of relief may have particular transportation requirements. For instance, medical products are urgent relief with high value which should be transported within a relative short time. In reality, they are usually transported by air mode. Generally, different transportation modes have their specific advantages in aspects with capacity, unit freight and transportation time. Therefore, not only the scheduling of multi-type relief, but also multimodal transportation should be taken into considerations in the hub-and-spoke transportation network for satisfying various transportation requirements.
As is known for all, time is life, particularly faced with such cruel pandemic. The time efficiency of basic living supplies transition should always be taken in the first place. While considering transportation time consuming, the transportation cost should not be ignored since the economic expenditure is tighter than usual. Thus a proper transportation network for transporting emergency relief with both time efficiency and economic superiority is of essential necessity. Namely, in this research, minimizing both transportation time and transportation cost of the hub-and-spoke network should be considered.
Undoubtedly, the problem becomes much more complicated when we take all the mentioned aspects (multi-type relief, multimodal transportation, minimize both transportation time and transportation cost) into account. Based on considerations of two objectives mentioned in last paragraph, such a complex problem can be formulated as a bi-objective mixed integer nonlinear programming (MINLP) model which could not be directly solved by an MIP solver [9], [10]. In addition, due to its NP-hardness, the problem cannot be solved optimally by exact algorithms within a reasonable computational time, particularly for large-scale instances [11]. Therefore, it is essential to design efficient meta-heuristic approach to solve such problems. Among the existing meta-heuristic algorithms, Grey Wolf Optimizer (GWO) is a population-based nature-inspired algorithm recently proposed by Mirjalili in 2014 [12]. It simulates the social behavior of grey wolf for hunting prey which is a swarm intelligence algorithm based on leadership hierarchy. The application of GWO has been greatly active in the literature and related engineering fields [13], [14], [15], [16], [17], [18]. In this study, customized GWO is designed to cope with problems in pickup (from supply nodes to hubs) and delivery processes (from hubs to demand nodes) within a hub-and-spoke transportation network. To validate the correctness of model and the proposed algorithm, a real-world case is introduced for tests. Two other state-of-the-art algorithms: Firefly Algorithm (FA) [19] and Particle Swarm Optimization (PSO) [20] are also presented to make comparisons with customized GWO for algorithm efficiency verification.
From the aspects of transportation network design, tailored model establishment, customized GWO algorithm design, and important management insights for related authorities, the main contributions of this study are concluded and given as follows:
• We are dedicated to designing and optimizing a comprehensive emergency relief supply transportation network with hub-and-spoke structure with high efficiency. In the network, multi-type relief and multimodal transportation are both considered.
• A bi-objective MINLP model is established for the specific network which considers not only transportation time consumption but also transportation cost. In reality, transportation time consuming has greater priority than transportation cost with higher weights in the calculation.
• To solve the model with efficiency, a customized GWO is designed and applied to solve a real-world case. The other two heuristic approaches are then introduced to make comparisons. The experimental results validate the superiorities of customized GWO.
• The research can provide practical management insights for both related government departments and transportation companies. For government departments, the effective transportation network provides basic safeguards for medical aid and life order guarantee. For transportation companies undertaking transportation tasks, this study will guarantee both transportation capacities and economic benefits.
The remainder of the paper is organized as follows. In Section 2, a literature review of existing researches for solving emergency relies supply transportation problem and current applications for routing problems solved by GWO are given. In Section 3, we establish a bi-objective MINLP model minimizing both transportation time and cost to optimize the whole emergency relief transportation network. The basic GWO and customized GWO are presented in details in Section 4. In Section 5, to benchmark our algorithm, a real-world case are tested with three solution methods which include other two state-of-the-art heuristics. From the industrial case, practical management insights are summarized in Section 6. Finally, conclusion is given in Section 7.
Fig. 1 The structure of hub-and-spoke transportation network.
2 Literature review
In this study, we aim at designing an efficient transportation network for emergency relief under COVID-19 pandemic. To effectively solve such a complex problem, a tailored GWO was designed. As a newly proposed meta-heuristic algorithm, GWO has wide applications in routing problems. Therefore, in this section, we first summarize typical emergency relief transportation research. Subsequently, the classical research on solving routing problems with GWO are reviewed and summarized.
2.1 Researches on emergency relief transportation
The emergency relief transportation, also called as emergency relief logistics, has long been researched by related scholars. Pettit et al. [21] present a refined model for logistics requirements in emergency conditions. The model takes the existing military and non-military response models into consideration. Sheu [22] presents a hybrid fuzzy clustering-optimization approach for emergency relief logistics in the crucial rescue period. Two recursive mechanisms containing disaster-affected area grouping and relief co-distribution are involved in a three-layer emergency logistics co-distribution framework. Numerical experiments are conducted based on earthquake disaster occurring in Taiwan and the corresponding results validate the superiority of the proposed method. Lei [23] proposes a novel decision support system for relief logistics in natural disasters. Capacity limitations, priority of commodities and dynamic demand requirements are considered in the system. An interactive solution approach is then introduced for solving dynamic and goal programming model. Altay [24] gives a detailed presentation about existing modeling approaches that relate to disaster relief. Also, some challenging directions that cannot be easily incorporated into mathematical models have also been presented. Customer service is then considered in the international emergency relief chains by Oloruntoba and Gray [25]. Inspired by the immune system, Hu [26] models container multimodal transportation emergency relief system as an affinity network. To solve such problem, an integer linear programming model is then proposed. Afterwards, the simulation results of case studies verify the promising effects of model. It is known that humanitarian relief logistics is one of the most important elements of emergency relief logistics management. For reality, Ali et al. [27] develop a multi-objective robust stochastic programming approach for disaster emergency relief logistics under uncertainty. It is worth mentioning that the uncertain parameters contain demand uncertainty, supplies uncertainty and procurement and transportation cost uncertainty. Malek and Moghaddam [28] present a bi-objective mixed integer mathematical model for Humanitarian Relief Logistics (HRL) which determines optimal warehouse locations, emergency relief amounts of warehouse, and transportation plans. Then a Reservation Level Tchebycheff Procedure (RLTP) method is proposed to solve the bi-objective model. Liu et al. [29] propose a stochastic model for post-disaster relief logistics considering the particular environmental conditions after a catastrophic earthquake in mountainous areas. A robust optimization approach is introduced to tackle with uncertainties of the proposed stochastic model. Considering the post-disaster road network repair work scheduling and relief logistics, Li and Teo [30] establish a multi-period bi-level programming model for the problem. To work it out, a maximum relative satisfaction degree based steady-state parallel genetic algorithm is proposed. From the new aspect of minimizing the late arrival of relief vehicles, Davoodi and Goli [31] proposed an integrated model for relief operations in critical situations. It is worth mentioning that the covering tour approach is applied for vehicle routing part in the model which can speed up the disaster logistics system systems. To work out the model, a hybrid benders decomposition and variable neighborhood search approach is designed and introduced whose applications in the case study are proved to be highly efficient.Boostani et al. [32] present a three-level relief chain problem in pre- and postdisaster duration. The objective functions contain three aspects: (1) minimizing total costs of the humanitarian relief supply chain, (2) maximizing the social welfare and (3) minimizing the environmental impacts. A multi-objective mixed integer stochastic programming model is established to decide facility locations, procurement and resource allocation.
2.2 Applications for GWO solving routing problems
The applications of GWO for solving routing problems are in a quite few amount. While there are still some researchers dedicated to introducing GWO to solving complex routing problems. A ‘K-GWO’ algorithm is designed by [33] combining GWO with the traditional K-means clustering algorithm to solve CVRP. The results tested on benchmark datasets validate the efficiency of ‘K-GWO’. A new technique to solve TSP based on standard GWO is proposed and verified among several numerical experiments [34]. Furthermore, swap operator and swap sequence are also considered to adapt GWO for TSP. A novel D-GWO [35] is recently presented for solving symmetric TSP, with which 2-opt algorithm also is combined. D-GWO is then verified by comparing the results with several hybrid algorithms among 17 instances from TSPLIB. More researches related to GWO and its applications can be found in [36]. Although GWO is a relative fresh algorithm compared with other classical ones, its superiorities on solving routing problems can be clearly observed from related researches. In this study, while enhancing the solution efficiency, we continue employing and redesigning a customized GWO for solving such emergency relief supply routing problem under COVID-19 pandemic.
3 Model establishment
In this section, we first present a formal description of the multi-type relief and multimodal transportation network design problem. Some necessary assumptions and notations are given in details subsequently. We then introduce a tailored bi-objective mixed integer linear programming (MILP) model established for the specific problem.
3.1 Problem description
Basic living and medical emergency relief (like food and mask) in the epidemic areas are always in critical shortage status at the initial stage of COVID-19 pandemic outbreak [3], [4]. Thus filling the basic supply shortage as soon as possible by scheduling emergency relief from other nearer regions is of great significance. While transportation cost should also be taken into considerations even though transportation time is more prioritized. Taking fully consideration of improving transportation time efficiency and minimizing transportation cost, a bi-objective MINLP model with reasonable constraints is proposed.
In reality, emergency supplies come in all directions from other regions functioned with sufficient material storage and relative optimal distance [37]. However, it would easily lead to high time consuming and cost waste if all the supply areas connect directly to each demand region. Thus hub-and-spoke transportation network is adopted in this research due to scale of economies. In the designed hub-and-spoke network, different transportation modes are also introduced since particular transportation mode has its own characteristics which caters for the specific transportation requirements. For instance, railway mode has advantages in freight volumes and unit transportation cost, but it cannot guarantee transportation time. While air mode is quite the contrary.
Based on what has mentioned above, a multi-type relief and multimodal transportation network with hub-and-spoke structure is designed in this study. Given supply and demand nodes, candidate hub nodes, demand quantities and other related parameters, the following terms can be determined:
• which hub(s) is/are selected
• which supply nodes and demand nodes are allocated to hub(s)
• which transportation modes are selected to deliver the specific type of relief supplies
• how many particular-type supplies are transported en-route
3.2 Assumptions and notations
For convenience to establish tailored model, some necessary assumptions and notations need to be given here. The assumptions are listed as bellows and notation explanations are given in Table 1.
• The reserve in supply nodes are comprised of original reserve, social donation and other supply channels.
• All the candidate hubs are established ones whose construction cost will not be reconsidered.
• The areas where hubs are located have already been sufficiently supplied and do not need extra relief from supply nodes.
• The direct connections between hubs are not allowed.
Table 1 Notations explanation.
Set
I The set of supply nodes, i ∈ I
O The set of candidate hubs, o ∈ O
J The set of demand nodes, j ∈ J
K The set of transportation modes, k ∈ K
W The set of emergency relief types, w ∈ W
Parameter
mw The unit weight of the w-type emergency relief
tiokw The transportation time of the w-type emergency relief picked up by the k-type vehicle from supply node i∈I to hub o∈O
tojkw The transportation time of the w-type emergency relief delivered by the k-type vehicle from hub o∈O to demand node j∈J
tow The transshipment time of the w-type emergency relief at hub o∈O
Mk The maximum capacity of the k-type vehicle
ciokw The unit transportation cost of the w-type emergency relief picked up by the k-type vehicle from supply node i∈I to hub o∈O
cojkw The unit transportation cost of the w-type emergency relief delivered by the k-type vehicle from hub o∈O to demand node j∈J
cow The transshipment cost of the w-type emergency relief at hub o∈O
diok The distance between supply node i∈I and hub o∈O when emergency relief is picked up by the k-type vehicle
dojk The distance between hub o∈O and demand node j∈J when emergency relief is delivered by the k-type vehicle
Siw The reserve of the w-type emergency relief at supply node i∈I
Cow The maximum capacity of hub o∈O
Djw The demand of the w-type emergency relief at demand node j∈J
Qiok The maximum available vehicle number transported from supply node i∈I to hub o∈O
Qojk The maximum available vehicle number transported from hub o∈O to demand node j∈J
φjw The minimum demand ratio of the w-type emergency relief at demand node j∈J
Decision Variables
xiokw xiokw is 1 if the w-type emergency relief is transported by the k-type vehicle from supply node i∈I to hub o∈O, is 0 otherwise
xojkw xojkw is 1 if the w-type emergency relief is transported by the k-type vehicle from hub o∈O to demand node j∈J, is 0 otherwise
xoo xoo is 1 if node o is selected to be a hub, is 0 otherwise
hiokw The amount of the w-type emergency relief picked up by the k-type vehicle from supply node i∈I to hub o∈O
hojkw The amount of the w-type emergency relief delivered by the k-type vehicle from hub o∈O to demand node j∈J
3.3 Mathematical model
Based on problem assumptions and necessary notation explanations, the model for emergency relief hub-and-spoke transportation network under COVID-19 pandemic can be detailed given in this subsection.
3.3.1 Objective function
Objective function contains two parts: (1) minimizing transportation time and (2) minimizing the total transportation cost.
COVID-19 pandemic is undoubtedly a serious emergency event and the pandemic will rapidly expand as time passes for the sake of high-infectious characteristics and COVID-19 variant [37], [38]. To some extent, time is life. Therefore, the scheduling of emergency relief should always take transportation time efficiency as the first place. The transportation time contains three parts: transportation time from supply nodes to hubs, transshipment time inside hubs and transportation time from hubs to corresponding demand nodes (Eq. (1)). (1) F1=min∑i∈I∑o∈O∑k∈K∑w∈Whiokw⋅mwMk⋅tiokwxiokw
+∑i∈I∑o∈O∑w∈Whiokwtowxoo
+∑o∈O∑j∈J∑k∈K∑w∈Whojkw⋅mwMk⋅tojkwxojkw
Secondly, the consideration of transportation cost should also be taken after transportation time consuming. Once the transportation started from supply nodes, corresponding transportation cost will generate. Particularly, more urgent the supplies are, more expensive the transportation cost will be. It can be explained that the most urgent relief will be transported by air mode to assure the time efficiency whose transportation cost is much more higher than that of other modes (road and railway mode). As is known to all that the economy is rather tense during the COVID-19 pandemic due to distribution of regular social work and life. Therefore, optimizing total transportation cost should also be considered as the second objective which contains three aspects: Transportation cost from supply node to hub, transshipment cost in hub and transportation cost from hub to demand node (Eq. (2)). (2) F2=min∑i∈I∑o∈O∑k∈K∑w∈Wciokwdiokwhiokwmwxiokw
+∑i∈I∑o∈O∑w∈Wcowhiokwmwxoo
+∑o∈O∑j∈J∑k∈K∑w∈Wcojkwdojkwhojkwmwxojkw
3.3.2 Constraints
Reasonable constraints are essential components of a model since they can restrict the model and make the solutions accurate. Firstly, the hub location and allocation should be constrained as follows:
For hub nodes, each hub node can be connected with more than one supply nodes: (3) ∑i∈Ixiokw≥1∀o∈O,k∈K,w∈W
For demand nodes, each demand node can be served by more than one hub: (4) ∑o∈Oxojkw≥1∀j∈J,k∈K,w∈W
Only if the hub is established and selected can the arcs between supply nodes and hub (or between hub and demand nodes) exist (5) xiokw≤xoo∀i∈I,o∈O,k∈K,w∈W
(6) xojkw≤xoo∀o∈O,j∈J,k∈K,w∈W
Each supply node has their own reserve limitation, the amount of relief supplies transported from the supply nodes should not exceed the corresponding reserve limitation. Similarly, each hub has its own capacity limitation for the specific relief, the amount of relief arrived and shortly stored at hubs should be within the limitation respectively: (7) ∑o∈Ohiokw≤Siw∀i∈I,k∈K,w∈W
(8) ∑i∈Ihiokw≤Cow∀o∈O,k∈K,w∈W
The flow balance principal should always be obey, that is, the amount of relief flowing into the hub equals to the amount flowing out of the hub whatever the types: (9) ∑o∈Oxojkw=1∀j∈J,k∈K,w∈W
The demand requirements should be satisfied as much as possible. In fact, the emergency relief may not be quite adequate when COVID-19 pandemic suddenly breaks out, but the minimum demand must be fulfilled: (10) ∑j∈Jhojkw≤Djw∀o∈O,k∈K,w∈W
(11) ∑j∈Jhojkw≥φjwDjw∀o∈O,k∈K,w∈W
For the transportation modes, the relief supplies with specific type can only be delivered by one transportation mode on the corresponding arc: (12) ∑k∈Kxiokw=1∀i∈I,o∈O,w∈W
(13) ∑k∈Kxojkw=1∀o∈O,j∈J,w∈W
The available vehicle number of each transportation mode is different at each supply node and hub. The vehicles put into use should not exceed the corresponding transport capacity of each node: (14) hiokwmwMk≤Qiok∀i∈I,o∈O,k∈K,w∈W
(15) hojkwmwMk≤Qojk∀o∈O,j∈J,k∈K,w∈W
All the decision variables domains are defined as follows: (16) xiokw∈{0,1}∀i∈I,o∈O,k∈K,w∈W
(17) xojkw∈{0,1}∀o∈O,j∈J,k∈K,w∈W
(18) xoo∈{0,1}∀o∈O
(19) hiokw≥0∀i∈I,o∈O,k∈K,w∈W
(20) hojkw≥0∀o∈O,j∈J,k∈K,w∈W
4 Meta-heuristic approach
In this section, we first give a brief introduction to basic GWO. Subsequently, our customized GWO is described at length in four parts: construction stage, fitness calculation, improvement stage, and the customized GWO. To make it a clear and vivid readership, we finally depict the whole model solution framework.
4.1 Basic GWO
Grey Wolf Optimizer (GWO) is a population-based meta-heuristics algorithm inspired by the hunting and social behavior of the grey wolf pack. Grey wolf maintains a hierarchy of their society. Specifically, α represents the leader wolf, β represents the second-hierarchy wolf and δ is the third-hierarchy wolf. The rest wolves are called ω. Tracking, pursuing, and attacking are the main phases of grey wolf hunting. For vivid readership, detailed introduction of basic GWO is presented in Algorithm 1.
In order to model the social hierarchy of grey wolves, the first three best wolves (α, β, δ) will instruct other wolves rushing to the target. The rest wolves (ω) always update their locations according to α, β and δ.
In the process of hunting, encircling action can be defined as following: (21) D→=|C→⋅X→p(t)−X→(t)|
(22) X⃗(t+1)=Xp⃗(t)−A⋅⃗D⃗
where t indicates the current iteration, A⃗ and C⃗ are coefficient vectors, Xp⃗(t) is the position vector of the prey, and X⃗(t) indicates the position vector of a grey wolf.
The vectors A⃗ and C⃗ are calculated as follows: (23) A⃗=2a⃗⋅r1⃗−a⃗
(24) C⃗=2⋅r2⃗
where components of a⃗ are linearly decreased from 2 to 0 over the course of iterations and r1⃗, r2⃗ are random vectors in [0,1].
Each wolf uses the potential of α, β and δ wolves in hunting strategy as they are best in pack. The wolves update their position with the help of α, β and δ as follows: (25) X1⃗=Xα⃗−A1⋅(Dα⃗)X2⃗=Xβ⃗−A2⋅(Dβ⃗)X3⃗=Xδ⃗−A3⋅(Dδ⃗)
(26) X⃗(t+1)=X1⃗+X2⃗+X3⃗3
where Xα⃗, Xβ⃗ and Xδ⃗ are the approximated positions of α, β and δ wolves. X⃗(t+1) represents the updated position of wolf.
4.2 Customized GWO
The model given in Section 3 is a nonlinear one which could not be directly solved by MIP solver. In addition, due to its NP-hardness, the model cannot be solved optimally by exact algorithms within a reasonable computational time particularly for large-scale instances. Therefore, we design a meta-heuristic approach based on GWO structure. The proposed algorithm is comprised of two stages: construction stage and improvement stage. In construction stage, some initial operations are conducted and respective constraints are checked for validation. In improvement stage, we design a HD move strategy to update GWO solutions.
Our model can be simply described as Fig. 2. As is shown in Fig. 2, the designed transportation network is divided into three processes: (1) pickup process (from supply nodes to hubs), (2) transshipment process (transshipment operations inside hubs) and (3) delivery process (from hubs to demand nodes). The transportation planning of pickup process shares the same logic with that of delivery process. Thus we only introduce detailed solutions of pickup process. The solutions of delivery process can be obtained according to the same method used in pickup process. Now we proceed to design and introduce customized GWO for solving transportation problems in pickup process.
Fig. 2 The diagram of the proposed transportation network.
4.2.1 Construction stage
In construction stage, we firstly initialize the pickup amount of food and mask. Specifically, initialize and generate a transportation-amount matrix with the scale of N(numberofsupplynodes)×M(numberofhubs). For instance, if the number of supply nodes and hubs is both two, then we generate a 2 × 2 matrix formed as [[A1, A2], [B1, B2]]. During construction of transportation-amount matrix, it should be guaranteed that the sum of A1 and A2 is no more than the reserve of current first supply node. Similarly, the total of B1 and B2 should not exceed the reserve of current second supply node. Each item in the matrix represents detailed supply amount which is always non-negative. For instance, A1 denotes the transportation quantity from the first supply node to the first hub. Two sets of N×M transportation-amount matrices are generated to represent the transportation amount of food and mask respectively. According to the model described in Section 3.3, constraint examinations should be conducted to initial transportation-amount matrices. Here, only the constraint related to hub capacity need to be checked. Take the first hub (hub1) for example, the current capacity of hub1 is the sum of A1 and B1, then we need to check whether the current capacity is within the limitation of hub1’s capacity. If all the capacity constraints of hubs are satisfied, then a transportation-amount matrix [[A1, A2], [B1, B2]] is successfully obtained. The initialization operations for transportation amounts then end up. Otherwise, regenerate transportation-amount matrix until all the hub constraints are satisfied.
Two matrices of transportation amount for food and mask could be obtained based on steps mentioned above. For the two transportation-amount matrices, we need to generate two respective transportation-mode matrices. For instance, given ‘road mode = 1, railway mode = 2 and air mode = 3’, the transportation-mode matrix can be initialized as [[2, 3], [1, 2]]. Then it can be described as: railway mode is selected to transit freights from the first supply node to the first hub. We generate transportation-mode matrices respectively against food and mask. Thus two specific transportation-mode matrices are obtained. Now we proceed to check constraints of vehicle number in each supply node. Namely, it should be examined that whether the available vehicle number can cater for current vehicle demand based on above-mentioned transportation mode. If the constraints are violated, then we regenerate transportation-mode matrices until the vehicle number constraints are satisfied.
Finally, we obtain a solution of pickup process which contains transportation-amount matrices of food and mask (food_amount, mask_amount) and corresponding matrices of transportation mode (food_trans, mask_trans). In summary, an initial solution of customized GWO will be formed as (food_amount, mask_amount, food_trans, mask_trans).
4.2.2 Fitness calculation
Each solution can be regarded as a wolf in GWO structure. After construction stage, qualified wolves are obtained. Then we proceed to calculate the fitness of each wolf according to Eq. (27): (27) fitness=w1⋅ftime−minftimeminftime+w2⋅ftrans−minftransminftrans
where ftime is the whole time consuming and ftrans denotes the total transportation cost for one solution. ftime and ftrans of pickup process can be calculated respectively by the first item of Eqs. (1), (2). w1 and w2 are particular weights of transportation time and transportation cost. The sum of w1 and w2 equals to 1 whereas w1 is set to be more than 0.5 due to the priority of time efficiency under COVID-19 pandemic. It is worth mentioning that the solutions obtained will be better when w1 = 0.6 and w2 = 0.4. minftime and minftrans are obtained by ordering the time and transportation cost among all the solutions.
4.2.3 Improvement stage
According to the fitness calculation, the first three optimal solutions are selected to be α, β, δ wolf mentioned in basic GWO. In our proposed algorithm, improvement part is focus on enhancing transportation modes, that is, the value within food_trans and mask_trans.
In improvement stage, Hamming distance (HD) concept [39] is introduced to update each ordinary wolf. In informatics, between two strings with equal length, the number of different characters in the corresponding positions is called hamming distance. For instance, the two binary strings S1= [0 1 0 1] and S2= [1 0 1 1], the first, second and third place are different between S1 and S2, then HD is 3. Now we define the transportation-mode matrix needed to improve as X and the target transportation-mode matrix is L (matrix in α, β or δ). Then, the moving distance of X attracted by L is defined as follows (Eq. (28)), that is, the random number between 0 and HD. New solutions are obtained after such HD move, as shown in Algorithm 2. After each HD move, we need to examine the constraints of vehicle number. If the new transportation mode cannot cater for the vehicle number, we will keep the original one. Otherwise, update current transportation mode. (28) Random[0,HD(X,L)]
4.2.4 The customized GWO
The design of customized GWO is given in Algorithm 2. At first, we initialize the transportation amount of food and mask by the methods introduced in Section 4.2.1, after which initial transportation-amount solutions food_amount and mask_amount are obtained. Then, based on the food_amount and mask_amount, we proceed to get transportation-mode solutions food_trans and mask_trans. A wolf in customized GWO is defined as (food_amount, mask_amount, food_trans, mask_trans).
In Algorithm 3, for the food_amount and mask_amount, there are ten different transportation modes food_trans and mask_trans being constructed respectively. Thus we form a wolf population with ten wolves. Afterwards, improvement stage introduced in Section 4.2.3 is conducted to update the wolf population. We firstly calculate fitness of wolf groups and then select the first three wolves with minimum fitness as α, β and δ. Carrying out HD move to enhance food_trans and mask_trans for obtaining better results. Continually repeat the above steps until it reaches iteration time settings. Finally we output wolf α (food_amount, mask_amount, food_trans, mask_trans) as the solution of customized GWO where food_trans and mask_trans are the optimal transportation mode against food_amount and mask_amount via customized GWO.
4.3 The whole model solution framework
The whole model solution framework is given in Algorithm 4. As is mentioned above, the transportation process contains three parts: pickup process, transshipment process and delivery process. Firstly, we conduct customized GWO (Algorithm 3) to the pickup process. Solutions of pickup process are then obtained which contain transportation amount of food and mask (food_amount and mask_amount) and their respective transportation mode (food_trans and mask_trans) from supply nodes to hubs. Secondly, calculate transshipment time and cost of food and mask in transshipment process. After that, we proceed to solve delivery process using Algorithm 3 since the solution logic is the same of both pickup and delivery process. Solutions of delivery process can also be obtained which are comprised of transportation amount of food and mask, and their respective transportation mode from hubs to demand nodes. Above all, we get solutions of pickup process, transshipment process and delivery process. According to solutions of each process, the model transportation time consuming and transportation cost can be calculated respectively by Eqs. (1), (2). Whilst solving the model, repeat the above solving process until iteration time N reaches. Meanwhile, the number of N results are obtained, from which we choose the result with minimum fitness as the final output result. By conducting the Algorithm 4, solutions of pickup process, transshipment process and delivery process are finally obtained which also give answers to Section 3.1.
5 Numerical experiments and analysis
In this section, we conduct the customized GWO to solve a real-world case of Hubei Province in China. To verify the efficiency of proposed algorithm, FA [19] and PSO [20] are also conducted and compared with customized GWO. The proposed algorithm is coded in Python and computational tests are performed on the computer with Intel(R) Core (TM) i7-5200U, CPU 2.20 GHz with 8 GB RAM. For statistical reliability, all the conducted algorithms take the same 20 independent runs.
5.1 Data collection
We use the real-life case of emergency relief (food and mask) transportation under COVID-19 pandemic in Hubei Province. The whole transportation network contains five supply nodes (Shijiazhuang, Xian, Chengdu, Guiyang and Nanning), three candidate hubs (Wuhan, Ezhou and Xiantao) and five demand nodes (Xiaogan, Huanggang, Huangshi, Tianmen and Xianning). The geographical locations of 13 nodes are shown in Fig. 3. The data comes from Gaode map, related offices and communities in Hubei province. It includes GIS (shown in Fig. 3) and parameter-related data (shown in Table 2). In Table 2, the food and mask amount are presented in the form of ‘(food-amount/ton,mask-amount/unit)’.
Fig. 3 The geographical locations of 13 nodes.
Table 2 Information of supply, hub capacity and demand.
Supply Hub capacity Demand
Shijiazhuang (3000,1700k) Wuhan (15000,10000k) Xiaogan (4900,1000k)
Xian (3800,1500k) Ezhou (8000,8000k) Huanggang (6300,2100k)
Chengdu (5650,1500k) Xiantao (9000,8500k) Huangshi (2500,1900k)
Guiyang (2650,1400k) Tianmen (1300,810k)
Nanning (1900,1000k) Xianing (2000,2000k)
5.2 Result of real-world case
Fig. 4 and Fig. 5 visualize the results of food and mask transportation in the hub-and-spoke network solving by customized GWO. The more detailed route results are listed in Table 3 and Table 4. In two tables, pickup or delivery amount and transportation mode are given in the form of ‘(amount, transportation mode)’ whereas 1 represents road mode, 2 represents railway mode and 3 represents air mode. In addition, respective transportation time consuming cost and transportation cost of food and mask are given in Table 5.
Fig. 4 The transportation network of food.
Fig. 5 The transportation network of mask.
Table 3 Pickup and delivery processes of food transportation.
Process Supply/Demand nodes Hub nodes
Wuhan Enzhou Xiantao
Pickup Shijiazhuang (0,0) (2600,2) (0,0)
Xian (3400,2) (0,0) (0,0)
Chengdu (0,0) (214,2) (5036,2)
Guiyang (2250,2) (0,0) (0,0)
Nanning (1500,2) (0,0) (0,0)
Delivery Xiaogan (0,0) (0,0) (4126,2)
Huanggang (6300,2) (0,0) (0,0)
Huangshi (0,0) (1750,2) (0,0)
Tianmen (0,0) (0,0) (910,2)
Xianning (850,2) (1064,2) (0,0)
Table 4 Pickup and delivery processes of mask transportation.
Process Supply/Demand nodes Hub nodes
Wuhan Enzhou Xiantao
Pickup Shijiazhuang (0,0) (1200k,2) (0,0)
Xian (207.9k,3) (643.9k,3) (208.1k,3)
Chengdu (0,0) (1978k,2) (0,0)
Guiyang (0,0) (0,0) (847k,3)
Nanning (565k,3) (0,0) (0,0)
Delivery Xiaogan (0,0) (0,0) (700k,2)
Huanggang (0,0) (1470k,1) (0,0)
Huangshi (0,0) (1330k,2) (0,0)
Tianmen (0,0) (567k,2) (0,0)
Xianning (772.9k,2) (454.9k,1) (355.1k,2)
Table 5 Time cost and transportation cost of real-world case.
Relief supplies Time cost (h) Transportation cost (CNY)
Pickup Transshipment Delivery Pickup Transshipment Delivery
Food 131.00 65.60 9.73 2906644.16 7287850.00 191696.00
Mask 82.97 10.40 36.83 3626481.24 1959192.42 77730.53
Total cost 336.53 16049594.34
5.3 Comparative analysis of numerical results
To further verify the efficiency of proposed algorithm, comparisons with FA [19] and PSO [20] are conducted to solve the same case. The reason for choosing PSO and FA is that they both belong to Swarm Intelligent algorithm and they exhibit great performances on solving such combinatorial problems. The comparative results are given in Table 6 which are the best ones obtained by respective algorithms in 20 runs. From the table, it can be concluded that customized GWO makes better performance on solving the problem within a reasonable time. It is worth mentioning that running time of customized GWO is not the best, but it is in a reasonable range.
Table 6 Comparisons among Customized GWO, FA and PSO.
Algorithm Cost Running time (s)
Time cost (h) Transportation cost (CNY)
Customized GWO 336.53 16049594.34 27.32
FA 374.80 16276706.55 29.13
PSO 433.79 17057410.01 26.55
6 Management insights from the industrial case
As a sudden and fast-spread disease, COVID-19 pandemic caught related epidemic areas unawares. In the real-world case given in Section 5, when COVID-19 pandemic seriously breaks out, residents in epidemic areas need to stop working and keep themselves stay at home. Thus the production and economic activities in epidemic areas need to be suspended for weeks or even months until the epidemic is basically controlled. However, during this closure period, residents’ normal medical protection equipment and basic daily necessities need to be guaranteed in quantity and quality. Local reserves are often difficult to cover basic needs, so emergency supplies need to be transported from neighboring regions with sufficient supplies. For the epidemic areas, transportation time for basic emergency relief is in the first place since time means life. Besides, transportation is accompanied by a cost. Therefore, on the basis of meeting the transportation time and demand, the economy of transportation also needs to be considered. Therefore, in this study, we make efforts to design a practically time-efficient and cost-effective transportation network when faced with COVID-19. The results of the real-world case prove the efficiency of our methods and can provide significantly practical suggestions for related authorities. From such an industrial case, some practical management insights can be extracted and concluded for related government departments and transportation companies that undertake transportation tasks.
For relevant government departments, when COVID-19 pandemic suddenly broke out, it is of paramount importance to quickly control COVID-19 pandemic situation and ensure the stability of residents’ living order during the epidemic. The first aspect needing to consider is the isolation and medical measures for infected people and the medical protection for other residents, which requires timely transportation and guarantee of medical materials. The good living order of residents is based on enough food, so the basic food demand must be satisfied, which requires the timely guarantee of basic living materials. Therefore, the transportation network designed in this study is important for delivering necessary materials on time and on-demand, which also provides the basic safeguard of management for relevant government departments.
For related transportation companies which undertake such important transportation tasks, what they need to consider is transportation capacity and economic benefits. First of all, the transportation means (trucks, trains, and airplanes) should be sufficiently used and the transportation capacity should not exceed the limited standard, which requires that the balance between demand and capacity should be fully considered when designing the transportation network. In addition, transportation companies have economic costs. Minimizing total transportation cost on the basis of meeting transportation capacity is also an essential aspect of company operation. Therefore, the transportation network designed in this study also takes the transportation cost into account. In a word, the method proposed in our study can minimize the transportation cost for transportation company meanwhile catering to the transportation capacity, which has certain practical significance for related companies undertaking transportation tasks.
7 Conclusion
COVID-19 pandemic, a world-wide hazard disease, has spread over 210 countries with unbelievable speed. The suddenness of COVID-19 outbreak will lead to great shortage of basic living materials and medical protection products in the disaster-affected areas. Therefore, it is urgent to schedule aided materials from other nearer districts to injured areas. In this study, we make efforts to design a comprehensive multimodal transportation network with hub-and-spoke structure for transporting food and mask. Considering both transportation time efficiency and transportation cost, a bi-objective MINLP model is established. Due to its nonlinearity, related MIP solver can not directly cope with it. In addition, as a NP-hard problem, it cannot be solved by exact algorithms with efficiency as the problem scales expand. Therefore, to solve such complex problem with efficiency, a meta-heuristic algorithm called customized GWO is designed and proposed in detail. Two stages are contained in proposed algorithm. In construction stage, transportation amount and transportation mode are well initialized. In improvement stage, HD move concept is introduced to further enhance solution accuracy. Taking the actual cases of Hubei Province as research background, the model is verified with real-world example. To prove that customized GWO is a promising approximation method to solve such problem, its performance is compared with other two state-of-the-art algorithms. The simulation results support the fact that our proposed algorithm can solve such problem with higher accuracy within a reasonable time.
The research has strong practical guiding significance for emergency relief supply transportation network design under COVID-19 pandemic. And some important management insights can be extracted and summarized for related government departments and transportation companies. For related government departments, this study can provide basic safeguards for medical aid and life order guarantee. For transportation companies undertaking transportation tasks, this study will guarantee both transportation capacities and economic benefits.
CRediT authorship contribution statement
Chi Li: Conceptualization, Programming, Validation. Peixiu Han: Conceptualization, Visualization, Writing – original draft. Min Zhou: Responsible for gathering information. Ming Gu: Writing – review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
==== Refs
References
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2 Alkan N. Kahraman C. Evaluation of government strategies against COVID-19 pandemic using Q-rung orthopair fuzzy TOPSIS method Appl. Soft Comput. 110 2021 107653
3 Organisation for Economic Co-operation and Development N. The Face Mask Global Value Chain in the COVID-19 Outbreak: Evidence and Policy Lessons 2020 OECD Publishing
4 Bauchner H. Fontanarosa P.B. Livingston E.H. Conserving supply of personal protective equipment—A call for ideas JAMA 323 19 2020 1911 32196543
5 Cunha C.B. Silva M.R. A genetic algorithm for the problem of configuring a hub-and-spoke network for a LTL trucking company in Brazil European J. Oper. Res. 179 3 2007 747 758
6 Meng Q. Wang X. Intermodal hub-and-spoke network design: Incorporating multiple stakeholders and multi-type containers Transp. Res. B 45 4 2011 724 742
7 Jeong S.-J. Lee C.-G. Bookbinder J.H. The European freight railway system as a hub-and-spoke network Transp. Res. A 41 6 2007 523 536
8 Aykin T. Lagrangian relaxation based approaches to capacitated hub-and-spoke network design problem European J. Oper. Res. 79 3 1994 501 523
9 Kokash N. An introduction to heuristic algorithms 2005 1 8 Department of Informatics and Telecommunications
10 Žerovnik J. Heuristics for NP-hard optimization problems: Simpler is better!? Logist. Sustain. Transp. 6 1 2015 1 10
11 Martí R. Reinelt G. Heuristic methods Exact and Heuristic Methods in Combinatorial Optimization 2022 27 57
12 Mirjalili S. Mirjalili S.M. Lewis A. Grey wolf optimizer Adv. Eng. Softw. 69 2014 46 61
13 Nadimi-Shahraki M. Taghian S. Mirjalili S. An improved Grey Wolf Optimizer for solving engineering problems Expert Syst. Appl. 166 2021 113917
14 Banaie-Dezfouli M. Nadimi-Shahraki M.H. Beheshti Z. R-GWO: Representative-based Grey Wolf Optimizer for solving engineering problems Appl. Soft Comput. 106 2021 107328
15 Ghalambaz M. Yengejeh R.J. Davami A.H. Building energy optimization using Grey Wolf Optimizer (GWO) Case Stud. Therm. Eng. 27 2021 101250
16 Seyyedabbasi A. Kiani F. I-GWO and Ex-GWO: Improved algorithms of the Grey Wolf Optimizer to solve global optimization problems Eng. Comput. 37 1 2021 509 532
17 Goli A. Zare H.K. Tavakkoli-Moghaddam R. Sadeghieh A. An improved artificial intelligence based on gray wolf optimization and cultural algorithm to predict demand for dairy products: A case study 2019
18 Rezk H. Arfaoui J. Gomaa M.R. Optimal parameter estimation of solar PV panel based on hybrid particle swarm and grey wolf optimization algorithms Int. J. Interact. Multimed. Artif. Intell. 2021
19 Altabeeb A.M. Mohsen A.M. Ghallab A. An improved hybrid firefly algorithm for capacitated vehicle routing problem Appl. Soft Comput. 84 2019 105728
20 Ai T.J. Kachitvichyanukul V. Particle swarm optimization and two solution representations for solving the capacitated vehicle routing problem Comput. Ind. Eng. 56 1 2009 380 387
21 Pettit S.J. Beresford A.K. Emergency relief logistics: An evaluation of military, non-military and composite response models Int. J. Logist.: Res. Appl. 8 4 2005 313 331
22 Sheu J.-B. An emergency logistics distribution approach for quick response to urgent relief demand in disasters Transp. Res. E: Logist. Transp. Rev. 43 6 2007 687 709
23 Lei F. Dynamic multi-objective emergency relief logistics: A decision support system framework 2007 IEEE International Conference on Grey Systems and Intelligent Services 2007 IEEE 779 783
24 Altay N. Issues in disaster relief logistics Large-Scale Disasters: Prediction, Control, and Mitigation 2008 120 146
25 Oloruntoba R. Gray R. Customer service in emergency relief chains Int. J. Phys. Distrib. Logist. Manage. 2009
26 Hu Z.-H. A container multimodal transportation scheduling approach based on immune affinity model for emergency relief Expert Syst. Appl. 38 3 2011 2632 2639
27 Bozorgi-Amiri A. Jabalameli M.S. Al-e Hashem S.M. A multi-objective robust stochastic programming model for disaster relief logistics under uncertainty OR Spectrum 35 4 2013 905 933
28 Rezaei-Malek M. Tavakkoli-Moghaddam R. Robust humanitarian relief logistics network planning Uncertain Supply Chain Manag. 2 2 2014 73 96
29 Liu Y. Lei H. Zhang D. Wu Z. Robust optimization for relief logistics planning under uncertainties in demand and transportation time Appl. Math. Model. 55 2018 262 280
30 Li S. Teo K.L. Post-disaster multi-period road network repair: Work scheduling and relief logistics optimization Ann. Oper. Res. 283 1 2019 1345 1385
31 Davoodi S.M.R. Goli A. An integrated disaster relief model based on covering tour using hybrid benders decomposition and variable neighborhood search: Application in the Iranian context Comput. Ind. Eng. 130 2019 370 380
32 Boostani A. Jolai F. Bozorgi-Amiri A. Designing a sustainable humanitarian relief logistics model in pre-and postdisaster management Int. J. Sustain. Transp. 2020 1 17
33 Korayem L. Khorsid M. Kassem S. Using grey wolf algorithm to solve the capacitated vehicle routing problem IOP Conf. Ser.: Mater. Sci. Eng. 83 1 2015 012014
34 Sopto D.S. Ayon S.I. Akhand M. Siddique N. Modified grey wolf optimization to solve traveling salesman problem 2018 International Conference on Innovation in Engineering and Technology ICIET 2018 IEEE 1 4
35 Panwar K. Deep K. Discrete Grey Wolf Optimizer for symmetric travelling salesman problem Appl. Soft Comput. 105 2021 107298
36 Faris H. Aljarah I. Al-Betar M.A. Mirjalili S. Grey Wolf Optimizer: A review of recent variants and applications Neural Comput. Appl. 30 2 2018 413 435
37 Tirkolaee E.B. Goli A. Ghasemi P. Goodarzian F. Designing a sustainable closed-loop supply chain network of face masks during the COVID-19 pandemic: Pareto-based algorithms J. Clean. Prod. 333 2022 130056
38 Dur-e Ahmad M. Imran M. Transmission dynamics model of coronavirus COVID-19 for the outbreak in most affected countries of the world Int. J. Interact. Multimed. Artif. Intell. 2020
39 M. Norouzi, D.J. Fleet, R.R. Salakhutdinov, Hamming distance metric learning, in: Advances in Neural Information Processing Systems, 2012, pp. 1061–1069.
| 0 | PMC9744582 | NO-CC CODE | 2022-12-15 00:01:50 | no | Pädiatrie. 2022 Dec 13; 34(6):60-61 | latin-1 | null | null | null | oa_other |
==== Front
Pädiatrie
Pädiatrie
1867-2132
2196-6443
Springer Medizin Heidelberg
4785
10.1007/s15014-022-4785-7
Praxis Konkret
Lichtblicke beim Umsatz und den Fallzahlen in der Pädiatrie - doch neues Ungemach droht
Schmid Raimund
Medienbüro, Ziegelbergstrasse 17, 63739 Aschaffenburg, Germany
13 12 2022
2022
34 6 6161
© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
issue-copyright-statement© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2022
==== Body
pmcDas starke Absinken der Fallzahlen in der Pädiatrie seit dem Ausbruch der COVID-19-Pandemie ist gebremst. Erfreulich ist auch, dass die Praxisumsätze weiter steigen. Wunschlos glücklich sind die Pädiaterinnen und Pädiater dennoch nicht, da weitere Restriktionen drohen.
Glücklicherweise eben nicht bei den Fallzahlen. Mit im Mittel 4.257 Patientinnen und Patienten konnte die Fachgruppe im vergangenen Jahr wieder 250 Fälle mehr pro Praxis abrechnen, als das noch 2020 der Fall war. Diese vorläufigen neuen Zahlen präsentierte Dr. Reinhard Bartezky aus Berlin, Honorarexperte im Berufsverband der Kinder- und Jugendärzte (BVKJ), beim Herbstkongress des Verbandes in Frankfurt/Main. Mit seinen Daten aus fast allen Bundesländern ist der BVKJ den offiziellen Veröffentlichungen durch die Kassenärztliche Bundesvereinigung (KBV) oder durch das Zentralinstitut der KBV stets um etwa zwei Jahre voraus.
Allerdings sei die Pädiatrie mit ihren Fallzahlen noch weit von Spitzenwerten entfernt, die man 2018 (4.460) und 2019 (4.475) erreicht hatte. Dennoch sind die Umsätze 2021 auf rund 300.000 € - nach 292.300 € ein Jahr zuvor - gestiegen. Allerdings würde diese Steigerung von den höheren Lebenshaltungskosten und den stark gestiegenen Personalkosten überkompensiert. Erschwerend komme zudem der Rückgang der Fallwerte hinzu. Sie sind 2021 (70,93 €) im Vergleich zu 2020 (72,23 €) wieder gesunken.
Weiteres Ungemach droht zudem, da die Neupatientenregelung fällt. Gemäß einer Simulation aus Berlin würden Pädiaterinnen und Pädiater laut Bartezky dabei 2,9 % Honorar einbüßen. Hinzu kommt eine Inflation von zuletzt 10 %, gestiegene Kosten für die Praxisausstattung und eine - längst überfällige - Aufstockung der Gehälter für die MFA. Angesichts dieser Trends werde die Steigerung des Orientierungspunktwertes von 11,26 auf 11,5 Cent im Jahr 2023 keinesfalls die steigenden Kosten in den Praxen auffangen können, hieß es in Frankfurt.
Umso wichtiger ist es, dass pädiatrisch Tätige zeitgemäße Trends nicht verschlafen. Wenn die Fachgruppe im 1. Quartal 2022 - und das während einer Pandemie - lediglich 7.647 Videosprechstunden abgerechnet hat, ist das gerade einmal gut eine Abrechnungsziffer pro Praxis und Quartal. Auch das Potenzial der mühsam erstrittenen Sozialpädiatrie-, Entwicklungsneurologie und Chroniker-Ziffern ist noch längst nicht ausgeschöpft. Hier könnten Honorarspielräume ausgeschöpft werden, mit denen zum Teil die gestiegenen Praxis- und Energiekosten aufgefangen werden könnten.
Basierend auf: Herbst-Seminar-Kongress des Berufsverbands der Kinder- und Jugendärzte e.V. (BVKJ), 7./8. Oktober 2022, Frankfurt/Main
| 0 | PMC9744584 | NO-CC CODE | 2022-12-15 00:01:50 | no | Pädiatrie. 2022 Dec 13; 34(6):61 | utf-8 | null | null | null | oa_other |
==== Front
Pädiatrie
Pädiatrie
1867-2132
2196-6443
Springer Medizin Heidelberg
4785
10.1007/s15014-022-4785-7
Praxis Konkret
Lichtblicke beim Umsatz und den Fallzahlen in der Pädiatrie - doch neues Ungemach droht
Schmid Raimund
Medienbüro, Ziegelbergstrasse 17, 63739 Aschaffenburg, Germany
13 12 2022
2022
34 6 6161
© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
issue-copyright-statement© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2022
==== Body
pmcDas starke Absinken der Fallzahlen in der Pädiatrie seit dem Ausbruch der COVID-19-Pandemie ist gebremst. Erfreulich ist auch, dass die Praxisumsätze weiter steigen. Wunschlos glücklich sind die Pädiaterinnen und Pädiater dennoch nicht, da weitere Restriktionen drohen.
Glücklicherweise eben nicht bei den Fallzahlen. Mit im Mittel 4.257 Patientinnen und Patienten konnte die Fachgruppe im vergangenen Jahr wieder 250 Fälle mehr pro Praxis abrechnen, als das noch 2020 der Fall war. Diese vorläufigen neuen Zahlen präsentierte Dr. Reinhard Bartezky aus Berlin, Honorarexperte im Berufsverband der Kinder- und Jugendärzte (BVKJ), beim Herbstkongress des Verbandes in Frankfurt/Main. Mit seinen Daten aus fast allen Bundesländern ist der BVKJ den offiziellen Veröffentlichungen durch die Kassenärztliche Bundesvereinigung (KBV) oder durch das Zentralinstitut der KBV stets um etwa zwei Jahre voraus.
Allerdings sei die Pädiatrie mit ihren Fallzahlen noch weit von Spitzenwerten entfernt, die man 2018 (4.460) und 2019 (4.475) erreicht hatte. Dennoch sind die Umsätze 2021 auf rund 300.000 € - nach 292.300 € ein Jahr zuvor - gestiegen. Allerdings würde diese Steigerung von den höheren Lebenshaltungskosten und den stark gestiegenen Personalkosten überkompensiert. Erschwerend komme zudem der Rückgang der Fallwerte hinzu. Sie sind 2021 (70,93 €) im Vergleich zu 2020 (72,23 €) wieder gesunken.
Weiteres Ungemach droht zudem, da die Neupatientenregelung fällt. Gemäß einer Simulation aus Berlin würden Pädiaterinnen und Pädiater laut Bartezky dabei 2,9 % Honorar einbüßen. Hinzu kommt eine Inflation von zuletzt 10 %, gestiegene Kosten für die Praxisausstattung und eine - längst überfällige - Aufstockung der Gehälter für die MFA. Angesichts dieser Trends werde die Steigerung des Orientierungspunktwertes von 11,26 auf 11,5 Cent im Jahr 2023 keinesfalls die steigenden Kosten in den Praxen auffangen können, hieß es in Frankfurt.
Umso wichtiger ist es, dass pädiatrisch Tätige zeitgemäße Trends nicht verschlafen. Wenn die Fachgruppe im 1. Quartal 2022 - und das während einer Pandemie - lediglich 7.647 Videosprechstunden abgerechnet hat, ist das gerade einmal gut eine Abrechnungsziffer pro Praxis und Quartal. Auch das Potenzial der mühsam erstrittenen Sozialpädiatrie-, Entwicklungsneurologie und Chroniker-Ziffern ist noch längst nicht ausgeschöpft. Hier könnten Honorarspielräume ausgeschöpft werden, mit denen zum Teil die gestiegenen Praxis- und Energiekosten aufgefangen werden könnten.
Basierend auf: Herbst-Seminar-Kongress des Berufsverbands der Kinder- und Jugendärzte e.V. (BVKJ), 7./8. Oktober 2022, Frankfurt/Main
| 36510047 | PMC9744585 | NO-CC CODE | 2022-12-15 00:01:50 | no | MMW Fortschr Med. 2022 Dec 13; 164(21-22):10 | latin-1 | MMW Fortschr Med | 2,022 | 10.1007/s15006-022-2216-x | oa_other |
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Autorenseite
Seniorinnen und Senioren fit und mobil halten!
Heppner Hans Jürgen [email protected]
grid.419804.0 0000 0004 0390 7708 Klinik für Geriatrie und Geriatrische Tagesklinik, Klinikum Bayreuth – Medizincampus Oberfranken, Preuschwitzer Str. 101, 95445 Bayreuth, Deutschland
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© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2022
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pmcAlle Jahre wieder … aber man kann es nicht oft genug wiederholen, liebe Kolleginnen und Kollegen. Deshalb greift Dr. Anja Kwetkat das Thema "Aktuelles zum Impfen im Alter", passend zur Jahreszeit, in bewährter Form mit den Empfehlungen der STIKO auf (ab S. 40). Sie lesen nicht nur Neues zur Influenza-Impfung, auch die Pneumokokken- und die COVID-19-Impfung sind wichtige Themen.
Um im Alter mobil zu bleiben, braucht es neben körperlicher Aktivität kräftige Knochen. Prof. Markus Gosch gibt Ihnen ein Update zur Osteoporosetherapie im höheren Lebensalter (ab S. 44). Nicht nur die Indikationsstellung wird beleuchtet, es wird Ihnen auch eine übersichtliche Zusammenstellung der Behandlungsoptionen an die Hand gegeben.
Guter und erholsamer Schlaf ist wichtig, um fit in den Tag zu starten. Prof. Helmut Frohnhofen und Kollegen gehen der Frage nach, welche Beziehung zwischen geriatrischen Syndromen und gestörtem Schlaf besteht. Es werden u. a. die Zusammenhänge zwischen Demenz und Schlaf, Sturz und Schlaf sowie Frailty und Schlaf genauer betrachtet (ab S. 48). Sicherlich alles andere als ein ermüdender Beitrag!
Und damit es bis zuletzt spannend bleibt, berichtet Prof. Holger Rupprecht in einem klinischen Fall hautnah von einer rüstigen 96-jährigen Patientin mit akuten Bauch- und Rückenschmerzen, bei der ein ungewöhnlicher Befund eine rasche Notfalleinweisung nach sich zog (ab S. 51). Ich wünsche Ihnen eine interessante Lektüre!
| 36510044 | PMC9744587 | NO-CC CODE | 2022-12-15 00:01:50 | no | MMW Fortschr Med. 2022 Dec 13; 164(21-22):5 | utf-8 | MMW Fortschr Med | 2,022 | 10.1007/s15006-022-2082-6 | oa_other |
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Heppner Hans Jürgen [email protected]
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13 12 2022
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© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
issue-copyright-statement© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2022
==== Body
pmcAlle Jahre wieder … aber man kann es nicht oft genug wiederholen, liebe Kolleginnen und Kollegen. Deshalb greift Dr. Anja Kwetkat das Thema "Aktuelles zum Impfen im Alter", passend zur Jahreszeit, in bewährter Form mit den Empfehlungen der STIKO auf (ab S. 40). Sie lesen nicht nur Neues zur Influenza-Impfung, auch die Pneumokokken- und die COVID-19-Impfung sind wichtige Themen.
Um im Alter mobil zu bleiben, braucht es neben körperlicher Aktivität kräftige Knochen. Prof. Markus Gosch gibt Ihnen ein Update zur Osteoporosetherapie im höheren Lebensalter (ab S. 44). Nicht nur die Indikationsstellung wird beleuchtet, es wird Ihnen auch eine übersichtliche Zusammenstellung der Behandlungsoptionen an die Hand gegeben.
Guter und erholsamer Schlaf ist wichtig, um fit in den Tag zu starten. Prof. Helmut Frohnhofen und Kollegen gehen der Frage nach, welche Beziehung zwischen geriatrischen Syndromen und gestörtem Schlaf besteht. Es werden u. a. die Zusammenhänge zwischen Demenz und Schlaf, Sturz und Schlaf sowie Frailty und Schlaf genauer betrachtet (ab S. 48). Sicherlich alles andere als ein ermüdender Beitrag!
Und damit es bis zuletzt spannend bleibt, berichtet Prof. Holger Rupprecht in einem klinischen Fall hautnah von einer rüstigen 96-jährigen Patientin mit akuten Bauch- und Rückenschmerzen, bei der ein ungewöhnlicher Befund eine rasche Notfalleinweisung nach sich zog (ab S. 51). Ich wünsche Ihnen eine interessante Lektüre!
| 0 | PMC9744588 | NO-CC CODE | 2022-12-15 00:01:50 | no | Pädiatrie. 2022 Dec 13; 34(6):17-18 | latin-1 | null | null | null | oa_other |
==== Front
MMW Fortschr Med
MMW Fortschr Med
Mmw Fortschritte Der Medizin
1438-3276
1613-3560
Springer Medizin Heidelberg
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10.1007/s15006-022-2082-6
Autorenseite
Seniorinnen und Senioren fit und mobil halten!
Heppner Hans Jürgen [email protected]
grid.419804.0 0000 0004 0390 7708 Klinik für Geriatrie und Geriatrische Tagesklinik, Klinikum Bayreuth – Medizincampus Oberfranken, Preuschwitzer Str. 101, 95445 Bayreuth, Deutschland
13 12 2022
2022
164 21-22 55
© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
issue-copyright-statement© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2022
==== Body
pmcAlle Jahre wieder … aber man kann es nicht oft genug wiederholen, liebe Kolleginnen und Kollegen. Deshalb greift Dr. Anja Kwetkat das Thema "Aktuelles zum Impfen im Alter", passend zur Jahreszeit, in bewährter Form mit den Empfehlungen der STIKO auf (ab S. 40). Sie lesen nicht nur Neues zur Influenza-Impfung, auch die Pneumokokken- und die COVID-19-Impfung sind wichtige Themen.
Um im Alter mobil zu bleiben, braucht es neben körperlicher Aktivität kräftige Knochen. Prof. Markus Gosch gibt Ihnen ein Update zur Osteoporosetherapie im höheren Lebensalter (ab S. 44). Nicht nur die Indikationsstellung wird beleuchtet, es wird Ihnen auch eine übersichtliche Zusammenstellung der Behandlungsoptionen an die Hand gegeben.
Guter und erholsamer Schlaf ist wichtig, um fit in den Tag zu starten. Prof. Helmut Frohnhofen und Kollegen gehen der Frage nach, welche Beziehung zwischen geriatrischen Syndromen und gestörtem Schlaf besteht. Es werden u. a. die Zusammenhänge zwischen Demenz und Schlaf, Sturz und Schlaf sowie Frailty und Schlaf genauer betrachtet (ab S. 48). Sicherlich alles andere als ein ermüdender Beitrag!
Und damit es bis zuletzt spannend bleibt, berichtet Prof. Holger Rupprecht in einem klinischen Fall hautnah von einer rüstigen 96-jährigen Patientin mit akuten Bauch- und Rückenschmerzen, bei der ein ungewöhnlicher Befund eine rasche Notfalleinweisung nach sich zog (ab S. 51). Ich wünsche Ihnen eine interessante Lektüre!
| 36510089 | PMC9744589 | NO-CC CODE | 2022-12-15 00:01:50 | no | MMW Fortschr Med. 2022 Dec 13; 164(21-22):74 | latin-1 | MMW Fortschr Med | 2,022 | 10.1007/s15006-022-2196-x | oa_other |
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Wasser Abfall
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pmcBWK-Bundesverband Technisch-wissenschaftliches Regelwerk - Aufruf zur Stellungnahme
Entwurf Merkblatt DWA-M 102-5/BWK-M 3-5 - Regenwetterabflüsse: Hydromorphologische und biologische Verfahren zur immissionsbezogenen Bewertung
Die Verbände DWA und BWK haben den Entwurf zum Merkblatt DWA-M 102-5/BWK-M 3-5 "Grundsätze zur Bewirtschaftung und Behandlung von Regenwetterabflüssen zur Einleitung in Oberflächengewässer - Teil 5: Hydromorphologische und biologische Verfahren zur immissionsbezogenen Bewertung" vorgelegt, der hiermit zur öffentlichen Diskussion gestellt wird.
Das vorliegende Merkblatt enthält praktikable und erprobte Methoden der hydromorphologischen und biologischen Nachweisführung einschließlich detaillierter Hinweise zu dessen Anwendung. Mithilfe des Verfahrens können Auswirkungen niederschlagsbedingter Einleitungen auf den hydromorphologischen und biologischen Zustand in Fließgewässern spezifisch ermittelt und geeignete Maßnahmen zur Niederschlagswasser- und Gewässerbewirtschaftung gewählt werden, um die Abweichungen des lokalen ökologischen Gewässerzustands oder Potenzials in Siedlungsgebieten im Vergleich zu Referenzgewässern im unbebauten Zustand so gering zu halten, dass die Ziele des Gewässerschutzes und die Entwicklungsziele des Gewässers erreicht werden können.
Die Arbeits- und Merkblattreihe DWA-A/M 102 bzw. BWK-A/M 3 widmet sich wasserwirtschaftlichen Anliegen des Gewässerschutzes mit besonderer Fokussierung auf niederschlagsbedingte Siedlungsabflüsse ("Regenwetterabflüsse"). Sie enthält emissions- und immissionsbezogene Grundsätze und Vorgaben zum Umgang mit niederschlagsbedingten Siedlungsabflüssen und bezieht sich sowohl auf Niederschlagswasser als auch auf Mischwasserabflüsse im Mischverfahren.
Mit den immissionsbezogenen Regelungen in den Merkblättern DWA-M 102-3/BWK-M 3-3 und DWA-M 102-5/BWK-M 3-5 werden die Inhalte der BWK-Merkblätter 3 und 7 unter Berücksichtigung der zwischenzeitlich vorliegenden umfangreichen praktischen Anwendungen weiterentwickelt und zusammengeführt. Unter anderem betrifft dies die Punkte: Erweiterung der Methodik der Nachweisführung um eine Relevanzprüfung
Implementierung der Möglichkeit zur Anwendung eines Fließzeitverfahrens zur Abbildung der zeitgerechten Abflussüberlagerung bei der vereinfachten Nachweisführung
Beschreibung eines Verfahrens zur Plausibilisierung der potenziell naturnahen Hochwasserabflussspenden
Definition von Zielvorgaben für die Feinfraktion der abfiltrierbaren Stoffe (AFS63)
Erweiterung der Nachweisführung mit hydromorphologischen Kriterien
Erweiterung der Nachweisführung mit biologischen Kriterien.
Die Arbeits- und Merkblattreihe wird gemeinsam von der Deutschen Vereinigung für Wasserwirtschaft, Abwasser und Abfall e. V. (DWA) und dem Bund der Ingenieure für Wasserwirtschaft, Abfallwirtschaft und Kulturbau e. V. (BWK) fortgeschrieben und umfasst zurzeit folgende Veröffentlichungen: Teil 1: Allgemeines (Dezember 2020)
Teil 2: Emissionsbezogene Bewertungen und Regelungen (Dezember 2020)
Teil 3: Immissionsbezogene Bewertungen und Regelungen (Oktober 2021)
Teil 4: Wasserhaushaltsbilanz für die Bewirtschaftung des Niederschlagswassers (März 2022)
Teil 5: Hydromorphologische und biologische Verfahren zur immissionsbezogenen Bewertung (Entwurf Dezember 2022).
Das Merkblatt DWA-M 102-5/BWK-M 3-5 wurde von der BWK-Arbeitsgruppe 2.3 "Anforderungen an Misch- und Niederschlagswassereinleitungen unter Berücksichtigung örtlicher Verhältnisse" (Vorsitzender: Prof. Dr. Dr. h. c. Dietrich Borchardt) in enger Abstimmung mit der DWA-Arbeitsgruppe ES-2.1 "Systembezogene Anforderungen und Grundsätze" (Sprecher: Prof. Dr.-Ing. Theo G. Schmitt) erarbeitet. Es richtet sich an Planende, Wasserbehörden und Abwasserbeseitigungspflichtige.
Frist zur Stellungnahme
Das Merkblatt DWA-M 102-5/BWK-M 3-5 "Grundsätze zur Bewirtschaftung und Behandlung von Regenwetterabflüssen zur Einleitung in Oberflächengewässer - Teil 5: Hydromorphologische und biologische Verfahren zur immissionsbezogenen Bewertung" wird bis zum 28. Februar 2023 öffentlich zur Diskussion gestellt. Hinweise und Anregungen sind schriftlich, möglichst in digitaler Form, zu richten an:
BWK-Bundesgeschäftsstelle
Dr.-Ing. Birgit Schlichtig
Salzstraße 1, 21335 Lüneburg
E-Mail: [email protected]
Für den Zeitraum des öffentlichen Beteiligungsverfahrens kann der Entwurf kostenfrei im DWA-Entwurfsportal eingesehen werden: www.dwa.de/entwurfsportal. Dort ist auch eine digitale Vorlage zur Stellungnahme hinterlegt.
Entwurf Merkblatt DWA-M 102-5/BWK-M 3-5 "Grundsätze zur Bewirtschaftung und Behandlung von Regenwetterabflüssen zur Einleitung in Oberflächengewässer - Teil 5: Hydromorphologische und biologische Verfahren zur immissionsbezogenen Bewertung", Dezember 2022, 32 Seiten, ISBN 978-3-936015-97-3 (Printversion), 978-3-936015-96-6 (E-Book), Ladenpreis: 45,00 Euro, BWK-Mitglieder: 36,00 Euro.
Herausgeber und Vertrieb
Bund der Ingenieure für Wasserwirtschaft, Abfallwirtschaft und Kulturbau e. V. (BWK)
Salzstraße 1
21335 Lüneburg
Telefon: +49 4131 206 3 980
E-Mail: [email protected]
Internet: www.bwk-bund.de
Landesverband Brandenburg und Berlin 27. Landeskongress in Brandenburg und Berlin
Aufgrund von Covid 19 musste der LV Brandenburg und Berlin seinen 27. Landeskongress 2 Jahre lang verschieben und die nötigen satzungsgemäßen Mitgliederversammlungen online durchführen, was kein wirklicher Ersatz für einen "richtigen" Kongress war. 2022 war es endlich wieder möglich, ohne umfangreiche Sicherheitsvorkehrungen Präsenzveranstaltungen abzuhalten. "Urbane Sturzfluten" standen im Mittelpunkt der Fachtagung, die am 22. Oktober 2022 den Auftakt des Kongresses in Schönefeld bei Berlin bildete. Weitere Veranstaltungsteile waren die 31. Mitgliederversammlung sowie die Besichtigung der Baustelle des Regenüberlaufbeckens Chausseestraße in Berlin-Mitte.
Eröffnung der Fachtagung
Der Kongress wurde durch den scheidenden Vorsitzenden des Landesverbandes, Herr Dipl.-Ing. Ulrich Blüher, eröffnet, der die Teilnehmerinnen und Teilnehmer auf das Thema der Veranstaltung einstimmte. "Urbane Sturzfluten - Wasserwirtschaft im Zeichen des Klimawandels" passt so gar nicht in den derzeitigen Kontext von Niederschlagsdefizit, Trockenheit und Niedrigwasser. Und trotzdem hat sich der BWK entschieden, am 2019 gewählten Kongressthema festzuhalten, da schon ein Blick an die Ahr und die Erft zeigt, dass Starkniederschläge nicht der Vergangenheit angehören, sondern im Fokus von Fachleuten, Gesellschaft, Politik und Bürgen bleiben müssen, damit wir vorbereitet sind.
Die Entwicklung von Starkniederschlägen und Klima in Deutschland
Dr. Frank Kreienkamp vom Klimabüro Potsdam des Deutschen Wetterdienstes wies in seinem Referat zunächst darauf hin, dass nach dem linearen Trend der Jahre 1881 - 2020 die Erwärmung in Deutschland schneller fortschreitet, als weltweit. So stieg in Deutschland die Intensität des Sonnenscheins, zugleich nahmen die Sommertage seit 1961 deutlich zu. Das hat Auswirkungen auf die Niederschlagssummen und die Niederschlagsverteilung in Deutschland, da eine wärmere Atmosphäre mehr Feuchtigkeit aufnehmen kann. Im Ergebnis ändern sich seit 1961 die Niederschlagssummen. Zu beobachten ist eine Zunahme im Winterhalbjahr um 20 - 30 %, der eine Abnahme um 5% im Sommerhalbjahr gegenübersteht. Die Sturzflut im Juli 2021 wurde durch ein Niederschlagsereignis mit einer Wahrscheinlichkeit von 1 in 400 Jahren ausgelöst. Die Wahrscheinlichkeit solcher Ereignisse steigt zukünftig um den Faktor 1,2 - 1,4, ein vermehrtes Auftreten von Extremereignissen ist wahrscheinlich. Dabei wird davon ausgegangen, dass sich im Sommer Hitzeperioden und Starkregenereignisse abwechseln werden. Außerdem mehren sich die Hinweise auf eine Erhöhung der Stabilität von Wetterlagen und damit eine Verschärfung extremer Wettersituationen.
Urbane Sturzfluten - Hintergründe, Risiken und Vorsorge
Prof. Dr.-Ing. F. Wolfgang Günthert von der Universität der Bundeswehr München stellte im Anschluss zunächst die Hintergründe urbaner Sturzfluten heraus. Neben der Änderung des Klimas sind das: geringe Vorwarnzeiten bei lokalen Ereignissen, zunehmende Bebauung und Versiegelung, intensive Landwirtschaft und Einengung von Fließgewässern sowie technische und konstruktive Grenzen der öffentlichen Entwässerung. Zugleich beklagte er das Fehlen adäquater Rahmenbedingungen. Gefahrenkarten, die auch das Risiko von Überschwemmungen berücksichtigen und nach dem WHG für oberirdische Gewässer vorgeschrieben sind, sind für Starkregenereignisse nicht gefordert. Die LAWA hat 2018 eine Strategie für ein effektiveres Risikomanagement entwickelt, das die Rolle und Aufgaben der Kommunen auf der einen Seite und von Unternehmen/Personen auf der anderen Seite regeln soll. Auf dieser Basis haben Bund, Länder und Kommunen begonnen, Starkregengefahrenkarten entwickeln zu lassen, die die Risiken visualisieren und beschreiben sollen. Sie sollen zugleich von Betroffenen genutzt werden, um sich über das Risiko zu informieren und im Rahmen ihrer Zuständigkeit (Objektschutz) Vorsorge zu treffen.
Urbane Sturzfluten - Herausforderungen für die Stadtentwässerung
Die Leiterin Forschung und Entwicklung der Berliner Wasserbetriebe, Frau Regine Gnirß, begann ihren Vortrag mit der Frage, wie sich Sturzfluten in Berlin auswirken. Versiegelung, begrenzte Möglichkeiten zur Wasserabführung und innerstädtische Platzverhältnisse begünstigen das Risiko von Überflutungen. Der Kernbereich der Stadt wird im Mischsystem entwässert. Zwischen 2011 und 2016 nahm die städtische Versiegelung um 3 % zu. 2017 fielen innerhalb von 18 h - zu 150 l/m² Regenwasser, was zu spektakulären Bildern von überfluteten U-Bahnhöfen, Straßen und Unterführungen führte. Berlin versucht auf verschiedenen Wegen mehr Resilienz gegen Starkregenereignisse zu erreichen. So entstehen im Mischwassernetz Stauräume und Speicher, die künftig über ein Volumen von über 300.000 m³ verfügen werden. Auf den Kläranlagen Waßmannsdorf und Schönerlinde entstehen Mischwasserspeicher mit einem Rückhalteraum von 90.000 m³. Deutschlands erste Regenwasseragentur berät Verwaltung, Planer und Bürger und fördert ein dezentrales Regenwassermanagement. Auf dem Weg zur Schwammstadt liegt in Berlin der Schlüssel im dezentralen Regenwassermanagement, also auch in der Abkoppelung von Flächen.
Im Rahmen des Projekts SANSARE erfolgte zunächst an 12 Fokussenken eine Analyse des Gefährdungs- und Schadenspotenzials innerstädtischer Bereiche. Bis 2027 sollen flächendeckende Karten vorliegen. SANSARE könnte zukünftig zur Online-Warnplattform werden und Überflutungen vorhersagen. Mit dem Senso- und Funknetzwerk LoRaWAN ist eine Überwachung des Wasserstands im Kanal und an der Oberfläche möglich. Damit erhalten die BWB nicht nur Echtzeitwasserstände, sondern auch ein aktuelles Lagebild, was sie in die Lage versetzt, Verteilung, Rückhalt und Abfluss im Mischwassernetz zu steuern.
Modellgestützte Ermittlung von Gefährdungen durch Sturzfluten
Ziele, Grundlagen und Methoden von Starkregen-Risikomodellen standen im Fokus des Vortrags von Herr Dr.-Ing. Oliver Buchholz, Hydrotec Ingenieurgesellschaft Aachen. Die Vermeidung bzw. Verminderung von Schäden durch Sturzfluten und Überflutungen sind wesentliche Aufgaben des kommunalen Überflutungsschutzes und des Starkregenrisikomanagements. Stehen bei ersterem Häufigkeiten bis 30 Jahre im Mittelpunkt, werden bei letzterem außergewöhnliche bzw. extreme Abflussereignisse betrachtet. Hierzu gibt es bereits eine Reihe von Leitfäden und Arbeitshilfen, von denen weitere in Bearbeitung sind. Enthaltene Starkregengefahrenkarten basieren in der Regel auf Modellen.
Zur hydraulischen Gefährdungsanalyse wird ein finite Volumenmodell des Untersuchungsraums erstellt, das Versickerungsbereiche, Überläufe, Überstauungen des Kanalsystems oder Einläufe berücksichtigt. Online- und Offlinekopplungen mit dem Kanalnetz sind möglich. In den so entstehenden Gefahrenkarten werden kritische Bereiche kenntlich gemacht, die hydraulische Gefährdungsanalyse ist objektbezogen möglich. Ergebnisse können dynamisch visualisiert werden. Für besonders kritische Infrastruktur können Risikosteckbriefe angefertigt werden, für allgemeine kritische Objekte Risikokarten. Aus beidem lassen sich Maßnahmen zum Schutz der Bevölkerung und der Infrastruktur ableiten.
Starkregen - Schadenerfahrung und Risikobewertung
Dr. Tim Peters, Provinzial Versicherung Münster, ging zunächst darauf ein, dass Umfragen von FORSA und GfK zeigen, dass das Naturgefahrrisiko in Deutschland massiv unterschätzt wird. Nur etwa 50 % der Gebäude und Wohnungen sind durch eine Elementarschadenversicherung, die auch die Risiken von Rückstau, Hochwasser und Starkregen umfassen würde, abgesichert. Der marktweite Schadenaufwand in der Wohngebäudeversicherung steigt seit dem Jahr 2003 kontinuierlich an und betrug 2021 über 10,6 Mrd. Euro. Die meisten Schäden werden durch Starkregenereignisse mit kurzer Dauerstufe verursacht, die an jedem Ort Deutschlands mit im Wesentlichen gleicher Wahrscheinlichkeit auftreten können. Aufgrund klimatischer Veränderungen ist in Zukunft mit einer Häufung solcher Ereignisse zu rechnen. Schadensereignisse lassen sich durch die Ausnutzung der zur Verfügung stehenden georeferenzierten Daten relativ gut in ihrer Schadenwirkung erfassen und beschreiben. Trotz hoher Schadensummen sind in Deutschland lediglich die Hälfte der Wohngebäude gegen solche Ereignisse versichert.
31. Mitgliederversammlung und Wahlen zum Landesvorstand
Die 31. Mitgliederversammlung stand im Zeichen der Neuwahl des Vorstands des Landesverbands. Zunächst aber wurde der scheidenden Geschäftsführerin des LV, Frau Dipl.-Ing. Jeannette Riedel, namens und im Auftrag des BWK-Bundesvorstands für ihre Verdienste um den Verband die Ehrennadel des BWK verliehen. Anschließend berichtete der Vorstand über die Geschäfts- und Kassenführung 2021. Nach Vorstellung des Kassenprüfberichtes wurde die Entlastung des Vorstands beantragt.
Hieran schlossen sich Neuwahlen zum Landesvorstand an, dem zukünftig folgende Mitglieder angehören:
Geschäftsführender Landesvorstand:
Vorsitzender Dipl.-Ing. Silvio Alich, Wasser- und Bodenverband Spree-Neiße
stellv. Vorsitzender Dipl.-Ing. Jörg Priebe, PPN Prowa Neuruppin
Geschäftsführer Dipl.-Ing. Holger Haas, IPRO Consult GmbH
Schatzmeister Dipl.-Ing. Helge Brüggemann, Ing.-Büro WBL Potsdam
Referentinnen und Referenten:
Ausbildung Dipl. VerwW. Janina Meyer-Klepsch, Gemeinde Panketal
Fortbildung Dipl.-Ing. Jeannette Riedel, Büro AquaConstruct
Gesellschaftliche Dipl.-Ing. Michael Auswirkungen der Mucha, Wasser- und Umwelttechnik Bodenverband Oberland-Calau
Öffentlichkeitsarbeit Dipl.-Geophys. Bernd Modenbach, Ing.-Büro GeoModenbach
Im Anschluss an die Verkündung des Wahlergebnisses dankten die Vorsitzenden der Bezirksgruppen den ausgeschiedenen Vorstandsmitgliedern für ihre teils sehr lange Vorstandstätigkeit.
Fachexkursion
Passend zum Thema führte die Fachexkursion zur Baustelle des Regenüberlaufbeckens IV an der Chausseestraße in Berlin. Hier entsteht in einer Schlitzwand-Doppelbaugrube ein 21 m tiefes Rückhaltebecken mit einem Fassungsvermögen von bis zu 16.750 m³ Wasser. Frau Boldt von den Berliner Wasserbetrieben und Herr Lehmann von der Bauunternehmung Karl Köhler GmbH Heidenau erläuterten den Teilnehmerinnen und Teilnehmern der Exkursion zunächst Funktionsweise, Planung, Ausführung und Betrieb des Rückhaltebeckens. Anschließend wurden die Baugrube besichtigt, die aktuell durchgeführten Bauarbeiten erläutert und ein Ausblick auf die weitere Bauausführung gegeben. Die Exkursion endete mit angeregten Gesprächen in einem nahe gelegenen Restaurant.
Jeannette Riedel und Ulrich Blüher
LANDESVERBAND NORDRHEIN-WESTFALEN Landeskongress in Siegen zum Thema "Wald und Wasser - Aufbruch für ein Ökosystem"
Anlässlich des Landeskongresses 2022 war der BWK mit dem Thema "Wald und Wasser - Aufbruch für ein Ökosystem?" zu Gast in Siegen.
Vor 75 Jahren hat sich der BWK-Landesverband NRW in Siegen neu gegründet. Aus diesem Anlass hat der BWK NRW auch 75 Bäume bei OroVerde - Die Tropenwaldstiftung gestiftet.
Dieses besondere Jubiläum feiert der BWK nun das ganze Jahr und so war es naheliegend wieder einmal mit einer großen Veranstaltung nach Siegen zu gehen. Der Ort für den Kongress zeigt auch die Nähe zur Universität Siegen. Mitten in der Oberstadt liegt der neue Universitätscampus "Unteres Schloss". Im umgebauten Obergeschoss über einem Kaufhaus befindet sich das neue Hörsaalzentrum. Hier fand nun der Kongress mit dem interessanten und hoch aktuellen Thema statt.
Der BWK-Landesvorsitzende Prof. Dr.-Ing. habil. Bert Bosseler und Herr Schumann, Vertreter der Stadt Siegen, begrüßten die rund 80 Kongressteilnehmerinnen und -teilnehmer. Herr Schumann zeigt auch gleich, welche Rolle der Wald für Siegen und den Kreis Siegen-Wittgenstein hat. Hier zeigen sich viele Herausforderungen für den Wald als Reaktion auf den Klimawandel. Mangelnde Niederschläge, lange ausgeprägte Dürrephasen und erhöhte Temperaturen setzen dem Wald stark zu. Fast alle Baumarten stehen unter Trockenstress und große Teile der Fichtenbestände sind nach der Trockenheit, vom Borkenkäfer befallen, abgestorben.
Prof. Dr. Peter Annighöfer hat den gesamten Sachverhalt in seinem Vortrag "Der Wald im Dilemma unserer Erwartungen - ein Ausblick" ausführlich und gut verständlich zusammengefasst.
Die Veränderungen des Klimas mit dem Anstieg der Temperaturen, der Veränderung der Niederschlagsverteilung, der Verlängerung der Vegetationsperioden, Häufung von Witterungsextremen und der Zunahme von Trockenstress gefährden Baumarten und die jetzige Waldbewirtschaftung. Alle Aspekte unserer Erwartungen an den Wald sind davon beeinträchtigt. Um dem entgegenzutreten, ist es erforderlich, noch vitale Wälder zu stabilisieren und schon geschädigte Wälder unter Berücksichtigung natürlicher Prozesse umzubauen. Hier sind Vielfalt und viel Geduld angesagt.
Umweltpreis
Der BWK-Landesverband NRW hat im Anschluss an den Vortrag den mit 1000,- € dotierten BWK Umweltpreis NRW 2022 an die "KlimaWelten Hilchenbach" www.klimawelten.de verliehen. Die KlimaWelten haben eine alte Grundschule in Hilchenbach zu einem Ort umgebaut, in dem vor allem Kinder spielerisch den Umgang und Lösungen in Klima-Fragen erlernen können (siehe auch WASSER UND ABFALL Heft 9/2022). Passend zum Thema des Landeskongresses spielt dabei auch der Wald mit seiner Bedeutung für die Umwelt und die Region eine große Rolle.
Dr. Frank Thonfeld offenbart mit seinem Vortrag "Deutschlands Wald nach den Trockenjahren 2018-2020" die Auswirkungen der Dürre auf den Wald aus der Satellitenperspektive. Er erklärt, welche Informationen zum Waldzustand und der Entwicklung der Wälder mit Hilfe der Beobachtung der Erdoberfläche mit Satelliten möglich sind. Die Auswirkungen der Dürre und insbesondere das Absterben der Fichtenbestände wird besonders deutlich an einem Gürtel in der Mitte Deutschlands von der Eifel bis nach Sachsen. Schäden und Veränderungen zeigen sich auch in zahlreichen anderen Ländern der Erde. Die Satellitenbeobachtung ist ein wichtiges Instrument für die Forstwirtschaft und eröffnet neue Möglichkeiten für die Betrachtung von Waldgebieten.
Prof. Dr. Jürgen Jensen betrachtet mit der Vorstellung des Forschungsprojektes "WaldAktiv - Nutzung von Waldflächen als Schutz für Ortschaften oder Gewerbegebiete vor Auswirkungen von Starkregen in Siegen-Wittgenstein". Hier zeigt sich die große Bedeutung des Waldes, schon allein aufgrund seines hohen Flächenanteils, für die Auswirkungen von Starkregenereignissen. Wälder halten Niederschläge gut zurück, puffern den Oberflächenabfluss und fördern die Grundwasserneubildung. Schädigungen des intakten Waldes erhöhen den Oberflächenabfluss. Der Abfluss aus Waldflächen kann vor allem punktuell Siedlungsflächen und Infrastruktur gefährden. Über die Modellierung von Einzugsgebieten und gezielt berechneten Niederschlagsabflüssen kann man kritische Gebiete im Detail betrachten. Mit Hilfe der Untersuchungen von kleinen Einzugsgebieten kann man auch Maßnahmen zur Reduktion oder Umleitung der Abflüsse aus dem Wald entwickeln.
Dr. Mathias Niesar stellt mit seinem Vortrag "Wald der Zukunft aus Sicht des Klimaschutzes" dar, was ein anpassungsfähiger (elastischer) und stabiler Wald ist. Zahlreiche der aktuell in Monokulturen angebauten Bäume sind als Baumart und mit der jetzigen Bewirtschaftungsform nicht auf die klimatischen Veränderungen eingestellt und sind daher für massive Schädigungen sehr anfällig. Mischwälder mit unterschiedlichen Baumarten, möglichst in Gruppen, unterschiedlichen Alters und unterschiedlicher Größe sind am ehesten anpassungsfähig (elastisch) und stabil, um sich den veränderten Standortbedingungen anzupassen. Die Entwicklung solcher Wälder dauert sehr lange und verändert auch stark die Form der forstwirtschaftlichen Nutzung. Ein stabiler Wald hat einen jährlichen Holzzuwachs, den man nachhaltig und langfristig zur Nutzung entnehmen kann. Diese nachhaltige Nutzung von Holz bleibt auch weiterhin sehr sinnvoll, vor allem wenn das Holz so in Möbel und Bauwerken CO2 bindet.
Dr. Bitta Linnemann berichtet mit ihrem Vortrag "Fit für den Klimawandel - Maßnahmen für eine nachhaltige naturnahe Anpassung feuchter Wälder" über die speziellen Bedürfnisse solcher Waldformen. Feuchte Wälder mit sehr hoch anstehendem Grundwasserstand sind eine an die örtlichen Wasserstände besonders angepasste Waldform. Tiefe Wasservorkommen sind für die Bäume aufgrund der Bodenschichtung nicht nutzbar. Das Austrocknen dieser Wälder entzieht den Bäumen dann die Lebensgrundlage. Hier gilt es, mit gezielten Maßnahmen den Abfluss von Wasser aus dem Wald zu reduzieren und einen hohen Grundwasserstand zu halten. Wie das gehen kann, zeigt Frau Linnemann an einzelnen Beispielen.
Mit dem Vortrag "Klimaanpassung - grüne Infrastruktur in urban geprägten Räumen" bewertet Thorsten Stock die Bedeutung von Bäumen, Baumgruppen und Wald für das Klima in Städten und den urban geprägten Räumen. Bäume haben großen positiven Einfluss auf das Stadtklima. Insbesondere können Bäume und Baumgruppen bei sommerlicher Hitze abkühlen und die Aufenthaltsqualität verbessern. Die Wirkung vorhandener Bäume kann man messen und untersuchen. Dies hilft, mit gezielten Anpflanzungen oder Eingriffen in die Stadtgestaltung positive Veränderungen anzustoßen.
Die Vorträge und Diskussionen zeigen deutlich den Stellenwert des Waldes in unserer Gesellschaft und dessen Bedeutung über die forstwirtschaftlichen Belange hinaus. Wald in der aktuellen Form wandelt sich und reagiert empfindlich auf die Veränderungen des Klimas. Eingriffe und Maßnahmen bei der Umgestaltung der Wälder brauchen viel Zeit. Unser Tun muss wissenschaftlich begleitet, die Prozesse gut beobachten, damit wir den Wald besser verstehen. Auch das Eingreifen des Menschen muss sich flexibel anpassen und mehr Vielfalt wagen.
Mitgliederversammlung
Der Landeskongress endete wieder mit der anschließenden Mitgliederversammlung des Landesverbandes NRW, in deren Verlauf auch die Wahl des Referenten für Ausbildung erfolgte und Ehrungen von Mitgliedern für die langjährige Mitgliedschaft im BWK anstanden.
Im Beisein der Ehrenmitglieder des Landesverbandes Dr. Harald Irmer und Dieter Klähn sowie des Bundesverbandes Horst-Sigurd Schelp wurde der Geschäftsbericht 2021, die Berichte der Referenten und des Jungen Forums im BWK sowie der Haushalt vorgestellt. Insbesondere die weiterhin positive Mitgliederentwicklung fand bei den anwesenden Mitgliedern große Zustimmung.
Bei der Wahl des Referenten für Ausbildung wurde Prof. Dr.-Ing. Klaas Rathke wiedergewählt.
Geehrt wurden zudem 20 Mitglieder für die langjährige Mitgliedschaft im BWK. Darunter für die 50-jährige Mitgliedschaft das Ehrenmitglied und ehemaliger Bundesgeschäftsführer Horst-Sigurd Schelp. Allen anwesenden Jubilaren wurden die entsprechenden Ehrenurkunden feierlich überreicht.
Mit einem Dank an die ausrichtende Bezirksgruppe Siegen sowie der Einladung zum kommenden Landeskongress 2023, den die Bezirksgruppe Ruhrgebiet ausrichten wird, schloss ein schöner Landeskongress mit einem brandaktuellen Thema ab.
Am Tag nach dem Landeskongress in Siegen wurden wir noch vom frisch geehrten Umweltpreisträger 2022, den Klimawelten Hilchenbach, zur Ausstellungseröffnung über die Arbeit von OroVerde eingeladen und um uns direkt vor Ort einen Eindruck über die Arbeit der Klimawelten Hilchenbach zu machen. Beeindruckt fuhren wir nach Hause.
Peter Klein und Christian Sustrath
Landesverband Sachsen-Anhalt Positionspapier zur Wasserwirtschaft im Klimawandel
veröffentlicht anlässlich des Tages der Wasserwirtschaft des Wasserverbandstages Bremen, Niedersachsen, Sachsen-Anhalt e. V. in Magdeburg am 9. November 2022
Der Bund der Ingenieure für Wasserwirtschaft, Abfallwirtschaft und Kulturbau (BWK) mit seinem Landesverband Sachsen-Anhalt hatte sich schon 2019 in seinem Landeskongress und 2021 als Ausrichter des Bundeskongresses in Dessau dem Thema "Daseinsvorsorge Wasser" gewidmet.
Dabei hatten wir 2019 den Schwerpunkt auf den Nationalen Wasserdialog in Verantwortung des Bundesministeriums für Umwelt, Naturschutz und nukleare Sicherheit (BMU) und die Versorgungssicherheit mit Trinkwasser gelegt. Dies erscheint aus jetziger Sicht nach weiteren Trockenjahren und zunehmendem Faktenwissen um die Klimaveränderungen und deren Folgen nicht mehr ausreichend für uns als Verband, der sich: BWK - die Umweltingenieure nennt.
Auch die Formulierungen im Koalitionsvertrag in Sachsen-Anhalt: "…mit Blick auf den Klimawandel müssen wir neben der Wasserregulierung durch Stauanlagen auch die zielgerichtete Bewirtschaftung der Elbe und ihrer Zuflüsse ermöglichen."… und an anderer Stelle: "… ist Wasser durch fachlich geeignete Maßnahmen im Anfallgebiet zurückzuhalten, um den Gebietswasserhaushalt zu stabilisieren." machen die Bedeutung des Wassers im Hinblick auf den Klimawandel deutlich.
Dabei sind aus unserer Sicht aber Einstau und Rückhalt des Wassers in teilweise vor 30 und mehr Jahren ausgebauten Gewässer, deren Ausbauziele anderen Prämissen folgten, neu und umfassend zu bewerten. Besonderes Augenmerk verdient dabei die Gewässerunterhaltung, die an die klimatischen Veränderungen im Wasserhaushalt anzupassen ist. Unterhaltungsverbände (UHV), der Landesbetrieb für Hochwasserschutz und Wasserwirtschaft (LHW) und die Wasserstraßen- und Schifffahrtsverwaltung des Bundes (WSV) allein können die neuen Ziele nicht erfüllen.
Die Situation im Klima und Wasserkreislauf ist gekennzeichnet durch: steigende Mitteltemperaturen in allen Monaten
mehr Sommer- und Hitzetage und Verlängerung der Vegetationsperiode
höhere Verdunstung und höhere Wassertemperaturen in den Oberflächengewässern.
Dies führt nach Angaben des Landesamtes für Umweltschutz des Landes Sachsen Anhalt (LAU) schon jetzt zu einer negativen Entwicklung der klimatischen Wasserbilanz von -83,6mm in der Jahressumme mit positiver Bilanz nur im Winter, leicht ausgeglichenen Werten im Frühjahr und Herbst und deutlichem Rückgang im Sommer als Hauptvegetationsperiode. Besonders betroffen ist dabei das Grundwasser als unser größter Wasserspeicher mit den bekannten Auswirkungen der Verfügbarkeit im Wurzelhorizont für Land- und Forstwirtschaft, Garten- und Weinbau usw.
Diese Trendaussagen betreffen das gesamte Land aber nicht überall können wir versuchen, mit Stauanlagen auch in Kleingewässern der UHV oder in Elbe, Mulde, Saale oder Havel, zumal letztere schon staugeregelt sind, die Wasserbilanz vor allem im Grundwasser durch die Verringerung der Entwässerungstiefe zu verbessern.
Wir unterstützen daher als BWK-LV mit unseren Mitgliedern in den bestehenden regionalen Arbeitsgruppen Nord, Mitte, Süd und Harz und im Beirat des Ministeriums für Wissenschaft, Energie, Klimaschutz und Umwelt des Landes Sachsen-Anhalt die Lösung der aktuellen aber eigentlich Zukunftsaufgaben, wie sie auch im "Zukunfts- und Klimaschutzkongress" vom Juli 2022 für die Industrie, den Verkehr, die Gebäudewirtschaft und die Land- und Forstwirtschaft deutlich formuliert wurden.
In die Diskussion und Suche nach Lösungen sind alle Bereiche der Wirtschaft und des öffentlichen Lebens einzubeziehen. Arbeitsschwerpunkte wären aus unserer Sicht:die weitere Datenerhebung und ein Aufbau eines Monitorings im Wasserkreislauf auf wissenschaftlicher Basis
die Anpassung von Wasserstrukturen im natürlichen Kreislauf und in der Wasserversorgung/Abwasserbehandlung und der Regenwasserbewirtschaftung in Ortslagen (Schwammstädte)
die Untersuchung von Stützungsmöglichkeiten des Oberflächen- und Grundwassers durch Einstau bei gleichzeitig Beschattung, Prüfung der Wirksamkeit von Drainagen, Nutzung auch von Grünen Rückhaltebecken
Untersuchung zur Nutzung von Wässern aus verschiedenen Quellen (WaterReuse) für industrielle, gewerbliche und landwirtschaftliche Zwecke
die offene Diskussion der Konkurrenz zwischen EU-WRRL mit der ökologischen Durchgängigkeit und dem Wasserrückhalt an bewirtschaftbaren Stauanlagen
überprüfen des oftmals jahrzehntealten Ausbauzustandes der Gewässer hinsichtlich der Eignung für Niedrigwasserzeiten und Hochwasserabführvermögen
Die Gewässerunterhaltung und Bewirtschaftung durch die Unterhaltungsverbände ist in der Fläche dabei nicht die einzige Lösung; sie muss im Zusammenhang mit allen anderen Gebieten und Zuständigkeiten gesehen werden, ohne dabei vordergründig die Fragen der Beitragserhöhung bei Aufgabenzuwachs zu stellen, aber sie ist von Ausbaumaßnahmen und deren Finanzierung anzugrenzen.
Der LHW und der Talsperrenbetrieb Sachsen-Anhalt (TSB) aber auch die Wasserstraßen- und Schifffahrtsverwaltung des Bundes sind in den regionalen Arbeitsgruppen ebenso gefragt wie der Gewässerkundliche Landesdienst, das Landesamt für Umweltschutz, das Umweltforschungszentrum, die Kreisbauernverbände und der Waldbesitzerverband. Der Arbeit des Gewässerkundlichen Landesdienstes messen wir dabei eine besondere regionale Führungsrolle zu.
Der BWK-Landesverband bietet bei all diesen Aufgaben mit seinen persönlichen und fördernden Mitgliedern die Unterstützung an, die sich auch auf die Mitarbeit der Hochschulen des Landes über dortige Forschungen und studentische Arbeiten beziehen könnte. Im Rahmen der Studienpreisvergabe und der Unterstützung von Projekten der Wasserwirtschaft können wir dies auch in kleinem Umfang finanziell unterstützen.
Wichtig ist uns, gemeinsam mit den wasserwirtschaftlichen Institutionen eine fachlich begründete politisch-gesellschaftliche offene Diskussion über das Thema Wasser anzustoßen und das Wasser als Kernthema des Klimawandels in den Focus zu stellen.
Hans-Werner Uhlmann
Landesverband Sachsen Fachkonferenz "Gesellschaft im Wandel mit Wasser und Klima"
Der BWK veranstaltete anlässlich 30 Jahre UBV-Umweltbüro GmbH Vogtland und 20 Jahre Stiftung "Sauberes Wasser Europa" gemeinsam mit dem Freistaat Sachsen, dem DGFZ und den vogtländischen Institutionen am 22. September 2022 im Königlichen Kurhaus zu Bad Elster die Fachkonferenz "Gesellschaft im Wandel mit Wasser und Klima".
Im Beisein des Staatssekretärs des Sächsischen Staatsministeriums für Energie, Klimaschutz, Umwelt und Landwirtschaft (SMEKUL), Herrn Dr. Gerd Lippold, verfolgten 223 Teilnehmer aus Politik, Wissenschaft (darunter TU Dresden, TU BA Freiberg, HTW Dresden, TU Berlin, BA Riesa) und Wirtschaft (zahlreiche Wasserversorgungsunternehmen, Bohrunternehmen, Brunnenausrüster, Spezialfirmen und Ingenieurbüros) spannende und innovative Fachvorträge. Diese erfüllten mit ihrem Inhalt den hohen Anspruch der Konferenz - unter dem Motto Nachhaltigkeit, Klimawandel, Ressourcenschutz Wasser.
An in Deutschland beispielgebenden Vorhaben legten die Referenten die naturwissenschaftlichen und technischen Lösungen dar, die nachhaltig, ressourcenschonend und klimaverbessernd sind, so z. B.Renaturierung des Flusses Emscher, einer ehemaligen "Kloaka Maxima" zum technischen und ökologischen Refugium;
hydrothermale Kältenutzung des Grundwassers unter Beachtung naturschutzfachlicher Randbedingungen, gekoppelt mit Wärmerückgewinnung mittels Wärmepumpen;
Großräumiges Wassermanagement für die Lausitz und das Fitmachen des Industriestandortes Schwarze Pumpe unter Beachtung von Wasserressourcen- und Klimastress;
Die Entwicklung von fachlichen Vorschlägen für verbesserte und sichere Wasserversorgung der ostsächsischen Wassermangelgebiete durch vorsorgende Erkundung, Vernetzung von Wasserversorgungsunternehmen und eine gemeinsam umzusetzende Zusatzbesicherung;
Fachlich tiefgründiges Aufarbeiten von Wasserhaushaltskomponenten im Festgestein unter Beachtung von Klima- und Wasserstress als Grundlage präventiver Maßnahmen zum Heilwasserschutz;
die Arbeit von Bundesunternehmen für die Minimierung von Ewigkeitskosten und Erreichung von angemessenen Gütezielen;
Fachlich kompetente Leitlinien unseres Ministeriums mit beispielgebender Umsetzung durch die Unteren Wasserbehörde
und vieles mehr.
Besonders begeistert hat der "Festungskommandant" der Festung Königstein mit seinem Überraschungsvortrag zum Wasserhaushalt in seiner Domäne.
38 Fachaussteller umrahmten und bereicherten die Fachkonferenz maßgeblich mit einer sehr großen Vielfalt an präsentierten Spezialleistungen, Exponaten und neuesten innovativen Lösungen. Bereits vor dem Königlichen Kurhaus wurde man mit modernster Technik begrüßt (neueste KSB-Pumpe, Hochdruckspülgerät für Brunnenregenerierung der Fa, OSEL).
Die Firmen- /Ausstellerstände waren durchweg hochprofessionell, darunter u. a. eine gesponserte große Getränkevielfalt der Bad Brambacher Mineralquellen GmbH&Co.KG
die originale Ausschankvase der SCHILLER-Quelle zu Bad Brambach mit Heilwasser
Demonstrationsmodelle zur Geohydraulik und Brunnenfunktionalität der TU Dresden und HTW Dresden
verschiedene online-Leitsysteme mit live-Vorführung zum Betrieb der Anlagen des SIB Dresden, LMBV, ASG Spremberg mit WKS, ATS, 3DIT und UBV
Neuentwicklungen der Rohrreinigungstechniken und -materialien u. a. der Fa. UNI-Rohr und pigadi
der Prototyp eines Patentes für den "Anodischen Verockerungsschutz" durch UBV und STÜWA sowie
Spezialleistungen der Ingenieurbüros und Forschungsinstitute (z. B. Isodetect, BGD-Ökosax, CDM Smith und DGFZ)
Die von den Veranstaltern erwarteten drei Ziele der Konferenz:Freiheit der Wissenschaft und wissenschaftlichen Meinungsvielfalt in der Tradition von Humboldt,
Inspirierende Vorträge, Lösungsbeispiele aus Deutschland für die Fachdiskussion zur Anregung, zur gegenseitigen Bestärkung unserer Fähigkeiten und unseres Willens, noch rechtzeitig und zügig die richtigen Maßnahmen gegen oder mit dem Klimawandel zu ergreifen, gemäß dem Motto "Verantwortung" übernehmen
Vermittlung von Freude und Zuversicht durch unser aller Wirken auf der Konferenz wurden, so die zahlreichen Rückmeldungen von Teilnehmern, erreicht.
Thomas Daffner und Ulrike Schöbel
Liebe Aussteller und Unterstützer des BWK, Sie haben unseren Bundeskongress mit Ihrer Teilnahme oder durch Spenden unterstützt und waren so entscheidend am Erfolg des 37. BWK-Bundeskongresses in Trier beteiligt.
Durch Ihre Teilnahme und Unterstützung gelang es der Veranstaltung den richtigen, fachlich angemessenen Rahmen zu geben.
Im Namen aller Teilnehmerinnen und Teilnehmer möchten der veranstaltende BWK-Landesverband Hessen/Rheinland-Pfalz/Saarland und der BWK-Bundesverband Ihnen danken!
Die Aussteller und Spender des 37. BWK-Bundeskongresses in Trier waren:
Landesverband Sachsen Mitgliederversammlung und Neuwahl
Mit großer Vorfreude und endlich wieder in Präsenz fand am 12. September 2022 die diesjährige Mitgliederversammlung des BWK-Landesverbandes Sachsens statt. Diese war vor allen Dingen vor dem Hintergrund der Neuwahl von insgesamt 5 Positionen (Vorsitz, Geschäftsführung, stellvertretender Vorsitz, Öffentlichkeitsarbeit und Bezirksgruppe Dresden) von richtungsweisender Bedeutung. Zuvor wurde auf das vergangene Jahr 2021 zurückgeblickt, in dem das Verbandsleben stark von der Coronapandemie beeinflusst war. Glücklicherweise konnten die Dresdner Grundwassertage, als eine der wenigen Fachveranstaltungen in Präsenz stattfinden. Hier war eine gute Resonanz zu verzeichnen. Insbesondere die selten gewordene Möglichkeit des direkten persönlichen Austausches wurde dankend angenommen.
Nach dem Bericht zur Kassenrevision stand die Neuwahl des Vorstandes auf der Tagesordnung. Entsprechend gewürdigt wurde Herr Dr. Eckardt, welcher die Ausrichtung und das Verbandsleben in den letzten 12 Jahren als Landesvorsitzender maßgeblich bestimmte. Als neu gewählte Vorsitzende des Landesverbandes wird Frau Lange künftig die Geschicke des BWK Sachsen lenken. Besonderer Dank gilt auch Herrn Dr. Müller, welcher die letzten bei-den Jahre die Geschäftsführungstätigkeit wahrnahm. Ihm folgt Herr Düskau, welcher vormals die Position des Referenten für Öffentlichkeitsarbeit besetzte. Für die Öffentlichkeitsarbeit wird nun Frau Haenel tätig sein und ihre Ideen zielführend einbringen. Als stellvertretender Vorsitzender wird Herr Bielitz durch Herrn Dr. Sommer beerbt, welcher bereits langjähriger Vorsitzender des BWK-Arbeitskreises Altlasten und maßgeblicher Akteur des Sächsischen Altlastenkolloquiums ist. Für die Bezirksgruppe Dresden übernimmt Herr Noack die Leitung und führt damit die Arbeit von Herrn Beier fort. Die aktuellen Ansprechpartner finden Sie unter: www.bwk-sachsen.de/ansprechpartner .
Herr Dr. Eckhardt, Herr Dr. Müller und Herr Beier sind dem BWK weiter verbunden und stehen dem neuen Vorstand mit Rat und Tat zu Seite.
Insgesamt ist der Fokus auch im BWK-Landesverband Sachsen zukünftig wieder auf mehr Präsenzveranstaltungen ausgerichtet. Auch die Gewinnung weiterer Interessierter, gern auch junger Fachkolleginnen und Fachkollegen, sowie die Zusammenarbeit mit den anderen Landesverbänden im BWK wollen wir intensivieren.
In diesem Sinne, auf eine gute Zusammenarbeit!
Birgit Lange und Toni DüskauVeranstaltungen von Dezember 2022 - März 2023 www.verbandonline.org/BWK_Bund/?module=events
Zeit und Ort Thema der Veranstaltung Veranstalter
10. Dezember 2022
Essen
Die Lösung im Fokus: Gespräche lösungsorientiert führen Junges Forum (BWK-Bundesverband)
19. Dezember 2022
Online
StarkRegenCongress - SRC 2022
Katastrophen, Sturzfluten, Platzregen - und was ist mit Trockenheit?
IKT - Institut für Unterirdische Infrastruktur
www.ikt.de
BWK-Landesverband Nordrhein-Westfalen
6. Februar 2023
Oberhausen
Arbeitsschutz für Führungskräfte - Rechtliche Pflichten & Anforderungen BWK-Landesverband Nordrhein-Westfalen
14./15. Februar 2023
Münster
Wassertage Münster 2023
Klimawandel - Trockenheit und Starkregen im urbanen Raum
FH Münster
BWK-Landesverband Nordrhein-Westfalen und DWA-Landesverband Nordrhein-Westfalen
www.wassertage-muenster.de
3. März 2023
Kassel
Bundesvorstandssitzung BWK-Bundesverband
| 0 | PMC9744591 | NO-CC CODE | 2022-12-15 00:01:50 | no | Wasser Abfall. 2022 Dec 13; 24(12):25-35 | utf-8 | null | null | null | oa_other |
==== Front
MMW Fortschr Med
MMW Fortschr Med
Mmw Fortschritte Der Medizin
1438-3276
1613-3560
Springer Medizin Heidelberg
36510070
2091
10.1007/s15006-022-2091-5
FB_Schwerpunkt-Übersicht
Aktuelles zum Impfen im Alter
Update on vaccination in old ageKwetkat Anja [email protected]
1500684343001
Heppner Hans Jürgen 1500684343002
Endres Anne-Sophie 1500684343003
Leischker Andreas 1500684343004
1500684343001 grid.500028.f 0000 0004 0560 0910 Klinik für Geriatrie und Palliativmedizin, Klinikum Osnabrück, Am Finkenhügel 1, 49076 Osnabrück, Deutschland
1500684343002 grid.419804.0 0000 0004 0390 7708 Klinik für Geriatrie und Geriatrische Tagesklinik, Klinikum Bayreuth – Medizincampus Oberfranken, Bayreuth, Deutschland
1500684343003 Innere Medizin/Geriatrie/Virologie/Infektionsepidemiologie, Evangelisches Geriatrie Zentrum Berlin GmbH, Berlin, Deutschland
1500684343004 grid.10253.35 0000 0004 1936 9756 Lehrbeauftragter für Geriatrie an der Philipps-Universität Marburg, Marburg, Deutschland
13 12 2022
2022
164 21-22 4043
© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Keywords:
Recommendations on vaccination
old age
specific vaccines in old age
issue-copyright-statement© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2022
==== Body
pmcGerade bei Älteren sind Impfungen wichtig, um schwere Verläufe von Infektionskrankheiten zu verhindern. Wo gibt es noch Impflücken? Welche Impfstoffe und Impfschemata empfiehlt die Ständige Impfkommission (STIKO) zum Schutz vor Influenza, Pneumokokken und COVID-19?
Ältere sind durch alterungsbedingte Veränderungen des angeborenen und erworbenen Immunsystems (Immunseneszenz) anfälliger für Infekte. Komorbiditäten und funktionelle Defizite begünstigen Komplikationen und schwere Verläufe, sodass nicht nur COVID-19, sondern auch Influenza und Pneumokokken-Pneumonien mit einer deutlich erhöhten Mortalität im Alter verbunden sind.
Umso wichtiger sind Impfungen. Obwohl die Immunseneszenz zu einer Abschwächung der Immunantwort auf Impfungen führt und dadurch Erkrankungen nicht sicher zu verhindern sind, blocken sie doch zuverlässig schwere Verläufe ab. Die Entwicklung neuerer, stärker immunogener Vakzine ist daher wichtig - gerade für diese Altersgruppe.
Unzureichende Impfquoten und ablehnende Haltung können dazu führen, dass die Wirksamkeit von Impfungen als Präventionsmaßnahme schwindet. Die Weltgesundheitsorganisation (WHO) hält daher Zweifel an der Wirksamkeit von Impfstoffen für eine der zehn größten Gesundheitsgefahren der Zukunft (https://www.who.int/news-room/spotlight/ten-threats-to-global-health-in-2019, letzter Zugriff 31.8.2022).
Aktuelle Impfempfehlungen der STIKO
Die Ständige Impfkommission (STIKO) gibt jeweils zum Jahresanfang Impf-Empfehlungen heraus, die auch unterjährig aktualisiert werden. Für die Altersgruppe 60+ finden Sie die aktuelle Empfehlung in Tab. 1 [1]. Wegen der nach wie vor häufigen Anpassungen zur COVID-19-Impfung wird auf die jeweils aktualisierten spezifischen STIKO-Empfehlungen verwiesen [2]. Für einen schnellen Zugriff auf alle neuen Informationen zum Impfen bietet die STIKO eine eigene, kostenlose App an. Impfung Empfehlung Wiederholungsimpfung
Tetanus Grundimmunisierung, falls nicht vorhanden Auffrischimpfungen in 10-jährigem Intervall mit Td-Kombinationsimpfstoff
Diphtherie Grundimmunisierung, falls nicht vorhanden
Pertussis Einmalig bei der nächsten fälligen Diphtherie-Impfung als Tdap-Kombinationsimpfung Derzeit keine Wiederholung empfohlen
Influenza Impfung im Herbst mit einem inaktivierten quadrivalenten Hochdosis- Impfstoff mit aktueller von der WHO empfohlener Antigenkombination. Jährlich
Pneumokokken Standardimpfung mit dem 23-valenten Polysaccharid-Impfstoff (PPSV23) für Senioren, die keiner Risikogruppe angehören Ggf. Wiederholungsimpfungen mit PPSV23 im Abstand von mindestens 6 Jahren nach individueller Indikationsstellung
Herpes Zoster Zweimalige Impfung mit dem adjuvantierten Herpes-Zoster-Totimpfstoff im Abstand von mindestens 2 bis max. 6 Monaten Derzeit keine Wiederholung empfohlen
COVID-19 Generelle Impfempfehlung zur Grundimmunisierung Zweimalige Auffrischimpfung mit mRNA-Vakzine nach jeweils 6 Monaten
Nahezu 90% der Todesfälle durch Influenza finden sich in der Altersgruppe 60+.
Influenza
Die durch Influenza-A- und -B-Viren verursachte Virusgrippe ist die Infektionskrankheit mit der höchsten bevölkerungsbezogenen Mortalität von bis zu 12% [3] bei hospitalisierten Grippepatienten. Nahezu 90% der Todesfälle durch Influenza finden sich in der Altersgruppe 60+.
Die hohe Variabilität der Virus-Subtypen macht eine alljährliche Anpassung der Antigene notwendig. Infektionen mit dem Influenza-Subtyp A(H3/N2) führen bei Älteren zu einer besonders hohen Krankheitslast [4]. Die Influenza-Impfung ist für alle ≥ 60-Jährigen als Standardimpfung empfohlen, für Senioren- und Pflegeheimbewohner gilt sie als Indikationsimpfung [1].
Derzeit sollen alle Personen ab 60 Jahren mit dem inaktivierten, quadrivalenten Hochdosisimpfstoff (Efluelda®) in aktueller, von der WHO empfohlener Antigenkombination geimpft werden. Das ist ein Ei-basierter Spaltimpfstoff, der die 4-fache Menge HA-Antigen (60 µg) enthält [5]. Für diesen konnte eine signifikant bessere Wirksamkeit gegenüber dem konventionellen Impfstoff in der Standarddosis gezeigt werden [6], und auch die Hospitalisationsraten in Verbindung mit einer Pneumonie sowie kardiorespiratorische Ereignisse traten bei älteren Patienten weniger auf [7]. Dieser Hochdosisimpfstoff wird von den Krankenkassen erstattet [8].
Mit Fluad® Tetra, einem adjuvantierten quadrivalenten Grippevakzin, steht ein weiterer stärker immunogener Impfstoff zur Verfügung [9]. Im Falle von Lieferengpässen für den Hochdosisimpfstoff sollte daher an Stelle der Standardimpfstoffe auf das adjuvantierte Vakzin ausgewichen werden.
Laut STIKO sind die Risikogruppen leider nur unzureichend geimpft [10] (Abb. 1). Dem gilt es entgegenzuwirken und die Impfquoten für die Influenzaimpfung deutlich anzuheben.
Pneumokokken
In Deutschland verursachen Pneumokokken-Infektionen jährlich etwa 12.000 Todesfälle. Von den Verstorbenen sind 80-90% über 60 Jahre alt. Daher wurden bereits in den 1970er-Jahren zunächst Polysaccharid-Impfstoffe gegen Pneumokokken entwickelt. Durch Kopplung der Polysaccharid-Antigene an Eiweiße konnte die Immunogenität deutlich gesteigert werden. Diese neuen Impfstoffe werden Konjugatimpfstoffe genannt [11].
Nach der aktuellen STIKO-Empfehlung sollen Ältere mit dem Polysaccharidimpfstoff PPSV23 (Pneumovax®) geimpft werden. Daten zur Serotypenverteilung in Deutschland zeigen, dass invasive Pneumokokken-Erkrankungen bei Menschen ab 60 Jahren zu gut 70% durch Serotypen verursacht werden, die in PPSV23 vorhanden sind. Der Konjugatimpfstoff PCV13 (Prevenar®) enthält die Antigene von 13 Serotypen und deckt damit etwa 30% der klinisch relevanten Serotypen bei Erwachsenen ab. Für PCV13 ist auch eine Schutzwirkung vor nichtbakteriämisch verlaufenden Pneumonien nachgewiesen.
Nur 20-51% der über 60-Jährigen in Deutschland sind gegen Pneumokokken geimpft.
Für Menschen mit besonderer Gesundheitsgefährdung im Alter über 18 Jahren empfiehlt die STIKO die Impfung mit PPSV23 mit einer einmaligen Auffrischimpfung nach 6 Jahren. Für Menschen mit angeborener oder erworbener Immunsuppression oder mit Asplenie empfiehlt die STIKO die sequentielle Impfung: PCV13, gefolgt von PPSV23 im Abstand von 6-12 Monaten [1]. Abb. 2 fasst die Empfehlungen der STIKO zur sequentiellen Pneumokokken-Impfung zusammen [12].
Seit Ende 2021 ist in der EU auch ein 15-valenter Konjugatimpfstoff (Vaxneuvance®) zugelassen zum Einsatz ab 18 Jahren. Er enthält zusätzlich ein aluminiumhaltiges Adjuvans. Anfang 2022 erfolgte die Zulassung eines 20-valenten Konjugatimpfstoffs (Apexxnar®) in der EU, ebenfalls zum Einsatz ab 18 Jahren. Beide Vakzine dürfen nicht bei Personen angewendet werden, die gegen Diphtherietoxoid (ein abgeschwächtes Toxin aus dem Diphtherie verursachenden Bakterium) überempfindlich sind. Beide Impfstoffe sind in den aktuellen STIKO-Empfehlungen noch nicht berücksichtigt.
Trotz der schon lange bestehenden Pneumokokken-Impfempfehlung sind nur 20-51% der über 60- Jährigen in Deutschland gegen Pneumokokken geimpft [13]. Auch hier gilt es, die Impfquoten zu steigern.
COVID-19
SARS-CoV-2 (severe acute respiratory syndrome coronavirus type 2) ist ein neues Beta-Coronavirus, das Anfang 2020 als Auslöser von COVID-19 identifiziert wurde. Zu den Beta-Coronaviren gehören u. a. auch MERS-CoV (Middle East respiratory syndrome coronavirus) sowie die als "Erkältungsviren" zirkulierenden humanen Coronaviren (HCoV) HKU1 und OC43.
Zur Immunisierung gegen eine SARS-CoV-2-Infektion stehen in Deutschland zwei mRNA-Vakzine zur Verfügung: Comirnaty® und Spikevax®. Zusätzlich sind hier zwei Vektor-basierte Impfstoffe, Vaxzevria® und Jcovden®, ein Protein-basierter Impstoff, Nuvaxovid®, sowie ein inaktivierter, adjuvantierter Ganzvirusimpfstoff, Valneva®, zugelassen [2].
In der letzten Aktualisierung zum Schutz vor COVID-19 empfiehlt die STIKO nun neben den zwei Impfungen zur Grundimmunisierung und einer ersten Auffrischungsimpfung allgemein eine weitere Auffrischungsimpfung bereits ab dem Alter von 60 Jahren (bisher ab 70 Jahren) sowie für Personen im Alter ab 5 Jahren mit einem erhöhten Risiko für schwere COVID-19-Verläufe infolge einer Grunderkrankung [2]. Die STIKO empfiehlt für Auffrischimpfungen ab 12 Jahren vorzugsweise einen der zugelassenen und verfügbaren Omikron-adaptierten bivalenten mRNA-Impfstoffe (Comirnaty Original/Omicron BA.1, Comirnaty Original/Omicron BA.4/5 oder Spikevax bivalent Original/Omicron BA.1) [2]. Ferner wird Nuvaxovid® zur Grundimmunisierung entsprechend der erweiterten Zulassung auch für Kinder und Jugendliche im Alter von 12-17 Jahren empfohlen. Alternativ für Personen zwischen 18 und 50 Jahren empfiehlt die STIKO außerdem zur Grundimmunisierung den adjuvantierten Totimpfstoff Valneva.
Für bestimmte Personengruppen ab 12 Jahren ist zusätzlich zur Impfung eine SARS-CoV-2-Präexpositionsprophylaxe als medikamentöse Prävention mit dem Kombinationspräparat Evusheld® empfohlen, welches aus den beiden SARS-CoV-2-neutralisierenden monoklonalen Antikörpern Tixagevimab und Cilgavimab besteht [2].
Insbesondere Ältere entwickeln oft schwere Verläufe der Infektion und leiden danach unter einer deutlichen Einschränkung der Selbsthilfefähigkeit [14]. Besonders bei Pflegeheimbewohnern ist die Erkrankung häufig und schwer verlaufend [15]. Vorerkrankungen wie Herzinsuffizienz, Übergewicht, Diabetes mellitus, Leberzirrhose, chronische Niereninsuffizienz, aktive hämatologische Erkrankungen und der Z. n. Organtransplantation zählen zu den Risikofaktoren für einen schweren Verlauf der Infektion [16].
Für Pflegeheimbewohner konnte gezeigt werden, dass die Impfung die Infektion zwar nicht verhindert, aber einen milderen Verlauf bewirkt [17]. Leider sind jedoch auch bei der COVID-19-Impfung die Impfquoten mit 76,3% Grundimmunisierten und 62,4% mit mindestens einer Auffrischungsimpfung zu gering, um den potenziellen präventiven Nutzen voll ausschöpfen zu können (https://impfdashboard.de/ letzter Zugriff 07.11.2022).
Im September 2022 hat die Europäische Arzneimittelagentur EMA angepasste COVID-19-Impfungen auf die Omicron-Variante BA.1 (Comirnaty Original/Omicron BA.1; Spikevax bivalent Original/Omicron BA.1) in der Europäischen Union zugelassen (https://ema.europa.eu/en). Künftig werden weitere Impfstoffe gegen andere Omikron-Varianten wie BA.2, BA.5, BA.4/5 geprüft.
Aufgrund der Veränderungen des Virus und der damit sich ständig verändernden Daten zu Übertragung, Schwere und Verlauf der Erkrankung sowie Impfeffektivität, werden die Vakzine kontinuierlich weiterentwickelt und angepasst. Daraus ergibt sich die Notwendigkeit, auch die Impfempfehlungen für COVID-19 ständig zu aktualisieren. Um hier immer auf dem Laufenden zu sein, sei nochmals auf die kostenlose STIKO-App verwiesen.
Autorinnen und Autoren: Dr. med. Anja Kwetkat
Klinik für Geriatrie und Palliativmedizin, Klinikum Osnabrück Am Finkenhügel 1, D-49076 Osnabrück, [email protected]; AG Impfen der Deutschen Gesellschaft für Geriatrie
Prof. med. Hans Jürgen Heppner
Klinik für Geriatrie und Geriatrische Tagesklinik, Klinikum Bayreuth - Medizincampus Oberfranken, Friedrich-Alexander-Universität Erlangen-Nürnberg; AG Impfen der Deutschen Gesellschaft für Geriatrie
Dr. med. Anne-Sophie Endres
Evangelisches Geriatrie Zentrum Berlin; AG Impfen der Deutschen Gesellschaft für Geriatrie
Dr. med. Andreas Leischker
Lehrbeauftragter für Geriatrie an der Philipps-Universität Marburg; AG Impfen der Deutschen Gesellschaft für Geriatrie
Fazit für die Praxis Ältere sind in besonderem Maße durch Influenza-, Pneumokokken- und SARS-CoV-2-Infektionen gefährdet.
Die konsequente Umsetzung der mindestens jährlich aktualisierten STIKO-Impfempfehlungen ist die wesentlichste Maßnahme zur Prävention dieser schwerwiegenden Infektionen.
Um gerade auch bei kurzfristig angepassten Empfehlungen zur COVID-19-Impfung immer einfach und sicher auf dem aktuellsten Stand zu sein, ist der Einsatz der STIKO-Impf-App zu empfehlen.
Supplementary Information
Interessenkonflikt
A. Kwetkat: Forschungsunterstützung: Pfizer; Beratungs-/Gutachtertätigkeit: Seqirus, GSK, Pfizer, Sanofi-Pasteur, Astra Zeneca; Vortragstätigkeit: Pfizer, MSD, Novartis, Daiichi-Sankyo, Bristol-Myers Squibb, Sanofi-Pasteur; H. J. Heppner: Forschungsunterstützung: Thermo Fisher Science; Vortragshonorare: Pfizer, Thermo Fisher Science, Janssen-Cilag; Beratertätigkeit: Pfizer, GSK; A.-S. Endres: Vortragshonorar: Pfizer; A. Leischker: Honorare für Vorträge und Beratungstätigkeit (Advisory Boards) für GSK, Pfizer Vaccines, Sanofi, Novartis
| 36510070 | PMC9744592 | NO-CC CODE | 2022-12-15 00:01:51 | no | MMW Fortschr Med. 2022 Dec 13; 164(21-22):40-43 | utf-8 | MMW Fortschr Med | 2,022 | 10.1007/s15006-022-2091-5 | oa_other |
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Prospects (Paris)
Prospects (Paris)
Prospects
0033-1538
1573-9090
Springer Netherlands Dordrecht
9626
10.1007/s11125-022-09626-5
Cases/Trends
A case study of support for girls’ access to primary school in Ghana
http://orcid.org/0000-0002-9761-6383
van de Waal Willem [email protected]
1Willem van de Waal
has more than twenty years of experience in development work, early-grade learning, language acquisition, curriculum design, and development of teaching and learning materials. He has worked with NGOs and Governments on projects aiming to improve the quality and quantity of education to provide children and adults with skills and knowledge, improving daily life for them and their families.
http://orcid.org/0000-0003-1111-7549
Ashon Maxwell Agyei [email protected]
2Maxwell Agyei Ashon
is a development practitioner with over 10 years of experience in development policy research and analysis. Maxwell has consulted and undertaken assignments for a number of high profile organisations including the European Union, USAID, MasterCard Foundation and UNDP. He currently works as the Monitoring, Evaluation and Learning Manager at World Education Incorporated on the Strategic Approaches to Girls’ Education project in Accra-Ghana. Maxwell holds a Bachelors in Planning and Master of Philosophy in Development Studies from the Kwame Nkrumah University of Science and Technology, Kumasi- Ghana and the University of Cambridge, Cambridge-UK respectively. He also holds an advance certificate in Research from the Weatherhead Center for International Affairs, Harvard University. Maxwell’s research interests are in the areas of Education and Youth Skills Development, Local Governance and Economic Development and Urban Planning. Maxwell is a William and Flora Hewlett Foundation Fellow and a Commonwealth Scholar.
http://orcid.org/0000-0002-6560-1961
Comings John P. [email protected]
3John P. Comings
is an adjunct faculty member at the University of Massachusetts at Amherst and teaches a course on system change in support of early-grade reading. He served in the Obama administration as an education policy advisor to USAID’s early-grade reading initiative. Before that, he was the director of the National Center for the Study of Adult Learning and Literacy and a member of the faculty at Harvard University’s Graduate School of Education. Prior to that, he was a vice president of World Education.
1 grid.430962.a 0000 0000 9738 7002 World Education, 44 Farnsworth St, Boston, MA 02210 USA
2 World Education Ghana, Accra, Ghana
3 grid.266683.f 0000 0001 2166 5835 Center for International Education, University of Massachusetts Amherst, Amherst, USA
13 12 2022
113
11 11 2022
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This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
The Strategic Approach to Girls’ Education (STAGE) project developed and implemented an intervention that helped marginalized out-of-school girls in the northern regions of Ghana enter and be successful in primary school. STAGE builds on the Government of Ghana’s Complementary Basic Education policy, which supports an accelerated learning program that provides literacy and numeracy classes in mother tongue to out-of-school girls between 8 and 14 years of age. This article reviews the literature that informed the design of STAGE, describes the intervention, reports on the impact on its participants, and suggests a model for replicating this intervention in Ghana and adapting it for implementation in other countries.
Keywords
Girls’ education
Ghana
Gender equality
Out-of-school
Community engagement
==== Body
pmcThe United Nations Sustainable Development Goal’s Target 4.5 calls for gender equality and inclusion in education. Ghana has made substantial progress toward the full inclusion of girls in education. However, a substantial number of girls living in Ghana’s three northern regions are still out of school, have low participation rates, or are likely to drop out. This is particularly true for girls who are facing barriers such as teenage pregnancy, child marriage, bonded slavery, extreme poverty, or other barriers. These girls need additional help to enter and succeed in primary school. Though the government of Ghana recognizes and is addressing this problem, the culture and traditions of some families in these three northern regions are unsupportive of girls’ participation in school.
The reasons that girls from low-income families are not in school are complex and context-specific, and any intervention to promote girls’ education should address this complexity with multidimensional and culturally appropriate interventions. The Strategic Approaches to Girls’ Education (STAGE) project developed and implemented an intervention that helped a sample of the remaining out-of-school girls in the three northern regions enter and be successful in school. STAGE has worked with 8333 girls, their parents or caregivers, and community members in the three northern regions. The girls will become role models and agents who support girls’ education in their communities.
Funding for STAGE from the United Kingdom Agency for International Development (UKAID) began in 2018 and will end in 2023. This paper reviews the literature that informed the design of this intervention, describes the intervention, reports on the impact of the intervention on the participants, presents the findings from an in-depth study of a sample of 36 girls, and suggests a model for replicating this intervention in Ghana and adapting it for implementation in other countries.
Literature review
In Ghana, increases in enrollment and retention of girls in formal education have stagnated (UIS, 2018). Unfortunately, socio-cultural practices and economic necessity cause some low-income parents to see school as a good investment for boys but not for girls (World Bank, 2011). When parents do send their girls to school, the girls face sexual harassment and abuse from their peers and teachers, which causes them to drop out (CRRECENT, 2009). Seasonal migration, fosterage, early marriage, extreme poverty, and teenage pregnancy also contribute to high dropout rates (CAMFED, 2010). The poor quality of teaching, teacher absenteeism (Alhassan & Adzahlie-Mensah, 2010; Hunt, 2008), and the lack of sanitation facilities (UNICEF, 2010) are additional factors contributing to the low retention rate of girls.
A nationwide analysis of girls’ education in Ghana by Associates for Change (2011) concluded that only a few of the projects that focused on girls’ education effectively addressed issues of gender equality and empowerment and reduced barriers to participation by girls. STAGE is an intervention that aims to foster aspirations and empower girls to be advocates for their education and help parents accept girls’ education as consistent with their cultural values and the well-being of their family and community. STAGE draws on the literature that explores the development of girls’ aspirations to attend school, examining how culture can constrain those aspirations, in order to understand ways to increase support and lower barriers to participation in school.
Aspirations
HART (2016) defines aspirations as “…future-oriented, driven by conscious and unconscious motivations, indicative of an individual or a group commitment to a particular trajectory or endpoint” (p.326). Nussbaum (2005) suggests that a person may not express their aspirations due to culture, habit, and fear. Ray (2003) argues that a person’s aspirations are often shaped by people who are similar to them in societies that do not have a lot of diversity. Out-of-school girls who live in communities that have low female participation in primary school may not aspire to be educated because they do not engage with people who have different experiences, social status, or resources. Bourdieu (2010) identifies this phenomenon as habitus, which he defines as the cultural aspects, interactions with others, and elements in a person’s surroundings that shape their perception of tradition, custom, and norms.
STAGE implemented participatory community mapping exercises that identified out-of-school girls in three of Ghana’s northern regions (Upper West Region, Upper East Region, and Northern East Region). The exercise focused on girls who were 10 to 14 years old and had not attended primary school or dropped out before grade 4. After enrollment, STAGE established community support structures and implemented a community-based accelerated learning program that built the girls’ aspirations to attend and succeed in school within their families and communities. Girls were supported to form and achieve the aspiration to join and be successful in school, but they were also supported to change their habitus and that of their parents and community. Hart (2016) argues that this change in habitus can happen throughout several generations through intergenerational transfers. Once they are adults, the girls who gained literacy and math skills in school can in turn provide resources and support to their children to form their own, more ambitious, aspirations. These girls can also have an impact on other parents in their communities.
The habitus is changed by conversion factors, which Robeyns (2021) defines as the support that enables a person to achieve an aspiration. Nussbaum (2015) suggests that conversion factors build new personal capabilities through actions motivated by aspiration, and Ray (2003) uses the term aspiration gap to describe the gap between the current situation and the aspired life an individual envisions. Ray (2003) suggests that if the aspiration gap is too small or too large, it might not motivate or could frustrate a girl in her efforts to achieve an aspiration. In STAGE, conversion factors take the shape of a conversation between girls and peer educators that is supported by the provision of student learning materials, the building of parental and community support, and the provision of remedial education that focuses on the skills they need to succeed in school.
DeJaeghere (2016) suggests that aspiring to complete an education might be a conversion factor because gaining an education has the potential to lead girls to more prosperous, healthier, and longer lives (UNICEF, 2021). A girl’s education can also benefit her family and the social and economic development of her country (Wodon, 2018).
In addition to the need to make education relevant and aligned with girls’ aspirations, Appadurai (2004) suggests that programs must address cultural influences that have an impact on aspirations. Vavrus (2002) suggests that culture is both constraining and a potential catalyst for change. Government, communities, and other stakeholders must work together to create an enabling environment that supports girls in their efforts to define and achieve their aspirations and also build agency, a process in which girls are accessing information, considering their options, and working toward achieving their aspirations (Sen, 2011). DeJaeghere (2016) suggests that this agency can lend support to girls in their effort to achieve individual and collective aspirations.
Culture
Culture can be a hindrance to girls’ education but can also support girls’ aspirations. In many cultures, including those that might be termed traditional, girls’ education has supporters. Fernandez (1986) and Appadurai (2004) demonstrate that a consensus in support of girls’ education can be reached through discussion, rituals, and the use of metaphors that lead to a change in the habitus. This support effort should identify and build on the forms and frequency of interactions in the girls’ culture that are needed to achieve collective aspirations in support of girls’ education. After identifying those interactions, an intervention could renegotiate the collective aspirations of the community members and change the habitus. This in itself can lead to a new consensus, which in turn can lead to support for girls’ participation in school. Hart (2016) suggests that the aspiration to pursue an education is a process that runs through generations. Even if it does not lead to an opportunity for a specific girl to attend school, those aspirations may lead to an opportunity for her children.
In Ghana, a cultural element that has an impact on aspirations is Ubuntu, which is the process of how people’s thoughts and actions are defined through their relationship with their community. Archbishop Desmond Tutu (1999) described Ubuntu as being a person through other persons. Ubuntu drives social life in many African countries. An African concept first described by Samkange (1980), Ubuntu is a philosophy passed on orally from generation to generation through literature, dance, art, poetry, and other means. An aspect of Ubuntu is the recognition that all humans are vulnerable, and with this recognition comes the acknowledgment of the need to cooperate with others. This cooperation then leads to improved well-being and prosperity of both the individual and the community as a whole (Baken, 2015). In Ghanaian culture, in the Akan language, Ubuntu is called Biako Ye, which translates as “unity is great.” The concept of Biako Ye can be used to engage a broader community in supporting girls to have an opportunity to attend school in Ghana.
Ghanaian culture and its national policy framework support girls’ education in general, but the cultural, social, and institutional context of each community in Ghana’s three northern regions influences the aspirations of the girls who live there. This context also dictates the level to which girls need support from a wider group to achieve their aspirations. The STAGE project built local support and lowered barriers to girls’ education in families, communities, and schools.
The intervention
The STAGE project is based on the Complementary Basic Education (CBE) policy of the Government of Ghana. The CBE policy aims to identify male and female out-of-school children and create the motivation and community support needed for these children to enter or reenter primary school and complete their basic education. Despite its initial successes, Casely-Hayford (2017) found that the implementation of the CBE policy had difficulty identifying the most marginalized girls and supporting them to enter and be successful in primary school. STAGE identified these girls, aged 10 to 14 years, and provided them with pedagogical, socio-cultural, and health support. After this initial identification, STAGE enrolled girls in an accelerated learning program that focused on attaining the skills and knowledge of the primary school curriculum, with an emphasis on literacy and math skills, and built community structures that supported girls to join and be successful in school after completion of the program.
STAGE began its intervention with a participatory community mapping exercise that identified 8,333 out-of-school girls, of whom 35% had been to school but dropped out before grade 4 and 65% had never attended school. Working with community stakeholders and district education officials, parents and caregivers were engaged in activities that built their motivation to support the girls in enrolling in a community-based accelerated learning program. The community-based accelerated learning program was led by a facilitator who, with support from a community oversight committee, organized daily lessons to build literacy, numeracy, and life skills.
To keep girls engaged, a study was conducted to identify the barriers that prevent girls from attending school or lead them to drop out before they acquire a basic education. STAGE identified eleven barriers that could potentially block success in school and recommended ways to address them, as follows:Teenage pregnancy—STAGE implemented a behavioral-change campaign that included sensitization for community members about the negative impact of teenage pregnancy on the health of girls and their academic future as well as on their communities. This campaign was coupled with a life-skills education program for the girls that included an orientation to the female reproductive system, contraceptive techniques, and the consequences of teenage pregnancy.
Child marriage—STAGE implemented a behavioral-change campaign for girls and community members about the impact of early marriage, the legal framework that governs marriage in Ghana, and the rights of girls. Working together with the Department of Social Welfare, potential cases of child marriage of girls in the STAGE program were investigated.
Sexual exploitation, abuse, and harassment—STAGE established a community-based and nationwide mechanism for reporting abuse. The project partnered with the Department of Social Welfare’s program of support for interventions that address prevention, investigation, and survivor support. The project includes a set of child and vulnerable-adult safeguarding policies and practices and a referral mechanism to sources of support for the safeguarding of children and vulnerable adults.
Distance and access to school—STAGE distributed bicycles, set up bicycle-maintenance protocols, and provided transition kits that included uniforms, pencils, books, and other learning materials. These materials were provided to each girl for three years after they transitioned to school.
Disability—STAGE conducted disability screening. The project worked with the Ghana Health Service to conduct medical assessments and, where needed, provided assistive devices to facilitate learning. In addition, learning spaces, both in the accelerated learning program and in school were screened and made accessible and disability-friendly for girls with impairments. STAGE also supported a behavioral-change campaign that informed the community about the causes of disability and ways to support children with disabilities in their community and schools.
Lack of community and parental support—STAGE implemented a behavioral-change campaign that included radio spots, posters, and community events that promoted the importance of girls’ education for the individual and her community. STAGE also established community oversight committees that conducted home visits to support homework and ensure that girls attended the Accelerated Learning Programme and school.
Lack of academic skills—STAGE provided peer tutoring, which ensured participants were supported by pupils who have been in school since grade 1, as well as training of a mentor teacher who oversaw academic performance and provided an after-school bi-weekly catch-up class organized by the mentor teacher.
Covid-19 or poor health—STAGE initiated a radio campaign that informed communities about prevention and safety measures in the community and households. During the Accelerated Learning Programme, STAGE conducted small group sessions that complied with Ghanaian COVID-19 regulations.
Absenteeism—The Community Oversight Committees promoted attendance in the Accelerated Learning Programme, while trained school-based mentor teachers oversaw attendance in the school and conducted home visits when girls were absent more than two days per week.
Safeguarding concerns in school—STAGE provided training for mentor teachers in the prevention and reporting of safeguarding concerns using both school and community-based reporting mechanisms.
Insufficient support in school—STAGE collaborated with the Ghana Education Services on joint monitoring visits, identification and training of mentor teachers, and establishment of a peer education system.
Of the total of 8,333 out-of-school girls who initially enrolled in STAGE, 8,245 transitioned to primary schools. After nine months in the Accelerated Learning Programme, the academic performance of the girls improved significantly, with the majority achieving learning levels similar to grade 4 or higher. However, a girl who is 14 years old might find it difficult to sit in a class with students who are seven or eight years old. In these cases, the project staff worked with school administrators to employ a set of indicators to determine the best grade placement. The first and most important indicator was educational achievement. However, school directors weighed each girl’s educational achievement against grade-level benchmarks and then took age, distance to school, and social-emotional development into account to make the final decision.
Another barrier that needed to be addressed was the language of instruction. While the STAGE classes use the girls’ mother tongue in teaching and learning, schools use only the local languages in grades 1 to 3, and that language might be one the girls do not know. Starting in grade 4, local language instruction is a subject, and all other subjects are taught in English (Nyamekya, 2021). In addition, some of the teachers in the upper primary grades do not speak or understand the local language of their students. The STAGE project responded to this need by developing a two-month learning program focused on oral English proficiency. Facilitators in the STAGE communities were trained to improve students’ English vocabulary and provide practice speaking English. However, the program did not include English reading instruction.
Learning gains
After completion of the Accelerated Learning Programme, 61.2% of the 8245 girls transitioned to grade 4 or higher, with 15.2% transitioning into grade 5, 16.1% into grade 6, and 7.9% into junior high school (WE, 2021). This indicates that learning gains during the nine-month program were higher compared to prior community-based education programs. To gain further insight into academic performance, the project assessed the learning gains for a sample of 36 girls (18 program participants and 18 school pupils), after the program participants had been in those schools for six months. The assessment employed the Annual Study of Education Report (ASER) test. The ASER reading test assesses five levels of skill: (1) not able to read letters, (2) able to read letters, (3) able to read words, (4) able to read short paragraphs, and (5) able to read a story. The ASER math test also assesses five levels of skill: (1) not able to solve problems; (2) knows numbers; (3) able to solve simple addition, subtraction, multiplication, and division problems; (4) able to utilize the same four functions with larger numbers; and (5) a test comprising the addition of fractions, simple measurement, and representing fractions as a percentage.
The sample was small, but the goal was limited to verification of the observations of STAGE staff and school teachers that the program participants were catching up to their peers who had been in school since grade 1. The findings in Figure 1 are the percentage of girls who tested at the top-two reading and top-three math levels. In two of the three regions, participants (former STAGE girls who transitioned to school) and school students (who had been in school since grade 1) had similar scores. The third region had much lower scores for program participants. The findings are presented in Figure 1 for both three and two regions.Figure 1 Reading and math scores
While the outcomes of this assessment cannot be applied to all girls in the program, the pattern of significant learning gains is confirmed by other data from external evaluations and program monitoring. In this particular sample, it is observed that in two of the three regions, the literacy and numeracy skills of the transitioned girls were similar to or higher than their peers who had been in formal education since grade 1.
Supports to learning
A qualitative study recorded the perceptions of participants regarding the impact of the program on their success in school and the fulfillment of their aspirations and the perception of their teachers about the impact of the program on learning and community support. Trained data collectors recorded interviews and produced transcripts. The research team read the interview transcripts and identified patterns in the data. The research team then discussed the patterns and constructed a thematic map by identifying correlations between codes, subthemes, and main themes (Creswell, 2013). The quality of the data analysis and report writing was assured by following the thematic analysis protocols of Braun (2006). Through this immersion in the data, the team was able to identify patterns of behavior and beliefs that led to conclusions about their meaning (Wolcott, 1994). The study collected data through (1) semi-structured interviews with girls and teachers, (2) in-school literacy and numeracy assessments, (3) a review of school-attendance data, and (4) a survey for parents and caregivers.
These studies employed a capability approach that was informed by findings from research about girls’ aspirations and how these aspirations are influenced (Okkolin, 2016). As outlined in the literature review, in countries that are similar to Ghana, aspirations are influenced by community and family members (Khattab, 2015), and this influence can create the enabling environment that girls need to form and achieve their goals (Cin, 2020, Appudarai, 2004). The capability approach identifies how well girls can access and convert the resources provided by STAGE into success in school. This study focused on the perceptions of the girls, their families, community members, and school staff as to the impact of the conversion factors supported by the STAGE project on the participant’s aspirations and achievements.
The study also employed Creswell’s (2013) approach to critical ethnographic design, which links the insights of individuals to the political, economic, and cultural structures that have an impact on their lives. This choice allowed girls and their communities an opportunity to articulate their lived experiences and identify the underlying beliefs and rules of behavior that guide that experience. As a cultural theme, the research team chose Transition to a Better Life. This transition has three stages: (1) from being out of school to being in the Accelerated Learning Programme, (2) transferring to a formal education program, and (3) living a better life of their choosing. The researchers collected data on (1) how effective the support system was in keeping girls in school from the perspectives of the community, family, and school, (2) if girls perceive their progress as fulfilling their initial aspirations, and (3) which specific program interventions were most effective in promoting individual, family, and communal well-being
Keeping girls in school
Community members said that they might not want to invest in the education of girls if they deem that girls’ aspirations for an education are not feasible. STAGE succeeded in identifying and enrolling a large number of marginalized girls into formal education, but the girls are always at risk of dropping out. The most effective support system component mentioned by the girls was the support of their parents, in particular their mothers. Research confirms that this is one of the most important factors in promoting attendance and improving student learning (Bryan, 2005; Suleman, 2012). Though girls’ parents voiced support for education, girls reported struggling to attend school because of their parents' request to work on the family farm.
Teachers stated that, despite difficulties with English language skills, STAGE participants were improving in reading and math and were competitive with their school peers. However, teachers judged both groups of students as having reading and mathematical skills that were not up to their grade level. These low competency levels in relation to the grade-level benchmarks set out in the Ghanaian basic education policy may suggest that the benchmarks are set too high. Program participants reported that the catch-up classes, organized twice per week, helped participants address academic challenges and complete their homework. The mentor teacher was often mentioned by participants as the person to whom they could go with challenges around attendance, learning, safeguarding, and personal well-being.
Many of the girls reported that their mothers supported them in going to school, but none of the girls mentioned their fathers. Mothers, particularly when empowered and working together in association with other community members, can have a positive impact on the enrollment and attendance of girls in school (Midling, 2005). Research (Awan, 2015; Jeynes, 2005) suggests that if girls are successful in school, their children are more likely to attend and be successful in school.
Mentor teachers and Community Oversight Committee members were mentioned by all girls as motivators and community-based supporters for girls’ education, but their roles could be strengthened to address challenges in learning and attendance. At the time of data collection, mentor teachers were not well trained or resourced to help girls with learning and attendance, although more rigorous support and training were scheduled to occur in the months ahead.
STAGE had success in identifying out-of-school girls and building community support for their enrollment into the Accelerated Learning Programme and later into formal education. Qualitative data from interviews with girls highlighted the community animation and entry component as the starting point of changed parental and community perceptions toward girls’ education. This is supported by the positive view of some parents toward girls’ education. The participatory approach of community mapping might be one support contributing to this success.
A short-term intervention, such as STAGE, may not lead to sustained change in community norms and beliefs regarding girls’ education. However, providing some girls with the resources and a support system that allows them to succeed in school may begin a generational change in attitudes about girls’ participation in school (Bourdieu, 2010). All the girls who were interviewed expressed that they aspired to finish primary school and would like to continue to junior high school. Some girls said they would like to go to senior high school as well. The high percentage of girls who transitioned from the accelerated learning program (95%) to school participation, the significant learning gains, and the girls’ appreciation of the accelerated learning program are signs of the effectiveness of the STAGE project and the ability of girls to convert resources into the achievement of their aspiration of enrolling into formal education.
Laube (2015) states that youth in the Northern Ghanaian regions are not different from their peers in the south or other countries. When provided with resources and support and when their vision and aspirations become broader, many aspire to modern careers, access to social services, and material improvements. Some girls reported that they aspire to become teachers or nurses. However, some parents were not confident that finishing basic education would provide their girls with a better chance to find a job. There is, therefore, a need to address youth unemployment to provide parents with a reason to support their daughters’ participation in formal education.
One key to the success of the program was meetings held with elders, community leaders, religious leaders, and government stakeholders to establish a new collective consensus (Fernandez, 1986). The concept of Ubuntu suggests that any effort for change should begin with a community discussion about the level of vulnerability of out-of-school girls and consider the benefits that education has on communal well-being (Baken, 2015). This communal well-being goes beyond the right of individual girls to have access to education. By presenting these facts and illustrating the position of the girls, following the Ubuntu principles community members could decide to cooperate. Collective action could be a critical support to girls’ education (Binder, 2009).
However, once communities unite in their aspiration to provide education to girls, the STAGE project experience has shown that community oversight could provide a liaison function between girls, their parents or caregivers, and traditional authorities. Community oversight committee members played important roles in monitoring attendance and learning and as trusted adults to whom girls could report safeguarding concerns. The committee members have the potential to sustain this intervention once project support stops, and they are in a position to support girls to achieve their aspirations (Robeyns, 2021).
Aspirations
During the community mapping interviews, girls expressed that they became motivated to enroll in the accelerated learning program when it became clear they would get support in their transition to school. During the community entry and the accelerated learning program, community oversight committee members, facilitators, and other partners conducted community sensitization activities to explain why it is important to educate girls. From the first contact with the program communities, program staff made it clear that the program would benefit individual children, their families, and the community. Many girls expressed that they now understand the importance of girls’ education and now want to complete primary education and continue to secondary education. All girls interviewed continued to express similar aspirations after being in school for six months. However, parents were not unanimously positive in their hopes that their children would find better jobs after finishing school. Five factors that threaten the fulfillment of these aspirations emerged in the interviews: (1) insufficient parental support, (2) corporal punishment by teachers, (3) low oral English and reading proficiency gaps, (4) poor learning environments, and (5) malnutrition.
On the positive side, girls reported that they enjoy their education and the opportunity to mingle with their peers who have been in school since grade 1. Several girls reported that this was because they were from the same community and already knew each other. Other girls reported that food and water were shared at school, and this created positive relationships among all the girls in a class. Another support was the bicycles provided to girls who were living far from the school. During community mapping, more than 250 girls were identified as living in remote areas (WE, 2020). Since the secondary schools were often even farther away, the bicycles made attendance possible.
Effective project interventions
In interviews with students and teachers, the distribution of transition kits (a uniform, student books, pencils, a bag, notebooks, and other materials that could be used during their study) was mentioned as a key intervention that supported attendance and learning. The kits also gave girls a feeling of dignity because they look just like their peers in school. The kits may have also supported the positive social integration that seems to have taken place.
In the interviews, girls reported that the support they received from the facilitators was also valuable. When asked, about catch-up classes, organized twice per week, girls said the classes helped them to address academic challenges and to complete their homework. However, the peer education component was not mentioned by girls or teachers as critical support. The mentor teacher was mentioned by girls as a person to whom they could go with challenges around attendance, learning, and safeguarding. However, at the time of data collection, training of these mentor teachers was limited.
Conclusions
Throughout the literature review, data collection, and analysis the project staff and leadership have explored how aspirations are formed, influenced, and achieved as well as which resources are supportive of conversion factors for the girls and their community. The staff and leadership have looked at this through a cultural lens, with the intent to identify culturally appropriate interventions to promote girls’ education. The staff of the STAGE project and others like it should constantly reflect on their project design to ensure that girls are indeed able to convert resources into the achievement of school participation and success. The Ubuntu philosophy, with its focus on human relations, harmony, and cooperation (Samkange, 1980), provides an African lens that can be used to focus the resources of a project on individual girls within their larger world of family and community. To allow girls to achieve their aspirations, the community, parents, and schools need to cooperate. This cooperation supports girls in making progress and succeeding.
Once a country builds a primary school system that provides an opportunity for all children, it must ensure that all children benefit from a successful project design for achieving that goal. STAGE accomplished this goal by (1) engaging with community leaders and parents, (2) providing reading and math instruction to prepare out-of-school girls for success in school, and (3) collaborating with primary schools. These three components might look different in another country, or even in a different region in Ghana, but the current study suggests that these three components should be part of any intervention to support girls’ participation in school.
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| 0 | PMC9744660 | NO-CC CODE | 2022-12-15 00:01:51 | no | Prospects (Paris). 2022 Dec 13;:1-13 | utf-8 | Prospects (Paris) | 2,022 | 10.1007/s11125-022-09626-5 | oa_other |
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Int J Hematol
Int J Hematol
International Journal of Hematology
0925-5710
1865-3774
Springer Nature Singapore Singapore
36510096
3499
10.1007/s12185-022-03499-2
Case Report
Development of Epstein–Barr virus-associated lymphoproliferative disorder and hemophagocytic lymphohistiocytosis during long-term lenalidomide maintenance therapy in multiple myeloma
Yoshida Mina 1
Morita Ken 1
Fukushima Hidehito 1
Jona Masahiro 2
Nishikawa Masako 2
Yatomi Yutaka 2
Kishino Yuya 3
Iwasaki Akiko 3
Ushiku Tetsuo 3
Imadome Ken-Ichi 4
Honda Akira 1
Maki Hiroaki 1
http://orcid.org/0000-0002-4034-2422
Kurokawa Mineo [email protected]
1
1 grid.26999.3d 0000 0001 2151 536X Department of Hematology & Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655 Japan
2 grid.412708.8 0000 0004 1764 7572 Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
3 grid.26999.3d 0000 0001 2151 536X Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
4 grid.63906.3a 0000 0004 0377 2305 Department of Advanced Medicine for Infections, National Center for Child Health and Development, Tokyo, Japan
13 12 2022
15
20 7 2022
17 11 2022
17 11 2022
© Japanese Society of Hematology 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Reactivation of Epstein–Barr virus (EBV) has been considered a very rare event among patients on immunomodulatory drugs (IMiDs) such as lenalidomide, and an association between the two has not well been recognized. We have recently experienced a rare case of multiple myeloma in which the patient had suffered EBV reactivation during long-term lenalidomide maintenance therapy. The patient subsequently developed EBV-associated lymphoproliferative disease (LPD) as well as EBV-associated hemophagocytic lymphohistiocytosis (EBV–HLH), which was fatal despite intensive treatment. Although rare, clinicians should be aware that such fatal EBV reactivation could occur as a minor yet critical complication of long-term maintenance therapy with IMiDs in multiple myeloma patients. Regular monitoring and early detection of EBV reactivation would be beneficial for these patients, so that proper diagnostic examinations can be initiated without delay.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12185-022-03499-2.
Keywords
Lenalidomide
Epstein–Barr virus
Lymphoproliferative disorders
Hemophagocytic syndrome
Immunomodulatory drugs (IMiDs)
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pmcIntroduction
Epstein–Barr virus (EBV) is one of the most prevalent viruses among humans, and approximately 90 to 95 percent of adults are EBV antibody seropositive [1]. Like other members of the herpesvirus family, EBV has a latency phase. However, unlike other herpesvirus, the principal human host cells for EBV are limited to B lymphocytes, T lymphocytes, NK cells, epithelial cells and myocytes. Chronic infection of EBV could sometimes transform these cells and develop various epithelial cell or hematological malignancies, especially among patients with immunosuppressive conditions [2]. Studies show that initial infection followed by lytic EBV replication and latent EBV infection could both contribute to the malignant transformation of the EBV-infected cells [3]. Interestingly, immunomodulatory drugs (IMiDs) such as lenalidomide have been shown to promote reactivation of EBV lytic replication in mammalian cells in vitro [4]. Under the presence of lenalidomide, substrate selectivity of cereblon, the key molecule that mediates protein degradation via the ubiquitin–proteasome systems, is directed toward a limited number of targets including transcription factors such as Ikaros (IKZF1) and Aiolos (IKZF3) [5]. Because Ikaros has been known as an indirect repressor of genes that are required for the activation of EBV [6], degradation of such transcription factor by lenalidomide treatment could lead to the reactivation of EBV in mammalian cells. Despite these findings from basic biological experiments, the development of EBV reactivation is very rare among patients on IMiDs treatment, and thus the association of lenalidomide use and EBV reactivation has not been well-recognized in clinical settings.
We have recently experienced a rare case of multiple myeloma who had suffered EBV reactivation during the long-term maintenance therapy with lenalidomide for 4 years. The patient subsequently developed EBV-associated lymphoproliferative disease (EBV-LPD) as well as hemophagocytic lymphohistiocytosis (HLH), which was fatal despite intensive treatment. Although rare, reactivation of EBV could occur in patients with multiple myeloma under long-term IMiDs treatment. Periodical monitoring and early detection of EBV reactivation could be beneficial for such patients to initiate proper diagnostic examinations without delay.
Case description
A 75-year-old Japanese male with a 4-year history of non-secretary multiple myeloma (international staging system I, international staging system-revised II), presented with malaise and periodical fever during the 45th course of the lenalidomide maintenance therapy. The patient had been in a stringent complete response after three courses of induction chemotherapy of bortezomib, lenalidomide, and dexamethasone (VRd), followed by autologous hematopoietic stem cell transplantation and lenalidomide maintenance therapy. During the initial workup, mild pancytopenia (white blood cell (WBC) count: 1500/µL, hemoglobin level: 118 g/L, platelet count: 1.3 × 105/µL) and inflammation (C-reactive protein (CRP): 1.2 × 104 µg/L) were noted. Positron emission tomography combined with computed tomography (PET-CT) showed significantly increased uptake of fluorodeoxyglucose (FDG) in the multiple lymph nodes systemically, as well as in the pituitary gland, the liver, and the spleen (Fig. 1A, B; Day 0 in Fig. 2). Extramedullary plasmacytoma or lymphoproliferative disease (LPD) was suspected, and the fine-needle aspiration biopsy (FNA/FNB) was performed. The biopsied lymph node did not contain enough B cells to examine their clonality by southern blotting or flow cytometry. After a 1-month follow-up in the outpatient department, the patient was admitted to the hospital for further investigations (1st admission in Fig. 2). Besides persistent fever above 38 ℃, the elevation of CRP to 1.3 × 105 µg/L, liver dysfunction (aspartate aminotransferase (AST) 122 IU/L, alanine aminotransferase (ALT) 103 IU/L, lactate dehydrogenase (LDH) 381 IU/L, γ-glutamyl transpeptidase (γ-GTP) 462 IU/L, alkaline phosphatase (ALP) 279 IU/L, total bilirubin 29.1 µmol/L), and progressive pancytopenia (WBC counts of 1000/µL, a hemoglobin level of 94 g/L, platelet counts of 4.7 × 104/µL) were noted. Results of physical examination and systemic imaging study with CT scan were negative for active bacterial or fungal infections. Notably, the serological antibody test for EBV resulted positive for VCA (virus capsid antigen)-IgG (320 ×) and EA (early antigen)-IgG (80 ×), while negative for EBNA (EBV nuclear antibody)-IgG. Purification of viral nucleic acids was performed using the QIA symphony DSP Virus/Pathogen Mini Kit version 1 (Qiagen). TaqMan gene expression assay of EBV–DNA was carried out using the TaqPath qPCR Master Mix, CG (Applied Biosystems). The reaction was carried out for 50 cycles of two-step PCR (denaturation at 94 ℃ for 15 s, and annealing/extension at 60 ℃ for 60 s). The fluorescence intensity was analyzed by the QuantStudio 12 K Flex Real-Time PCR System (Applied Biosystems). The whole blood EBV–DNA level was elevated to 900 copies/mL, indicating the reactivation of EBV infection. The symptoms gradually improved with supportive care and termination of the lenalidomide maintenance therapy for multiple myeloma, and the patient was discharged (Discharge in Fig. 2). Within 1 month after the discharge, the patient was readmitted to the hospital because of the aggravation of malaise and fever (2nd Admission in Fig. 2). Complete blood counts showed recurrence of prominent pancytopenia with decreased WBC counts of 700/µL (Neutrophil 500/µL), a hemoglobin level of 111 g/L, and platelet counts of 5.9 × 104/µL. Elevations of the serum CRP level to 1.1 × 105 µg/L, the serum ferritin level to 5.1 × 103 ng/mL, and soluble interleukin-2 receptor levels to 1.4 × 104 U/mL were observed. Persistent liver dysfunction (AST 115 IU/L, ALT 116 IU/L, LDH 377 IU/L, γ-GTP 913 IU/L, ALP 673 IU/L) with hyperbilirubinemia (total bilirubin 90.6 µmol/L, and direct bilirubin 57 µmol/L) was noted as well. Laboratory data at 3 months before the 1st admission, at the 1st and 2nd admission is shown in Supplemental Table 1. Imaging studies with CT scan showed hepatosplenomegaly, bilateral pleural effusion and ascites. In addition, the serum EBV-DNA level was significantly increased to 9.0 × 103 copies/mL. To examine the cell-lineage-specific infection of EBV, we sorted the hematopoietic cells into five lineages− CD19 + B cells, CD4 + T-cells, CD8 + T-cells, CD56 + NK cells and other cells–and extracted genomic DNA from each of the lineages. Quantification of the levels of EBV genomic DNA by the polymerase chain reaction (PCR) analysis showed specific amplification exclusively from the CD19 + B cells (1.1 × 103 copies/μg DNA). Together with proliferated EBV-positive B cells, multiple lymph node enlargement with active FDG incorporation by PET–CT, and increased levels of serum EBV–DNA, the present case was clinically diagnosed as EBV–LPD. Analysis of the bone marrow aspiration showed hypocellular bone marrow with a significant proliferation of phagocyting macrophages, as well as emergence of a few large lymphoid cells with basophilic cytoplasm (Fig. 1C, D). Considering the persistent pancytopenia, elevated ferritin level of 17,484 ng/mL, and hypertriglyceridemia of 3.7 mmol/L, the patient was also diagnosed as HLH based on HLH-2004 diagnostic criteria [7], in addition to EBV–LPD. With a hope to ameliorate severe pancytopenia, the patient immediately underwent HLH-2004 regimen, which includes continuous use of cyclosporine and dexamethasone with periodical use of etoposide [8]. The pancytopenia and immunosuppression, however, rapidly progressed despite intensive therapy, and the patient succumbed to death due to invasive pulmonary aspergillosis and multi-organ dysfunction on Day 25 of the HLH-2004 regimen. The autopsy has confirmed that the resolution of multiple lymph node enlargement followed by replacement with scarring fibrosis, indicating that the EBV-infected lymphocytes have been eradicated after administration of intensive HLH-2004 chemotherapy. The clinical course of the patient is summarized in Fig. 2.Fig. 1 Development of EBV–LPD and EBV–HLH following long-term lenalidomide treatment for multiple myeloma. A PET–CT showed increased uptake of FDG in multiple lymph nodes, pituitary gland, liver, and spleen (SUV max: 20.5). B, C Analysis of the bone marrow aspiration showed hypocellular bone marrow with significant proliferation of phagocyting macrophages indicated by arrowheads (B) and infiltration of a few large lymphoid cells with basophilic cytoplasm indicated by arrows (C)
Fig. 2 The clinical course of the case. The patient developed EBV-associated lymphoproliferative disease (LPD) as well as EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) after 4 years of lenalidomide maintenance therapy for multiple myeloma. Despite intensive treatment including HLH-2004 regimen, pancytopenia and immunosuppression did not improve and proved lethal. ALT aspartate alanine transferase, BMA/B bone marrow aspiration/biopsy, EBV-DNA EB virus deoxyribonucleic acid, G-CSF granulocyte colony-stimulating factor, HLH hemophagocytic lymphohistiocytosis, PET-CT positron emission tomography-computed tomography, Plt platelets, CRP C-reactive protein, WBC white blood cells
Discussion
EBV–LPD is a life-threatening complication in patients under immunosuppressive conditions. Because the immunodeficiency often disrupts the normal balance between latency infected B-cell proliferation and the EBV-specific T-cell response, the EBV-positive B cells outgrow and may develop into LPD [9]. Iatrogenic immunodeficiency is often induced by methotrexate and other well-known immunosuppressive medications in patients with autoimmune disease or post-organ transplant. Spontaneous development of EBV–LPD has repeatedly been documented in these immunocompromised patients [10]. Of note, novel agents with immunomodulatory effects have recently been shown to induce such chronic immunodeficiency and lymphoproliferative diseases [11, 12]. Lenalidomide, a derivative of thalidomide, is a potent anti-myeloma agent as well as a representative immunomodulatory drug. Although the present case might be the first and only report describing the clear association of lenalidomide use and EBV–LPD development, reactivation of EBV was seen in one out of the 30 patients with multiple myeloma under lenalidomide maintenance therapy in the HOVON76 Trial, and EBV–LPD was observed in one Japanese patient out of 96 East Asian patients after administration of a combination therapy of daratumumab, lenalidomide, and dexamethasone, which resulted in discontinuation of the therapy in the POLLUX study, both of which were regarded as an unrelated adverse event at that time [13, 14]. In clinical settings, it is difficult to tell replication of EBV, a condition that infectious virion is actively produced during lytic replication, from proliferation of EBV-infected B cells stimulated by latent EBV proteins. Based on the finding of high levels of serum VCA–IgG in the present patient, we speculate that reactivation of EBV is more likely in this case [15]. Considering the present case and the results from HOVON76 trial and POLLUX study, potential association of LPD development and IMiDs use is suspected, and its incidence might have been underestimated, which should be further investigated in future studies.
Besides developing EBV–LPD after long-term lenalidomide use, the present case progressed to HLH, which is usually a non-neoplastic, benign process with prominent but self-limited hemophagocytosis. In contrast, HLH is an often fatal, progressive condition with uncontrollable hemophagocytosis. The present case reminds hematologists in practice that reactivation of EBV could happen in patients under long-term IMiDs treatment, and periodical monitoring and early detection of EBV reactivation are critical in such patients to initiate proper management of this potentially fatal condition.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 16 KB)
Author contributions
MY collected data and wrote the manuscript. KM supervised research and wrote the manuscript, which was reviewed and edited by the other authors. MJ and MN analyzed the bone marrow aspiration samples. YK, AI, and TU collected the histopathological data. KI performed cell lineage-specific amplification and quantification of EBV. YY, HF, AH, and HM participated in the discussion and gave critical comments on research direction. MK supervised research and gave final approval for submission.
Data availability
Relevant clinical data is available upon request.
Declarations
Conflict of interest
M.K. received research funding from Pfizer, Otsuka Pharmaceutical, Chugai Pharmaceutical, Astellas, Kyowa Kirin, Takeda Pharmaceutical, Teijin, Eisai, Sumitomo Dainippon Pharma, Nippon Shinyaku, AbbVie, Daiichi Sankyo and Ono Pharmaceutical; advisory fees from Kyowa Kirin, Celgene, Chugai Pharmaceutical and MSD; and lecture fees from MSD, Astellas, Otsuka Pharmaceutical, Ono Pharmaceutical, Celgene, Daiichi Sankyo, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, Chugai Pharmaceutical, Janssen Pharmaceutical, Kyowa Kirin, AbbVie, Pfizer, AstraZeneca, Bristol-Myers Squibb, Amgen, Sanwa Kagaku, Sanofi, SymBio Pharmaceutical and Nippon Shinyaku. M.J. reports lecture fees from Bristol-Myers Squibb K.K.; and lecture fees from Novartis Pharma K.K. None of these are related to the current study.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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| 36510096 | PMC9744661 | NO-CC CODE | 2022-12-15 00:01:51 | no | Int J Hematol. 2022 Dec 13;:1-5 | utf-8 | Int J Hematol | 2,022 | 10.1007/s12185-022-03499-2 | oa_other |
==== Front
Neurocrit Care
Neurocrit Care
Neurocritical Care
1541-6933
1556-0961
Springer US New York
36510107
1653
10.1007/s12028-022-01653-6
Original Work
Characterization of Cerebral Hemodynamics with TCD in Patients Undergoing VA-ECMO and VV-ECMO: a Prospective Observational Study
Caturegli Giorgio [email protected]
1
Zhang Lucy Q. 1
Mayasi Yunis 1
Gusdon Aaron M. 1
Ergin Bahattin 1
Ponomarev Vladimir 1
Kim Bo Soo 2
Keller Steven 2
Geocadin Romergryko G. 1
Whitman Glenn J. R. 3
Cho Sung-Min 1
Ziai Wendy 1
HERALD (Hopkins Exploration, Research, and Advancement in Life support Devices) InvestigatorsActon Matthew
Rando Hannah
Alejo Diane
Calligy Kate
Anderson R Scott
Shou Benjamin
Kapoor Shrey
Sussman Marc
Wilcox Christopher
Brown Patricia
Peeler Anna
1 grid.21107.35 0000 0001 2171 9311 Division of Neurosciences Critical Care, Departments of Neurology, Neurosurgery, Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD USA
2 grid.21107.35 0000 0001 2171 9311 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD USA
3 grid.21107.35 0000 0001 2171 9311 Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD USA
13 12 2022
17
12 5 2022
14 11 2022
© Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Background
Extracorporeal membrane oxygenation has a high risk of acute brain injury and resultant mortality. Transcranial Doppler characterizes cerebral hemodynamics in real time, but limited data exist on its interpretation in ECMO. Here, we report TCD mean flow velocity and pulsatility index in a large ECMO population.
Methods
This was a prospective cohort study at a tertiary care center. The patients were adults on venoarterial ECMO or venovenous ECMO undergoing TCD studies.
Results
A total of 135 patients underwent a total of 237 TCD studies while on VA-ECMO (n = 95, 70.3%) or VV-ECMO (n = 40, 29.6%). MFVs were captured reliably (approximately 90%) and were similar to a published healthy cohort in all vessels except the internal carotid artery. Presence of a recordable PI was strongly associated with ECMO mode (57% in VA vs. 95% in VV, p < 0.001). Absence of TCD pulsatility was associated with intraparenchymal hemorrhage (14.7 vs. 1.6%, p = 0.03) in VA-ECMO patients.
Conclusions
Transcranial Doppler analysis in a single-center cohort of VA-ECMO and VV-ECMO patients demonstrates similar MFVs and PIs. Absence of PIs was associated with a higher frequency of intraparenchymal hemorrhage and a composite bleeding event. However, cautious interpretation and external validation is necessary for these findings with a multicenter study with a larger sample size.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12028-022-01653-6.
Keywords
Extracorporeal membrane oxygenation
Transcranial doppler
Brain injury
Stroke
==== Body
pmcIntroduction
Extracorporeal membrane oxygenation (ECMO) is a temporary mechanical circulatory support used for medically refractory pulmonary and/or cardiac failure. ECMO is used with exponentially increasing frequency in the United States, with 18,260 runs in 2020, up from 3,446 in 2010 [1]. Although often lifesaving, ECMO is commonly associated with thrombotic and hemorrhagic complications, which are significant risk factors for morbidity and mortality, and embolism propagated from a cardiac or circuit source is a potential source of acute brain injury (ABI) [2].
In-hospital mortality for ECMO patients remains high (56% in venoarterial [VA] and 36% in venovenous [VV] ECMO), but mortality risk approximately doubles in the presence of ABI such as ischemic stroke, intraparenchymal hemorrhage (IPH), and hypoxic-ischemic brain injury [3, 4]. These complications are common, ranging from 5–10% prevalence in Extracorporeal Life Support Organization registry studies [3–6]. These rates are likely underestimated, however, due to lack of standardized neuromonitoring and the challenges of neuroimaging ECMO patients, as is evidenced by the drastically higher prevalence (up to 85%) described in pathological [7–9] and prospective clinical studies [10–12].
Transcranial Doppler (TCD) is a noninvasive, low-risk, bedside technique that allows real-time characterization of regional cerebral hemodynamics. Because of the relative rarity of ECMO and the high operator proficiency required of TCD, data regarding cerebral hemodynamics and their clinical significance in this population remain limited. To date, five articles have recently described cerebral hemodynamics in ECMO patients, but with sample sizes ranging from 8–53 patients and limited clinical correlation with relevant hemodynamic parameters or clinical follow-up [13–17]. In this study, intracranial artery mean flow velocities (MFVs) and pulsatility indices (PIs) were captured in a large, clinically well-characterized cohort of VA-ECMO and VV-ECMO patients to describe cerebral hemodynamics, clinical correlates, and neurologic outcomes with TCD use in this population.
Materials and Methods
Study Design
This study derives from a multidisciplinary effort involving the cardiovascular intensive care unit, cardiac critical care unit, and neurocritical care unit to improve overall care and outcomes for patients treated with ECMO at a tertiary care medical center. All ECMO patients cannulated at the study site are included in a prospective cohort that undergoes a neurologic monitoring protocol [12]. This protocol, established in October 2017, includes neurocritical care consultation with baseline and serial neurologic examinations, serial TCDs as described below, and additional neurological studies as appropriate (electroencephalography, SSEPs, and computed tomography). This was a retrospective observational study reviewing prospectively collected TCD examinations from ECMO patients from November 2017 through November 2021 at a single tertiary care center. Although not a case–control study, for the purposes of comparison of TCD variables between ECMO and non-ECMO patients, a well-characterized previously published cohort was studied [18].
Study Participants
We included all adult patients (age > 18 years) who received ECMO. We excluded patients who underwent multiple runs to minimize potential bias resulting from severe illness, as we considered that morbidity during the inter-ECMO periods could introduce a significant confounder. Patients who did not receive TCD or had absent temporal windows were excluded. The reasons for not having TCD tests were early deaths or ECMO withdrawals and noncompliance with the standardized neuromonitoring protocol, largely due to logistical challenges in the early phase of the coronavirus disease of 2019 (COVID-19) pandemic. This study was approved by the Johns Hopkins University Institutional Review Board (IRB00216321), and all patients or their surrogates consented for participation.
Data Collection and Definitions
For all patients in the study, we collected pre-ECMO characteristics including demographics, past medical history, precannulation neurologic function (Glasgow Coma Scale), cardiac diagnoses, pulmonary diagnoses, and laboratory values. ECMO variables included the following: indication, cannulation method (central [right atrium-aorta] vs. peripheral [femoral-femoral, femoral-internal jugular, or internal jugular dual lumen]) [19], ECMO flow (L/min), and ECMO pump speed (revolutions per minute). A dedicated perfusion team assessed the ECMO circuit multiple times daily to identify the presence of fibrin and clot. Selected hemodynamic parameters (systolic blood pressure [SBP], diastolic blood pressure [DBP], mean arterial pressure, venous oxygen saturation, transthoracic echocardiographic ejection fraction, cardiac output, and cardiac index calculated by Fick’s formula) and laboratory findings (hemoglobin/hematocrit, arterial blood gas, aPTT, and INR) were collected at the closest available time to each TCD. Based on clinical availability, the closest available time was typically within several minutes for hemodynamic parameters and within hours for laboratory values. These parameters were selected based on physiological relevance to cerebral blood flow hemodynamics [20, 21].
TCD Protocol and Variables
Serial TCD (DWL; Compumedics DWL, El Paso, TX) studies were performed while patients were on ECMO. Standard TCD protocols were used, and all studies were performed by registered vascular technologists [22]. We assessed cerebral blood flow velocities (peak systolic velocity, end diastolic velocity, and MFV), measured bilaterally in anterior (internal carotid artery [ICA; C1 segment], middle cerebral [MCA; M1 segment], anterior cerebral artery [ACA; A1 segment]) and posterior (vertebral artery [VrA], basilar artery [BA]) intracranial circulation. As permitted by duration of ECMO support, three TCDs were scheduled routinely for all ECMO patients at ECMO day 1, days 3–5, and days 7–10 [12]. Additional studies were performed as clinically indicated, such as for positive microembolic signals, subarachnoid hemorrhage monitoring, or brain death evaluation. PIs were calculated for each vessel using Gosling’s formula: (peak systolic velocity − end diastolic velocity)/MFV.
Measures and Outcomes
Primary measures were MFV and PI on TCD, which were analyzed by ECMO mode. Secondary outcomes were clinical complications relevant to TCD including neurologic (ischemic stroke, ICH, subdural hemorrhage, subarachnoid hemorrhage, hypoxic-ischemic brain injury, seizure, brain death) and thromboembolic (intracardiac thrombus, pulmonary embolism, deep venous thrombosis, heparin-induced thrombocytopenia, disseminated intravascular coagulation) events. A composite bleeding event was defined as one of the following the bleeding events: surgical site, cannulation site, gastrointestinal, pulmonary, disseminated intravascular coagulation, or any intracranial hemorrhage. We investigated systemic thromboembolic and bleeding events with TCD measures as a surrogate marker for hypercoagulable state or low pulsatility leading to bleeding events. Neurologic outcomes were assessed by a study team of neurointensivists based on physical examination and imaging results as clinically indicated.
Statistical Analysis
Primary outcomes were described as proportions for categorical variables and as medians and interquartile ranges (IQRs) for continuous variables, applying χ2 test, Fisher’s exact test, or Mann–Whitney U-test as appropriate.
Using summary data from a published cohort of 364 healthy adults, mean TCD MFVs for each studied vessel were compared with our study results by using Welch’s t-test due to unequal variances; men and women were analyzed separately due to known differences in normal values of TCD MFV and PI [23]. MFVs and PIs were then compared between VA-ECMO and VV-ECMO as well as between VA-ECMO with and without intraaortic balloon pump (IABP). For the above analyses, each patient first TCD on ECMO was used.
Correlations between MFVs in bilateral paired vessels were assessed by Spearman’s coefficient. Due to high positive correlations (> 0.75 Spearman’s coefficient) between MFVs in left and right paired vessels, these values were averaged for further correlation with clinical and hemodynamic parameters at the time of TCD, using all available TCD studies. As previously described, the MCA M1 segment (the average of left and right MFV in each study) was used as a representative vessel when analyzing covariates of MFV and PI on binary logistic regression [21, 24].
p values below 0.05 were considered statistically significant. Analyses were conducted in STATA 16.0 (StataCorp LLC; College Station, TX).
Results
Study Participant Characteristics
During the study period, 215 consecutive patients received ECMO support. Of these, 135 (62.7%) patients underwent at least one TCD study while on VA-ECMO (n = 95, 70.3%) or VV-ECMO (n = 40, 29.6%, Fig. 1). MFVs were reliably captured in 85% of VA-ECMO patients and 99% of VV-ECMO patients. Reasons for not completing a TCD study included COVID-19 infection (n = 30, 37.5%), less than 24 h of ECMO support (n = 6, 7.5%), absent temporal windows (n = 3, 3.8%), and no TCD monitoring pursued by primary team (n = 41, 51.2%). The study cohort was 60.7% men with a median age of 55 years (IQR 42–65); baseline characteristics of included patients are presented in Supplemental Table 1. The only significant difference in baseline characteristics between included patients and those excluded due to lack of a TCD study was a lower rate of COVID-19 in included VV-ECMO patients (50.0 vs. 76.9%, p = 0.02; Supplemental Table 2). Of 95 VA-ECMO patients, 50 (52.6%) were centrally cannulated whereas 45 (47.4%) were peripherally cannulated; 41 (30.4%) had an IABP and 7 (5.2%) had a left ventricular assist device. These 135 included patients underwent a total of 237 TCD studies, and median time to first study was 41 h (23–72) after ECMO cannulation (Fig. 2).Fig. 1 Study design and participant selection from a prospective cohort of venoarterial (VA) extracorporeal membrane oxygenation (ECMO) and venovenous (VV) ECMO at a single tertiary care center. COVID-19, coronavirus disease of 2019, TCD, transcranial Doppler
Fig. 2 Number and timing of transcranial Doppler (TCD) studies in VA-ECMO and VV-ECMO patients. ECMO, extracorporeal membrane oxygenation, VA, venoarterial, VV, venovenous
TCD MFV
MFV values from the first TCD on ECMO for each insonated vessel by ECMO mode are described in Table 1. MFV was highest in the MCA M1 segment, followed by ICA C1 segment, ACA A1 segment, BA, and finally VrA. The BA, left VrA, and right VrA exhibited slightly lower MFVs in VA-ECMO as compared with VV-ECMO. This difference in MFV was preserved comparing peripherally cannulated VA-ECMO to VV-ECMO in all three recorded vessels (e.g., in the BA 31 [26–40] vs. 39 [33–45], p = 0.005), whereas there was no difference seen when comparing centrally cannulated VA-ECMO to VV-ECMO (BA 37 [24–45] cm/s vs. 39 [33–45] cm/s, p = 0.12). In VA-ECMO, no differences were observed in MFVs between central and peripheral cannulation, or between presence and absence of IABP (Supplemental Table 3).Table 1 Mean flow velocity from the first transcranial Doppler study on ECMO
MFV Normal, mean ± SD (cm/s) VA-ECMO (n = 95 studies), n (%) or median (IQR) (cm/s) VV-ECMO (n = 40 studies), n (%) or median (IQR) (cm/s) p value (VA vs. VV)
Right
MCA M1 60.1 ± 12.1 84 (88.4%) 52 (40–71) 39 (97.5%) 60 (45–65) 0.28
ACA A1 50.5 ± 10 78 (82.1%) 42 (30–58) 40 (100%) 46 (38–59) 0.13
ICA C1 36.5 ± 9.4 81 (85.3%) 50 (40–66) 40 (100%) 49 (33–64) 0.50
VrA 34.3 ± 9.4 82 (86.3%) 22 (18–28) 40 (100%) 26 (22–33) 0.006
Left
MCA M1 60.1 ± 12.1 82 (86.3%) 51 (37–70) 39 (97.5%) 55 (47–68) 0.52
ACA A1 50.5 ± 10 74 (77.8%) 44 (30–63) 40 (100%) 44 (38–62) 0.96
ICA C1 36.5 ± 9.4 79 (83.2%) 50 (30–65) 40 (100%) 44 (34–70%) 0.93
VrA 34.3 ± 9.4 80 (84.2%) 33 (25–43) 40 (100%) 39 (32–45) 0.04
BA proximal 39.7 ± 10.4 81 (85.3%) 32 (25–43) 40 (100%) 39 (33–45) 0.01
Clinical parameters at time of TCD
Systolic blood pressure (mm Hg) 87 (91.6%) 92 (76–110) 39 (97.5%) 116 (103–130) < 0.001
Diastolic blood pressure (mm Hg) 87 (91.6%) 62 (54–68) 39 (97.5%) 60 (54–68) 0.60
Hematocrit (%) 95 (100%) 24.8 (22.8–28.2) 40 (100%) 25.5 (23.7–27.8) 0.66
Arterial blood gas pCO2 (mm Hg) 95 (100%) 39 (34–45) 39 (97.5%) 45 (41–50) < 0.001
Ejection fraction (%) 67 (70.5%) 30 (10–60) 29 (72.5%) 60 (50–65) < 0.001
Normal values from a healthy adult cohort are listed for reference [18]
Bold values are statistically significant (p < 0.05)
ACA, anterior cerebral artery, BA, basilar artery, ECMO, extracorporeal membrane oxygenation, ICA, internal carotid artery, IQR, interquartile range, MCA, middle cerebral artery, MFV, mean flow velocity, SD, standard deviation, VA, venoarterial, VrA, vertebral artery, VV, venovenous
MFVs were highly positively correlated between left and right paired vessels, as demonstrated by high Spearman’s coefficients: 0.72 for the MCA, 0.85 for the ACA, 0.78 for the ICA, and 0.78 for the VA. There were no statistically significant differences in median MFV by laterality, except for in the VrA (median [IQR] 35 [28–44] cm/s in the left vs. 23 [20–28] cm/s in the right, p < 0.001).
Given high concordance between left and right vessels, these values were averaged for further analysis. Compared by Welch’s t-test to normal values obtained from a cohort of 364 healthy adults, there was no significant difference in mean MFV of the MCA M1 segment, ACA A1 segment, BA, or VrA [23]. In the ICA C1 segment, however, MFVs for both men and women and for both VA-ECMO and VV-ECMO were significantly higher than published normal values (p values not shown, Table 2).Table 2 PI from the first transcranial Doppler study on ECMO
PI VA-ECMO (n = 95 studies), n (%) VA-ECMO % abnormal (≥ 1.2), n (%) PI, median (IQR) VV-ECMO (n = 40 studies), n (%) VV-ECMO % abnormal (≥ 1.2), n (%) PI, median (IQR) p value (PI)
Right
MCA M1 47 (49.5) 22 (46.8) 1.1 (1.0–1.6) 38 (95.0) 12 (31.6) 1.1 (1.0–1.2) 0.46
ACA A1 44 (46.3) 23 (52.2) 1.2 (1.1–1.5) 38 (95.0) 18 (47.4) 1.1 (1.1–1.3) 0.23
ICA C1 44 (46.3) 19 (43.2) 1.1 (1.0–1.4) 38 (95.0) 12 (31.6) 1.1 (1.0–1.2) 0.82
VrA 43 (45.3) 28 (65.1) 1.2 (1.1–1.6) 37 (92.5) 20 (54.1) 1.2 (1.1–1.2) 0.11
Left
MCA M1 46 (48.4) 25 (54.5) 1.2 (1.0–1.6) 38 (95.0) 14 (36.8) 1.1 (1.0–1.2) 0.34
ACA A1 42 (44.2) 23 (54.8) 1.2 (1.0–1.5) 38 (95.0) 15 (39.5) 1.1 (1.1–1.2) 0.55
ICA C1 44 (46.3) 23 (52.3) 1.2 (1.0–1.6) 38 (95.0) 13 (34.2) 1.1 (1.0–1.2) 0.22
VrA 47 (49.5) 30 (63.8) 1.2 (1.1–1.6) 36 (90.0) 18 (50.0) 1.2 (1.0–1.2) 0.05
BA proximal 44 (46.3) 28 (63.6) 1.2 (1.1–1.5) 37 (92.5) 16 (43.2) 1.1 (1.0–1.2) 0.07
Pulsatility indices were calculated by Gosling’s formula: (peak systolic velocity − end diastolic velocity)/mean flow velocity
ACA, anterior cerebral artery, BA, basilar artery, ECMO, extracorporeal membrane oxygenation, IABP, intraaortic balloon pump, ICA, internal carotid artery, IQR, interquartile range, MCA, middle cerebral artery, PI, pulsatility index, VA, venoarterial, VrA, vertebral artery, VV, venovenous
No robust statistically significant associations were demonstrated between mean MFVs and any studied hemodynamic and clinical parameters (SBP, DBP, mean arterial pressure, Fick’s cardiac output, cardiac index, arterial blood gas pCO2 or pO2, hemoglobin/hematocrit, fibrinogen, or ECMO flow).
TCD PI
Presence of a recordable PI in any insonated vessel was strongly associated with ECMO mode: 54 (57%) in VA vs. 38 (95%) in VV (p < 0.001). PIs by ECMO mode for each insonated vessel from the first TCD on ECMO are described in Table 2. Compared with patients with only VA-ECMO, those who also had IABP exhibited similar PIs (Supplemental Table 4). Presence of a recordable PI in any insonated vessel on a patient’s first TCD examination was not significantly different between centrally and peripherally cannulated VA-ECMO (48.9 vs. 56.0%, p = 0.54).
Patients with recordable PI in any insonated vessel were younger than those without (53 [39–62] years in pulsatile TCD vs. 61 [49–69] years, p = 0.007). In VA-ECMO, hemodynamic covariates at the time of TCD study were strongly associated with presence versus absence of TCD pulsatility: pulse pressure (46 [34–60] mm Hg in pulsatile TCD vs. 18 [6–44] mm Hg in nonpulsatile TCD, p < 0.001), SBP (104 [90–118] mm Hg vs. 87 [72–100] mm Hg, p < 0.001), and DBP (60 [50–67] mm Hg vs. 62 [56–70] mm Hg, p = 0.02).
Clinical Outcomes
Clinical outcomes by ECMO type are presented in Supplemental Table 5. In VA-ECMO patients, absence of TCD pulsatility of any vessel in any study was more frequently associated with IPH (14.7% vs. 1.6%, p = 0.02) and was also more frequently associated with a composite event of any bleeding while on VA-ECMO (79.4% vs. 52.5%, p = 0.02).
Discussion
In this large cohort of ECMO patients with TCD studies, cerebral hemodynamics were characterized comprehensively and correlated with relevant physiologic parameters during TCD monitoring. MFVs were reliably captured and generally comparable to normal values. PIs were correlated with hemodynamic SBP and DBP and thus were often absent in VA-ECMO, an absence that was associated with a higher burden of IPH.
MFV
For both men and women on both VA-ECMO and VV-ECMO, MFVs were within published normal limits in all insonated vessels except the ICA C1 segment. This vessel exhibited slightly higher cerebral blood flow in both VA-ECMO and VV-ECMO, with MFVs approximately 5–10 cm/s above one standard deviation around the mean of a healthy cohort. This effect was preserved after subgrouping by ECMO type and cannulation method (central vs. peripheral, data not shown). Prior studies similarly exhibited MFVs largely within normal ranges in VA-ECMO [16].
Bilaterally paired vessels exhibited a high degree of correlation and similar MFVs, except in the VrA where the right side was approximately 10–13 cm/s lower than the left, an effect that was again conserved across analyzed subgroups, including cannulation method. Although too small to likely be clinically significant, this difference may be in part attributable to a higher prevalence of right VrA hypoplasia in the general population [25, 26].
When comparing VA-ECMO to VV-ECMO, MFVs were very similar in the anterior circulation, but studies in VA-ECMO exhibited 3–5 cm/s lower MFVs in both VrAs and the proximal BA. This difference was affected by cannulation method, as comparing peripherally cannulated VA-ECMO versus VV-ECMO preserved this effect, while no significant difference in MFV in these vessels was observed between centrally cannulated VA-ECMO and VV-ECMO.
PIs
Presence of pulsatile flow in at least one insonated vessel was more frequently observed in VV-ECMO as compared with VA-ECMO patients, and in VA patients with IABP as compared with those without IABP. These findings are expected given the underlying indications and mechanics of the two ECMO modes, but interestingly, no difference was observed in the presence of pulsatile flow between centrally and peripherally cannulated VA-ECMO patients. In contrast to a prior small study of TCD in VA-ECMO patients with severely reduced cardiac function that demonstrated invariably absent or very low PIs on VA-ECMO [13], here a majority of VA-ECMO TCD studies exhibited recordable PIs, with values in the normal or indeed slightly elevated range. TCD pulsatility was strongly associated with hemodynamic parameters at the time of TCD, namely SBP, DBP, pulse pressure, and ejection fraction, as previously described [13, 27]. Absence of pulsatile flow was associated with a higher frequency of IPH. Early low pulse pressure (< 20 mm Hg) has been associated with ABI in VA-ECMO patients, indicating low pulse pressure may serve as a marker of ABI risk, which is consistent with our TCD analysis [28]. However, this association needs to be interpreted carefully given the low number of patients with IPHs in our cohort.
Limitations
This study’s limitations include being conducted at a single center, which limits generalizability despite a sizable cohort. However, the high interobserver variability of TCD performance lends itself to a study design relying on a small group of experienced technologists [18]. The study was also subject to incomplete capture of eligible patients due to challenges obtaining TCD, such as clinical instability, short duration of ECMO support, staff availability, and COVID-19 restrictions. Most TCD studies were performed early during the ECMO support, limiting our analysis of the early phase of ECMO course and TCD measures. Lack of a suitable control population for comparison to normal TCD values is a further limitation, which was addressed by direct comparison to published literature but would benefit from paired case–control study in the future.
Conclusions
TCD analysis in a single-center cohort of VA-ECMO and VV-ECMO patients demonstrates similar MFVs and PIs. Absence of PIs was associated with a higher frequency of IPH and a composite bleeding event. However, cautious interpretation and external validation is necessary for these findings with a multicenter study with a larger sample size.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 20 kb)
Supplementary file2 (DOCX 21 kb)
Supplementary file3 (DOCX 17 kb)
Supplementary file4 (DOCX 83 kb)
Supplementary file5 (DOCX 73 kb)
Acknowledgements
HERALD (Hopkins Exploration, Research, and Advancement in Life support Devices) Investigators: Matthew Acton MD, Hannah Rando MD, Diane Alejo BA, Kate Calligy RN, R Scott Anderson BA, Benjamin Shou BS, Shrey Kapoor BA, Marc Sussman MD, Christopher Wilcox DO MS, Patricia Brown RD-AP CNSC, and Anna Peeler RN.
Author contributions
Concept/design: RGG, GJW, SMC, and WZ. Data collection: GC, LQZ, YM, AG, BE, and VP. Data analysis: GC. Data interpretation: GC, BSK, SK, RGG, GJW, SMC, and WZ. Drafting: GC, SMC, and WZ. Critical revision: LQZ, YM, AG, BE, VP, BSK, SK, RGG, GJW, SMC, and WZ. Approval: all authors.
Source of support
Sung-Min Cho is supported by the National Institutes of Health (NHLBI) 1K23HL157610. Dr. Ziai is supported by NIH R01 NS120557, R01AG069930, U24TR001609, and R01NS102583, and has received consultant fees from Integra and Bard.
Conflicts of interest
There are no conflicts of interest for the authors to disclose.
Ethical approval
All ethical guidelines were followed, and institutional review board approval was obtained.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Sung-Min Cho and Wendy Ziai have contributed equally as senior authors to this article.
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| 36510107 | PMC9744662 | NO-CC CODE | 2022-12-15 00:01:51 | no | Neurocrit Care. 2022 Dec 13;:1-7 | utf-8 | Neurocrit Care | 2,022 | 10.1007/s12028-022-01653-6 | oa_other |
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Eur J Dev Res
Eur J Dev Res
The European Journal of Development Research
0957-8811
1743-9728
Palgrave Macmillan UK London
568
10.1057/s41287-022-00568-4
Special Issue Article
Repercussions the Covid-19 Pandemic on the SDGs Achievement: Is it a New Era for the Development?
http://orcid.org/0000-0002-1077-2798
Belaîd Fateh [email protected]
1
Tiba Sofien [email protected]
2
1 grid.503365.6 0000 0000 9099 1370 Faculty of Management, Economics & Sciences, Lille Catholic University, UMR 9221-LEM-Lille Économie Management, 60 Boulevard Vouban, 59016 Lille, France
2 grid.412124.0 0000 0001 2323 5644 Faculty of Economics and Management, University of Sfax, Sfax, Tunisia
13 12 2022
110
5 10 2022
© European Association of Development Research and Training Institutes (EADI) 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Using monthly data, this article examines the influence of Covid-19 on poverty, inequality, well-being, and environmental quality for a sample of 14 African economies from 2018 to 2020. To do so, we employ a GMM approach to look at the influence of the pandemic on achieving the SDGs in Africa. According to our empirical findings, the pandemic significantly impacts poverty and pollution levels. The results show also that the pandemic coefficient considerably influences the inequality proxy. Due to social exclusion and inequities, these economies must embrace an integrated socio-economic vision to overcome the multi-faceted pandemic externalities and build more resilient economies..
Résumé
Cet article analyse l’effet de la COVID-19 sur la pauvreté, l’inégalité, le bien-être, et la qualité de l’environnement pour un échantillon de 14 économies Africaines pendant la période 2018–2020, à l’aide de données mensuelles. On utilise la méthode des moments généralisés (en anglais, « generalised method of moments», GMM) afin d’analyser l’effet de la pandémie sur la réalisation des Objectifs de Développement Durable (en anglais, « Sustainable Development Goals», SDG) en Afrique. Selon nos résultats empiriques, la pandémie a entraîné une répercussion significative sur la pauvreté et les niveaux de pollution. Les résultats montrent aussi que le coefficient pandémique influence significativement l’indice d’inégalité. À cause des exclusions sociales et des iniquités, ces économies doivent adopter une vision socio-économique intégré, afin de surmonter les externalités multiformes de la pandémie, et pour construire des économies plus résilients.
Keywords
Poverty
Inequity
Well-being
Environmental quality
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pmcIntroduction
COVID-19 inflicted a heavy toll on the global economy. The various policy responses, including mobility and stay-at-home restrictions, led to unparalleled supply chain disruption and economic downturn. The magnitude of service disruption has exacerbated many existing inequalities and created new ones.
Indeed, based on the World Bank estimates, COVID-19 pandemic slashed the annualized global economic growth rate to about − 3.2% in 2020.. In this context, Sub-Saharan Africa's growth rate will decrease by 2.8%; however, the Middle East and North Africa by 4.2%, Europe and Central Asia by 4.7%, and Latin America by 7.2%. Hence, these downturns negatively affect the achievement of development goals and tip 10 million people back into extreme poverty. Even more, with the persistence of the pandemic, the World Bank's forecasting estimate that the global economy will lose eight percent in 2020.
The majority of public spending is oriented towards supporting the weak health care systems, helping the needy social categories, and the caused technical unemployment, especially in Africa with the almost absence of online working. This additional pressure on the public finance and balance of payments needs emergence plans to face all these threats. This pandemic rends rare several agricultural goods and trade restrictions and supplies chain disruptions with the increase of the uncertainty in exporters of energy, and industrial commodities, which has triggered an unusual collapse in oil demand, a crash in oil prices, as well as food security. Conjointly with the emergence of Sustainable Development Goals (SDGs) as the main challenges in the current millennium with the phenomenal spread of Covid-19, we discuss the repercussions of this pandemic on the achievement of the SDGs. Indeed, poverty, energy, hunger, education, and foreign trade patterns faced profound changes during this pandemic. Also, the panic caused by the pandemic and the strict cross-border restrictions has a prominent role in the economic recession. To support economic activity, the IMF and the World Bank argued for three trillion dollars to stimulate the world economic recovery in accordance with Keynesian thought. In this context, several scenarios have been proposed as outcomes of the potential effect of this pandemic on the world, such as it could be structural changes in the world economy. In other words, the re-polarization of the world will be implemented with the emergence of new economic and geopolitical powers.
Africa as the globe is concerned by the evolution of the pandemic, and the repercussions should be assessed instantly to make the right decisions, policies, and actions at the right moments. Due to the gained momentum of this pandemic, controlling the outcomes will be difficult for the local governments. Moreover, the global lockdowns of movement of foreign trade inflows and the comparative advantage of exporting natural resources, energy, and raw materials seem insufficient to bring additional revenues to stimulate economic growth and public investments and support the national health systems. Motivated by this question, we attempt to assess the COVID-19 pandemic on the SDGs' achievement in the context of selected African countries. Specifically, we focus on examining the impact of COVID-19 on poverty, environmental quality, well-being, and inequality. This study is the first one that attempts to assess the effects of the pandemic on the macroeconomic sphere, and the SDGs achievement in the case of Africa, which is the most vulnerable with strong population density, leads to improving the pressure on local governments in terms of commitments towards their local community and the international society, rending the SDGs more challenging. For this purpose, we employ the Generalized Method of Moments to analyze the impact of the pandemic on poverty, well-being, inequity, and environmental quality using monthly data for a sample of 14 African economies over the period 2018–2020.
The socio-economic crisis experienced with the COVID-19 pandemic is significantly different from previous economic downturns in that it is more deeply rooted in constrained organization and individual behavior. Currently, it is uncertain how long and deep the crisis will be, what the recovery pathway will look like, and thus how economic conditions will be affected. Therefore empirical evidence on the pandemic impacts on the socio-economic trends may help inform policymakers' responses to mitigate the effects on society and individuals.
The rest of this paper is as follows: “Empirical Background” section portrays the method and material. “Empirical Results” section contains the discussions of the results. Section “Conclusion and Policy Implications” concludes the article and provides some policy implications.
Empirical Background
Model Specification
This analysis aims to assess the impact of the Covid-19 pandemic on achieving the SDGs in Africa. Specifically, our study includes as aspects representing the SDGs the environmental quality (see Tiba and Belaid 2020), poverty (see Azzarri and Signorelli 2020), well-being (see Costantini and Monni, 2008), and inequality (see Aiyar and Ebeke 2020; Bélaïd et al. 2020a), for 14 selected African economies. Besides, we use various control and instrumental variables to ensure our model validity, including the omission bias and some other drawbacks in line with the economic theory requirements. Indeed, we include economic growth (see Tiba and Belaid 2021; Tiba 2019a, 2020), foreign direct investment (see Tiba and Belaid 2020; Tiba and Frikha 2019), stock of capital (see Tiba and Frikha 2020; Tiba 2019b), energy consumption (Belaid and Youssef 2017; Tiba and Belaid 2020), as well as, government health expenditure, and public spending on education (see Tiba and Frikha 2020).
Accordingly, our four structural models are specified as follows:1 POVERTYit=α0+α1iGDPit+α2iKit+α3iFDIit+α4iLit+α5iCOVIDit+μit
2 HDIit=β0+β1iGDPit+β2iKit+β3iHEALTHEXPit+β4iEDUPUBSPENit+β5iCOVIDit+ζit
3 GINIit=λ0+λ1iGDPit+λ2iKit+λ3iFDIit+λ4iCOVIDit+πit
4 CO2it=ψ0+ψ1iGDPit+ψ2iGDPit2+ψ3iECit+ψ4iFDIit+ψ5iCOVIDit+ςit
where i, t, α0, β0, λ0, ψ0 μ,ζ, π, and ς portrays country, period, country-specific effect, and the error terms which are supposed to be identically normally distributed, respectively. The parameters α1i, α2i, α3i, α4i, and α5i represent the long-run elasticities of poverty with respect to GDP, gross fixed capital formation, foreign direct investment inflows, labor force, and a dummy variable representing the pandemic, respectively. The parameters β1i, β2i, β3i,β4i, and β5i are the elasticities of HDI1 with respect to GDP, gross fixed capital formation, government health expenditure, and public spending on education, and a dummy variable representing the pandemic, respectively. The parameters λ1i,λ2i,λ3i, and λ4i reflect the elasticities of inequality (GINI) with respect to GDP, gross fixed capital formation, foreign direct investment inflows, and a dummy variable representing the pandemic, respectively. The parameters ψ1i,ψ2i,ψ3i, ψ4i, and ψ5i portray the elasticities of the pollutant emissions (CO2) with respect to GDP, its square, energy consumption, foreign direct investment, a dummy variable representing the pandemic, respectively.
The Estimation Method
The Generalized Method of Moments (GMM) method in our frame is due to a set of reasons, such as using instrumental variables to overcome the endogeneity issue. Hence, the GMM technique gives efficient estimates conjointly with the presence of arbitrary heteroskedasticity. In addition, most of the diagnostic tests applied in our model can be expressed in a GMM framework. Consequently, the GMM method provides efficient estimates.
Data
Our empirical background uses monthly data of 14 African economies from 2018 to 2020. The sample consists of 14 countries as Algeria, Angola, Benin, Botswana, Egypt, Morocco, Mozambique, Senegal, South Africa, Tanzania, Togo, Tunisia, Zambia, and Zimbabwe. The data are obtained from the World Development Indicators (WDI 2021). The availability of data constrained the selection of countries and the starting period. The present study uses the poverty factor, which is proxied by the poverty headcount index; Per capita GDP is measured using real GDP in constant 2010 US$ (in millions). HDI has been used as a proxy for key dimensions of human development, including education level and life expectancy. Income is not included to avoid the multicollinearity between the index and economic growth. COVID is a dummy variable representing the pandemic. Energy consumption (EC) is measured using energy use in kg of oil equivalent per capita; government health expenditure as a share of GDP (HEALTHEXP), public spending on education as a share of GDP (EDUPUBSPEN), foreign direct investment net inflows (FDI) as a share of GDP; Gini index (GINI) is used as a proxy of income inequality; The labor force (L) in millions of persons; and per capita CO2 emissions in metric tons.
Empirical Results
The GMM estimation findings of the four structural models are reported in Table 1. The results pertaining to Model 1 reflect that income has no significant impact on poverty, implying that the income level in the short run couldn't reduce the effect of poverty in African society. Regarding the stock of capital, it has no significant effect on reducing poverty during the pandemic period. Indeed, during the pandemic, the stock of capital in the African region seems insufficient to overcome the urgent needs of the society in terms of providing the financial capacity for investing. However, the stock of capital is oriented towards saving for investment, but it is used to finance daily expenses as an emergent response to the pandemic panic and the demand shocks. While the coefficient of foreign direct investment has a significant positive impact on poverty, due to the strong dependence of these economies on foreign actors and investments, even the effect of a pandemic, these economies continue to seek foreign investment as the main element for the economy. However, these investments seem low in terms of value-added and contribute to enhancing poverty and disparities. Besides, the coefficient of the labor force has no significant impact on the poverty level. This implies that the pandemic caused the technical unemployment phenomena in these economies, which leads to an increasing the poverty level, and the majority of labor forces are in temporary jobs and vulnerable works, which justifies the marginal effect of the labor force on reducing poverty in the region as a whole. Finally, the coefficient of the pandemic exerts a significant positive impact on the poverty level. The magnitude of 11.077 means that a 1% increase in the number of Covid cases implies an 11.077% increase in poverty. This result is justified by the vulnerable structure of employment and the caused effects of temporary and technical unemployment, as well as the absence of actual design for online working and several inherent issues such as the infrastructure, etc.Table 1 The S-GMM estimations
Dependent variable: Variables GDP GFCF FDI L COVID AR(1)
POVERTY Coef 0.072 − 0.052 0.208 6.40E−05 11.077* 0.0000
P-value 0.1939 0.6760 0.0379 0.2326 0.0051
AR (1) is the first order autocorrelation of residuals. *** Means the significance at 1%. ** Shows the significance at 5%. * Shows the significance at 10%, respectively
The results of the CO2 modeling are recorded in Table 2. The insights reveal that the GDP and its square have no significant impact on the pollution level during the pandemic period. This result is due to the technical unemployment caused by the extensive lockdown designed to stop the spread of Covid-19. Policy actions taken during the COVID-19 pandemic radically reshaped energy demand patterns worldwide. Most international borders were closed, and individuals were constrained to their homes, resulting in reduced transportation and change in consumption patterns. Also, the foreign direct investment coefficient has no significant impact on the pollution level over the pandemic period. Indeed, the pandemic consequences are strongly linked to the loss of several opportunities in terms of investment and job creation. This explains the lack of an effective effect of foreign investment on Africa's environmental quality due to panic and the absence of economic stability and strategic perspectives in short to medium term. Finally, the coefficient of the pandemic has a significant positive impact on the pollution level. Results show that an increase of 1% in the number of cases leads to 1.64% increase in emissions. Indeed, the caused panic of Covid-19 leads to an increase in the use of private cars and online working /learning, which leads to additional energy demand, therefore, an increase in the pollution level, especially with weak ecological regulation in this region as a whole.Table 2 The S-GMM estimations
Dependent variable Variables GDP GDP_SQR EC FDI COVID AR(1)
CO2 Coef − 0.001 2.95E−08 5.15E−05 0.015 1.640* 0.0003
P-value 0.7184 0.5283 0.0277 0.3220 0.0000
AR (1) is the first order autocorrelation of residuals. *** Means the significance at 1%. ** Shows the significance at 5%. * Shows the significance at 10%, respectively
The highlights related to the inequality model are displayed in Table 3. The empirical results reveal that the income factor has no significant impact on the inequality proxy. As a result of the pandemic's expansion and the lack of a good strategy to overcome the covid-19's socio-economic effects, social movements will emerge due to poor social and economic choices. In addition, with the looming energy crisis, energy prices may increase and push many households into energy poverty.Table 3 The S-GMM estimations
Dependent variable Variables GDP GFCF FDI COVID AR(1)
GINI Coef 9.99E−06 0.012 0.004 0.446** 0.0014
P-value 0.7586 0.1113 0.4113 0.0235
AR (1) is the first order autocorrelation of residuals. ***Means the significance at 1%. **Shows the significance at 5%. *Shows the significance at 10%, respectively
Also, the stock of capital has no significant impact on inequality, implying that the national investment has no socio-economic role to play in the society, and the lack of institutional background and nationalism of the society is the primary justification for the absence of the State spirit. Presumably, inequality and disparities will increase during the pandemic due to Africa's vulnerable socio-economic panorama. Further, foreign direct investment has no significant impact on the inequality phenomenon.
The combination of ineffective measures to reduce inequality and the current geopolitical issue could trigger a wave of political instability. The escalating food and energy costs pressured individuals already frustrated with the government's leadership. Finally, the coefficient of the pandemic exerts a significant positive impact on the inequality proxy. The results show that a 1% increase in the number of cases leads to an increase in inequality by around 0.45%. Hence, the pandemic era leads to increasing inequality and favors inequity, and the most vulnerable social class suffered more from lockdowns and the resulted economic downturn. Many studies show that containment measures and stimulus packages adopted in response to the COVID-19 pandemic and the associated economic crisis have affected income and production distribution within and between countries (Ben Amar et al., 2020, 2021; Belaid et al., 2022).
The empirical findings of the HDI model are shown in Table 4. The results point out that the income factor, stock of capital, public spending on health, education expenditure, and the pandemic variable have no significant impact on the HDI. Consequently, the income level, health expenditure, education, public spending, and national investment lead to social exclusion and disparities. These economies are characterized by the absence of an integrated socio-economic vision for a better society. With the caused effects of the pandemic, social exclusion and disparities are more prominent. An emergent investment in national health systems, schooling is an emergent to overcome the disastrous impact of the spread of Covid19. A fiscal stimulus policy is recommended to stimulate economic growth, and also it will have a serious repercussion on the social stream. Since the investment in the human factor is already weak, the pandemic will empower inequality, social exclusion, and disparities, the main challenge for the decision-makers is how to ensure efficient and oriented investment towards equal access to the national wealth, investment, and basic needs for an integrated society for sustainable future.Table 4 The S-GMM estimations
Dependent variable Variables GDP GFCF HEALTHEXP EDUPUBSPEN COVID AR(1)
HDI Coef 0.0010 0.306 − 0.090 0.049 28.603 0.0003
P-value 0.6179 0.5289 0.8501 0.2547 0.3580
AR (1) is the first order autocorrelation of residuals. *** Means the significance at 1%. ** Shows the significance at 5%. * Shows the significance at 10%, respectively
Conclusion and Policy Implications
Due to the heavy impacts of the pandemic on the global economy, international trade, investment movements, and health systems, we attempt to assess the impact of the pandemic on the economic, social, and ecological streams in the case of Africa. Specifically, we use the Generalized Method of Moments method to examine the impact of the pandemic on poverty, well-being, inequity, and environmental quality, representing the sustainable development facets using monthly data for a sample of 14 African economies over the period 2018–2020.
Our empirical findings reveal that the pandemic exerts a significant positive impact on the poverty level. This can be explained by the vulnerability of the employment situation and the effects of temporary and technical unemployment, as well as by the lack of solid structures for online work and several inherent problems such as physical infrastructures.
Moreover, the results show that the pandemic has a significant positive impact on the pollution level. This implies that the caused panic the Covid-19 leads to an increase in the use of private cars and online working /learning, which leads to additional energy demand, therefore, an increase in the pollution level, especially with weak ecological regulation in this region as a whole. The highlights related to the inequality model reveal that the coefficient of the pandemic exerts a significant positive impact on the inequality proxy. Thus, the pandemic era increased inequality, and the most vulnerable social classes were strongly affected by the rigorous responses designed to stop the spread of the pandemic. The results of the lockdowns in several countries are inefficient and lead to aggravated inequalities. Furthermore, the results highlight that the income level, health expenditure, education, public spending, and national investment lead to social exclusion and disparities.
To respond and mitigate the extreme effects of the pandemic in Africa, investment in national health systems and schooling are urgent solutions to overcome the disastrous impact of the spread of Covid-19. A fiscal stimulus policy is recommended to stimulate economic growth, and also it will have a serious repercussion on the social stream. Since the investment in the human factor is already weak, the pandemic will empower inequality, social exclusion, and disparities. The critical challenge for policymakers is how to ensure efficient and equal access to national wealth, investment, and basic needs to ensure an integrated society and a sustainable future.
It is vital to have proper policy measures in place to improve social welfare and advancement of SGDs. As a result of the higher unemployment rates and projected problems in repaying debt, long-standing issues such as poverty, insufficient food supply, restricted access to health care, and poor roadways, among others, would become even more entrenched. These might endanger the vision of 2030 for Sustainable Development. As a result, the current crisis threatens Africa's growth potential, as recovery may take longer. As a result, it is essential to comprehend the necessity of ensuring a solid institutional regulatory system as well as the resources required to support long-term economic development. In particular, any plan should take a conflict-sensitive approach, incorporating risk and opportunity assessment as a significant component of ensuring that public policies do not amplify current instability. Sustainable development faced challenges before Covid-19, but the Covid-19 pandemic has exacerbated those challenges. Covid-19 has generated substantial hurdles for many sustainability initiatives and sustainable future development. As a result, governments, organizations, practitioners, and legislators must work together to minimize the pandemic's adverse effects on sustainable development.
It is also crucial to build on the lessons learned from the COVID-19 pandemic, as it can serve as a starting point for technological and socio-economic transformation to enhance long-term economic and environmental sustainability (Mongo et al., 2021a, b).
Declarations
Conflict of interest
We attest that in submitting our paper for your journal for publication, there is no potential conflict of Interest including financial, personal or other relationships with other people, or organizations within three years of beginning the submitted work that could inappropriately influence, or be perceived to influence, their work.
1 Many works tend to revise the conventional HDI by subtracting the income component from the formula. Thus, the HDI’s modified version does not include the income factor to eliminate the multicollinearity problem in the regression analysis. HDI formula will be presented as follows: HDI = 12($$Gross enrolment$$+$$Life expectancy$$).
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| 0 | PMC9744663 | NO-CC CODE | 2022-12-15 00:01:51 | no | Eur J Dev Res. 2022 Dec 13;:1-10 | utf-8 | Eur J Dev Res | 2,022 | 10.1057/s41287-022-00568-4 | oa_other |
==== Front
Neurol Sci
Neurol Sci
Neurological Sciences
1590-1874
1590-3478
Springer International Publishing Cham
36510090
6551
10.1007/s10072-022-06551-5
Covid-19
Being a technician during COVID-19: a qualitative cross-sectional survey on the experiences of clinical neurophysiology technicians
http://orcid.org/0000-0002-7070-2636
Sireci Francesca 1
Bellei Elena 2
Torre Gabriella 1
Ferrari Francesca 1
Minardi Valentina 1
http://orcid.org/0000-0001-7632-1271
Ghirotto Luca [email protected]
3
http://orcid.org/0000-0003-4887-1692
Valzania Franco 1
1 Neurology Unit, Neuromotor & Rehabilitation Department, Azienda USL - IRCCS Di Reggio Emilia, Reggio Emilia, Italy
2 Interactionist Cognitive Psychotherapy School, Padua, Italy
3 Qualitative Research Unit, Azienda USL - IRCCS Di Reggio Emilia, Reggio Emilia, Italy
13 12 2022
18
21 10 2022
6 12 2022
© Fondazione Società Italiana di Neurologia 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Background
During the Sars-CoV-2 virus pandemic, Italy faced an unrivaled health emergency. Its impact has been significant on the hospital system and personnel. Clinical neurophysiology technicians played a central role (but less visibly so compared to other healthcare workers) in managing the COVID-19 pandemic. This research aims to explore the experiences of clinical neurophysiology technicians during the pandemic and contribute to the debate on the well-being of healthcare workers on the front line.
Methods
We implemented a cross-sectional survey across Italy. It contained questions that were open-ended for participants to develop their answers and acquire a fuller perspective. The responses were analyzed according to the framework method.
Results
One hundred and thirty-one responses were valid, and the following themes were generated: technicians’ experiences in their relationship with patients, technicians’ relationship with their workgroup and directors, and technicians’ relationship with the context outside of their work. The first theme included sub-themes: fear of infection, empathy, difficulty, a sense of obligation and responsibility, anger, and sadness. The second theme contained selfishness/solidarity in the workgroup, lack of protection/collaboration from superiors, stress, and distrust. The last theme included fear, stress/tiredness, serenity, sadness, and anger.
Conclusion
This study contributes to building a humanized perspective for personnel management, bringing attention to the technical work of healthcare professionals in an emergency and the emotional and relational dimensions. These are the starting points to define proper, contextually adequate support.
Keywords
COVID-19
Clinical neurophysiology technician
Survey
Framework analysis
Italy
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pmcIntroduction
Italy was among the first countries in the world to face the unrivaled health emergency related to the Sars-CoV-2 virus pandemic. The impact of this has been significant on the hospital system and personnel [1, 2]. In this regard, many studies have observed the psychological sequela of the pandemic on Health Care Workers (HCWs) [3–5], particularly nurses [6, 7] and physicians [8, 9], during training [10, 11], within and outside hospital [12, 13].
Nonetheless, in their way and work contexts, many other professionals had to deal with the impact of the pandemic. Leaving their experience out of the picture would result in a non-comprehensive understanding of the implications of the pandemic. In particular, the literature addressing the experiences of technicians is scarce. To our knowledge, only a few studies investigated the experience of radiology technicians [14–16].
As for clinical neurophysiology technicians (CNTs), a gap in the research must be noted even though they played a central role (but less visibly so compared to other HCWs) in the health management of the COVID-19 pandemic. They immediately got involved in all the COVID-19 diagnostic processes related to COVID-19-positive patients. In this scenario, CNTs’ role mainly was in identifying neurological and neurophysiological virus’ secondary effects by performing electroencephalographic monitoring tests on COVID-19-positive patients in intensive care units [17, 18]. Concurrently, elective and “non-urgent” procedures, like neurophysiological exams, were suspended, with routine outpatient visits postponed. The continuity of care was not adequately ensured, locally [17] and internationally [19].
This research aims to explore the experiences of CNTs during the pandemic and contribute to the debate on the well-being of HCWs. Results may provide health managers and human resource supervisors with insights and practical implications to improve staff management.
Methods
We employed a descriptive qualitative design utilizing an online survey service (i.e., Google form) to address the study’s aim [20]. We found the qualitative methodology appropriate for the data collection of first-person perspectives on experienced phenomena, and we chose it over standardized scales measuring constructs already defined by the literature.
Questionnaire development and pilot
In May 2021, we set version 1 of the questionnaire on the Google platform, which was administered to a convenient sample for assessing its comprehensibility. To ensure clarity, readability, and appropriate length, seven CNTs participated in the pilot study. The participants commented on the structure and content of the survey and suggested modifications. After making some changes, the final version of the questionnaire was composed as follows:Questions to collect sociodemographic and professional information (8 close-ended questions).
Six open-ended questions investigating three main issues: relationships with patients, relationships within the team and their group dynamics, and experience outside the work context.
Survey administration and participants’ recruitment
Participants were anonymously invited by posting the survey on social networks and through the Italian Association of Neurophysiology Technicians’ (AITN) mailing list. The target population was invited to complete it. At the beginning of the study, participants were provided with a written description of the study’s aim and the contact details of the principal investigators (GT and VM). Participation was voluntary. The questionnaire was available online from July 1 to August 31, 2021.
The software used for the survey returned a total of 133 respondents. The dataset was then cleaned of duplicate responses. The final dataset included n = 131 valid responses.
Data analysis
Responses to closed-ended questions were analyzed using descriptive statistics, including frequencies and percentages.
As for the text analysis from the open-ended questions, we applied the framework method [21, 22] according to an inductive (bottom-up) orientation (the content of the data directs theme developments) and a thematic approach [23]. We followed these steps:We decided to focus the analysis on the following areas (triggered by the survey questions): the relationship with patients, the relationship with colleagues, and the context outside of work.
For each of those areas, F.S., G.T. F.F., and V.M. read a selection of responses to the open-ended questions.
Independently, the researchers generated three provisional analytical frames by labeling the responses and grouping the labels into themes.
The frameworks were discussed and compared in teams (L.G., F.S.). Disagreements between researchers were resolved through comparison, and a version for each frame was agreed upon.
The researchers (L.G., F.S.) then applied these analytical frames to the remaining data.
Any occurring changes made to the frames were discussed and endorsed by the team.
All the authors agreed on the last version of the findings.
Ethical considerations
The relevant Ethics Committee was approached. It was unnecessary to seek formal approval as the data was anonymous at source, in compliance with current privacy legislation (GDPR—Regulation 2016/679). However, the following suggestions were made:To include the principal investigator’s contact details in case participants wanted to get in touch
To collect sociodemographic information by age range and avoid asking the municipality or province where the professionals were working, opting instead for the region
Participants were informed that by continuing to fill in the questionnaire, they consented to their data being processed by the researchers of the Qualitative Research Unit of the Azienda USL-IRCCS of Reggio Emilia. The software used for the survey returned anonymous responses labeled by timestamps. Researchers saved the dataset in a password-protected access location, assigning each respondent a numeric code.
Results
Study population
There were 131valid responses from participants, and their demographic information is shown in Table 1. The majority (31.3%) was aged 31–40, and 76.3% were female. The participants’ main work setting was public hospitals (87%).Table 1 Sample’s characteristics
Number Percent
Study population 131 100.0
Gender F 100 76.3%
M 31 23.7%
Age (years) 18–30 19 14.5%
31–40 41 31.3%
41–50 38 29%
51–60 31 23%
> 61 2 1.2%
Macro-regions Northern Italy 90 68.7%
Central Italy 15 11.5%
Southern Italy 26 19.8%
Work setting Public hospitals 114 87%
Other public services (territorial, residential) 5 3.8%
Private services 12 9.2%
Work experience (years) 0–5 18 13.7%
6–10 20 15.3%
11–20 47 35.9%
21–30 31 23.7%
> 31 15 11.4%
Work contract Employee — permanent 120 92.6%
Other contracts (i.e., self-employed) 11 8.4%
Ninety-five respondents (75,5%) declared they had assisted COVID-19-positive patients during the pandemic, predominantly in sub-intensive or intensive care units.
Findings
Our analysis generated themes that provide insights into the experience of Italian CNTs during the COVID-19 pandemic. As for their relationship with patients, the participants reported a fear of being infected/infecting, empathy, difficulties in dealing with patients, a sense of obligation and responsibility, and sadness. Responses addressed the following themes with regard to the relationship with colleagues and directors: selfishness/solidarity in the workgroup, lack of protection/collaboration from supervisors, stress, and distrust. Finally, the extra-work context was described with several emotions (fear, stress/tiredness, serenity, sadness, anger), revealing that the emotional impact of working through the pandemic also affected personal and domestic life.
The technicians’ relationship with patients
For our participants, being there for their patients during the pandemic meant living their time at work in fear of being infected. CNTs reported experiencing this feeling in different situations, mostly while conducting examinations. They were also scared of infecting patients and of making their health conditions worse. In this context, greater attention was paid to keeping and maintaining physical distance than to the analyses.
CNTs reported they were having the same experience as patients: the pandemic was affecting everyone’s lives, pushing CNTs to try and help beyond their duty and to understand patients’ experiences. Participants reported feeling compelled to respond more promptly to patients’ needs and pain, to give greater importance to explaining the exam procedures, and to promote trust. CNTs thought they played an essential role in creating and maintaining a positive environment.
In this context, some participants reported that their relationships with patients improved because patients showed appreciation towards them. On the other hand, some participants described how their relationship with patients worsened as procedures got more complicated due to social distancing and the perceived lack of respect for the protective rules by the patients. Moreover, wearing personal protective equipment (PPE) hindered successful communication.
In general, CNTs described an increased sense of obligation and responsibility towards patients: beyond the physical distance, they felt induced to pay more attention to equipment disinfection, using PPE, and performing examinations while leaving discouragement or fear out.
Many participants reported feelings of anger and sadness. According to them, sadness was due to witnessing the progression of patients’ symptoms, pain, isolation, and loneliness. Table 2 shows sub-themes and meaningful quotations from participants.Table 2 Theme: The technicians’ relationship with patients. Sub-themes and meaningful quotations
Sub-themes Quotations
Fear of being infected/infecting “The most relevant aspects that I have noticed in all types of patients as common denominators are fear, sense of bewilderment, hesitancy whether or not to show up to perform a diagnostic test during the pandemic’s first and second wave.”
“My first emotion was the fear of infecting the patient.”
Empathy “I’ve been close to people with COVID-19; I’ve tried to work with an atmosphere of positivity.”
“I always maintained professionalism and empathy with the patient, trying to figure out how I could be even more helpful.”
Difficulties “The relationship with the patients has changed radically because by adopting all the required norms and using the medical devices to prevent contagion, it was difficult to have a normal relationship with them.”
“The relationship with patients in the pandemic changed, becoming less empathetic.”
“The use of the protective equipment has made communication even more difficult.”
Sense of obligation and responsibility “It’s always important to remain clear-headed and alert to ensure safety and protect fragile patients.”
Anger and sadness “Fundamentally, the aspect that always strikes me is the total isolation of the person, beyond the low or high level of severity of the individual patient with COVID.”
The relationship between colleagues and directors
Perceptions of working with colleagues were ambivalent. Some participants reported that the emergency provided an occasion for some “selfish” colleagues to take days off or pretend to be sick to stay at home. Already feeble relationships became more detached. On the other hand, other participants described that trust was strengthened within the workgroup. These respondents saw colleagues supporting each other by reorganizing shifts, sharing more personal experiences and emotions, and helping each other more than before during examinations.
Furthermore, the tone of the answers addressing CNTs’ relationship with directors and managers was dichotomic. Some participants felt superiors did not value the work and efforts that were being made (in some cases, they commented on ineffective management). On the other hand, some participants reported that they perceived there to be more comprehension and sympathy from superiors.
Finally, working in a team was considered more stressful than in the pre-pandemic period: participants expressed concerns, frustration, and psychological fatigue due to an increase in the workload combined with the risk of infection. We reported the sub-themes and meaningful quotations in Table 3.Table 3 Theme: The relationship between colleagues and with directors. Sub-themes and meaningful quotations
Sub-themes Quotations
Selfishness/solidarity in the workgroup “Perhaps it was a condition that pushed us to help each other more, considering the need to share the workload in the COVID area.”
“In my case, the work dynamics were non-existent: those who could/ ‘had to’ stayed at home on leave. I managed the outpatient clinic and other activities myself.”
Lack of protection/collaboration from superiors “Relationships with superiors were excellent. My supervisor never left me alone in any COVID department. He was always present at every examination.”
Stress “There was such prolonged tension that it created burdensome relationships, and many colleagues are still very stressed.”
The extra-work context
Most of the respondents described that they lived in fear and sadness at any time at home: fear of becoming infected and infecting loved ones, even losing them, of being sick alone, re-living the past difficult days of the pandemic, or dying.
The stress experienced at work continued at home for many of the participants: they disclosed that they were tired of the workload, disoriented, and forced to keep their distance from their loved ones with no psychological/emotional support.
For those respondents who could live with their families, a sense of serenity was reported: catching up for the lost hugs, being reassured/assuring their family members they were doing something useful for the entire community. In addition, receiving the anti-COVID-19 vaccine triggered feelings of hope.
Finally, some participants described that they were angry with citizens’ behaviors and non-compliance with social-health rules, interpreting them as a lack of respect for the infected persons and HCWs. Table 4 summarizes the sub-themes with participants’ meaningful quotations.Table 4 Theme: the extra-work context. Sub-themes and meaningful quotations
Sub-themes Quotations
Fear “There is a concern because there is always the thought that one may be responsible for possibly infecting loved ones.”
“Fear of bringing COVID into the family setting despite being vaccinated and using the correct procedures within the workplace.”
Stress/tiredness “I lived in a constant state of anxiety, washed my hands frequently (more than I should have), did not go out or meet people for many months, even when it was allowed”
Serenity “I constantly reassured my family”
Sadness “I felt great sadness for the families who lost loved ones.”
Anger “I felt anger over people’s disregard for the rules.”
Discussion
Our analysis shed light on the multifaceted, emotional, less visible experiences of CNTs during the COVID-19 pandemic.
The participants’ relationship with patients has changed significantly with impacts on the diagnostic processes given that they were involved in diagnosing neurological and neurophysiological virus’ secondary effects [24, 25]. During the pandemic, performing electroencephalographic monitoring tests on patients admitted to intensive care units assumed a different meaning. CNTs feared infection, aligning them to what other HCWs experienced [2]. They also experienced empathy in their relationship with patients due to the need to be more understanding towards patients’ needs and requests during exams and healthcare procedures.
The performance of outpatient examinations required special precautions in the emergency context, such as using PPE, maintaining physical distance, and the need to shorten the examination time. This led Italian CNTs to make an increased effort to create a welcoming atmosphere and foster trust with the patients. That experience is similar to what Liu et al. [3] have reported about healthcare providers’ experiences during the COVID-19 crisis in China: they made efforts to support the patients emotionally and not only to treat their disease.
On the other hand, this has led to difficulties for Italian CNTs in managing their relationship with patients and performing diagnostic exams. As reported in studies about radiographers’ and radiation therapists’ experience during the pandemic, infection control increased the time required for medical examinations and the complexity of procedures [16]. Furthermore, for HCWs with close relationship with patients — such as CNTs — the obstacles encountered were non-verbal communication and building empathic closeness. This emotional experience can be considered similar to that of other frontline HCWs, such as nurses [26].
Due to the pandemic, CNTs felt a sense of obligation and responsibility to maintain a physical distance from patients and to pay more attention to using PPE and to disinfect sanitary equipment in medical examinations. Several qualitative studies in the literature describe the experience of healthcare workers and technicians in relation to the shortage of PPE during the early stages of the COVID-19 pandemic [9, 27]. In our study, CNTs reported the use of PPE and how that made it more difficult to relate to patients and carry out medical procedures. Indeed, the role of CNTs is very much involved in activities that require physical and empathic proximity to the patients. This could explain why several emotions were reported by Italian CNTs in their relationship with patients. Research participants also reported anger and sadness when referring to their relationship with patients during the pandemic because of some patients’ pain, isolation, loneliness, distrust, superficiality, and selfishness.
The second theme concerns CNTs’ relationship with their workgroup and superiors during the COVID-19 pandemic. This theme includes the following sub-themes: selfishness/solidarity in the workgroup, lack of protection/collaboration from directors, stress, distrust.
CNTs reported contrasting experiences regarding relationships among colleagues. On the one hand, they highlighted the selfishness of some colleagues, who took advantage of the emergency to defend personal interests (e.g., taking holidays). On the other hand, technicians described greater cohesion and trust between colleagues in the team. Italian CNTs also described opposite experiences regarding their relationships with managers. Some research participants reported an absence of protection from health managers, while others reported good cooperation with managers during the pandemic. These contrasting experiences are not dissimilar to what has emerged in the literature focusing on other healthcare roles: Bennett et al. [2] noted that some HCWs participating in their research reported supportive and cohesive relationships in the work team and with management. In contrast, others expressed a sense of being abandoned by management.
By what was expressed by the participants in our study, the literature describes the experience of HCWs who found the work team very supportive during the period of the COVID-19 pandemic: diagnostic radiographers participating in Naylor et al.’s research [15] spoke about “high morale, team spirit, and colleagues looking after one another.” To the best of our knowledge, nothing has been found in the literature about selfishness in the work team and HCWs’ experiences of distrust when describing the relationships between colleagues, except for studies related to COVID-19 vaccine-related decision [28].
The sub-theme concerning the work team’s increased stress is not new, particularly concerning the heavy workload that Italian CNTs and other healthcare workers have been facing. Many studies reported the overwhelming workload that HCWs have faced during the COVID-19 pandemic [29].
The third theme concerns the Italian CNTs’ experience outside their work context during the COVID-19 pandemic. This theme includes the following sub-themes: fear, stress/tiredness, serenity, sadness, and anger.
Just like fear refers to the possibility of infecting patients, CNTs experienced fear, indicating the possibility of infecting their family members and loved ones, losing them, or being alone or dying.
CNTs reported experiences of stress/tiredness, both physical and mental, characterizing the pandemic period. Their feelings are consistent with the pandemic fatigue [29] in HCWs’ experience, the emotional exhaustion reported by González-Gil et al. [26] on nurses, and the rollercoaster of emotions pointed out by Naylor et al. [15] on diagnostic radiographers during the COVID-19 pandemic.
One of our study’s findings that stands out is the participants’ experience of serenity and resilience. CNTs also experienced sadness in their non-work environment due to the uncertain situation, the need to isolate themselves, the loss of freedom, and the feeling of abandonment. HCWs’ similar experience is associated, in the literature, with uncertainty about the nature of the disease and their fear of possible transmission of the virus [29].
CNTs reported feeling anger about some citizens’ failure to comply with social and health rules. That experience is not dissimilar to what Sethi et al. [30] have reported about the impact of the pandemic on health professionals working in the hospital. HCWs had to deal with the indifferent attitude of the public and their non-compliance to simple rules, such as social distancing. The participants in our study consider indifference to show a lack of respect that affected those who worked in hospitals during the pandemic.
Undoubtedly, the pandemic has brought new needs to the surface for HCWs, including those who work in hospital settings. Given the complexity of emotions and reactions of the CNTs — on the question of balancing safety, collaboration with colleagues and managers, and daily life — specific psychological support intervention programs for HCWs are desirable. This would align with the World Health Organization’s urgent call for tailored and culturally sensitive mental health interventions [31]. A recent review [32] highlighted the urgency to create better connections between research and intervention programs. To define psychosocial support interventions, it is necessary to start with the needs and experiences of the HCWs. This study contributes to the evidence base.
Our study highlights the need to consider the emotional experiences of the CNTs to inform more functional management to prevent stress, isolation, and hostile feelings in work relationships and promote group cohesion.
Finally, considering the impact of reported sentiments and views on the quality and effectiveness of the work of the CNTs, in the long run, is a desirable relaunch of research. A qualitative study such as this one cannot measure such effects. Still, it can help explain why, if any, deviations in the quality and adequacy of clinical activities — compared to the pre-pandemic period — exist. For HCWs in general, much literature has provided preoccupying evidence in this regard: we know they experienced burnout [33], psychological burden [34], moderate to high work-related stress, and low to moderate resilience [35], low self-efficacy [36], to name a few. The emotional and psychological impact of caring for COVID-19-positive patients and, more generally, during the pandemic, on the professional and personal identity of HCWs has been widely studied. In the future, correlating this with CNTs’ work effectiveness and quality could broaden our understanding of the effects of an unprecedented emergency experience.
Declarations
Ethical approval
This is an observational study. The AVEN Ethics Committee has confirmed that no ethical approval is required.
Informed consent
The participants were informed that by continuing to fill in the questionnaire, they would be giving their consent to data processing by the researchers of the Qualitative Research Unit, Azienda USL-IRCCS of Reggio Emilia (Italy).
Conflict of interest
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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| 36510090 | PMC9744665 | NO-CC CODE | 2022-12-15 00:01:51 | no | Neurol Sci. 2022 Dec 13;:1-8 | utf-8 | Neurol Sci | 2,022 | 10.1007/s10072-022-06551-5 | oa_other |
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Environ Dev Sustain
Environ Dev Sustain
Environment, Development and Sustainability
1387-585X
1573-2975
Springer Netherlands Dordrecht
2827
10.1007/s10668-022-02827-0
Article
The impact of climate risk on credit supply to private and public sectors: an empirical analysis of 174 countries
Li Shouwei [email protected]
12
Li Qingqing [email protected]
1
Lu Shuai [email protected]
1
1 grid.263826.b 0000 0004 1761 0489 School of Economics and Management, Southeast University, Nanjing, 211189 People’s Republic of China
2 grid.263826.b 0000 0004 1761 0489 Development Center for System and Information Engineering, Southeast University, Nanjing, 211189 People’s Republic of China
13 12 2022
123
12 8 2022
4 12 2022
© The Author(s), under exclusive licence to Springer Nature B.V. 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
In recent years, risk has been increasingly a long-term environmental problem that cannot be underestimated due to its tremendous impacts on various sectors including banking sector. Accordingly, the credit supply to private and public sectors is affected by the increased climate risk. In order to examine the climate risk effect from an international comparison, this paper empirically investigates the impact of climate risk on credit supply by using a sample of 174 countries during 2000–2019 from the perspective of the difference between private and public sectors. The results show that climate risk has a significant negative effect on the credit supply to private sector and a positive effect on that to the public sector. Further, we provide new evidence that the climate risk effect has a more significant effect on the private and public sector credit supply in the high-income countries than that in the low-income countries, suggesting a quick risk contagion in the high-income countries.
Keywords
Climate risk
Bank credit
Private sector
Public sector
International evidence
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pmcIntroduction
The failure of climate action, extreme weather, and biodiversity are currently the top three global risks with the highest probability of occurrence and the most severe consequences. Among them, the failure of climate action will be one of the most threatening risks in the next decade. It is evident that climate change will gradually become a tough constraint for global economic development in the future. The potential threat of climate-related financial risk to the stable and healthy development of the financial system is also rising. The climate change is transformed into financial risk by two main channels: first, climate change will increase climate risk, and frequent weather disasters will directly increase the economic loss of financial institutions; second, if climate changes are not effectively controlled, climate risk will indirectly increase the risk of financial institutions by reducing the productivity of the real sector of the economy. As a fundamental financial institution, banks have an important role in regulating macroeconomic leverage and allocating social capital. Climate risk may have impacts on banks’ credit business, leading to significant distorted credit markets and mismatch of financial resources (Garmaise & Moskowitz, 2009). Due to the differences in the objectives, structures, and organizational culture between the private and public sectors, which suffer from climate risks discrepantly, banks may adopt different credit supply strategies for the private and public sectors when facing climate risk. Based on this, we attempt to empirically investigate the impact of climate risk on the supply of bank credit to the private and public sectors from a country-level perspective.
The issue of climate risk has received increasing attention from scholars in recent years, and many studies have begun to analyze the relationship between climate risk and the financial system, including the credit supply (Clarvis et al., 2014; Oguntuase, 2020; Da Mata & Resende, 2020; Christophers et al., 2020; Nwani & Omoke, 2020; Birindelli et al., 2022), the governance of fund markets (Bowman & Minas, 2019; Cui & Huang, 2018; Lu et al., 2022), the insurance institutions’ responsibility (Surminski et al., 2016) and so on. Campiglio et al. (2018) recognize that climate risks cause losses to the balance sheets of financial market players, leading to the repricing of carbon-intensive assets and threatening the stability of financial markets. In the case of the banking sector, as climate change threatens the stable operation of financial markets, the banking sector as an important component of the financial industry is also affected by climate change. Lamperti et al. (2019) analyze the effects of climate change on the stability of the global banking system using an agent-based climate-macroeconomic model and find that climate change will make bank crises more frequent. Dafermos et al. (2018) argue that climate change will first exert the impact on the banking sector, with higher environmental standards, joint and several liability for emissions, reputational risk, and collateral damage increasing banks' climate change-related risks. Caby et al. (2022) demonstrate that climate risk and financial performance for banks in emerging and developed countries are positively correlated over the period 2011–2019.
As the core business of banks, credit has led to more and more studies to analyze the relationship between climate risk and bank credit. More specifically, regarding climate risk and bank credit, scholars focus on the following aspects: first, the impact of climate risk on bank credit pricing. Kleimeier and Viehs (2016) reveal the negative relationship between the cost of bank loans and the level of carbon dioxide emission. High-polluting firms must pay higher costs for their bank loans (Chava, 2014; Javadi & Masum, 2021). Jung et al. (2018) point out that both higher carbon emissions and carbon intensity of firms lead to higher credit costs, and the loan spreads of firms with voluntary carbon emission disclosure are lower than those of non-disclosed firms. Meanwhile, commercial banks' loan values are also depreciated by carbon tax shocks, and state-owned commercial banks are significantly more affected than joint-stock commercial banks (Chava, 2014). Second, the impact of climate risk on credit supply. Climate risks from climate change will inevitably cause imbalances in loan supply and demand, and such shocks may significantly affect macroeconomic activities (Golosov et al., 2014). For example, Berg and Schrader (2012) find that loan demand would increase following unforeseen shocks from climate change, but the proportion of applicants actually receiving loan supply would decrease due to the higher risks involved. Islam and Wheatley (2021) reveal that firms exposed to climate risk tend to use less credit due to the impact of liquidity shocks. Hosono et al. (2016) suggest that in the presence of shocks from extreme weather hazards, banks may shy away from lending under the impact of an extreme weather disaster, resulting in illiquidity in the financing market. In addition, David (2010) suggests that bank lending shyness is pronounced in developing countries after a climate disaster. Faiella and Natoli (2018) show that banks respond to climate risks such as abnormally high temperatures and floods by reducing credit amounts and credit approval rates. Third, the impact of climate risk on banks' credit transformation. Climate risk will prompt banks to launch more green credit projects, which promotes the green transformation of macroeconomy and makes credit resources flow more to low-carbon industries (Sun et al., 2019). Banks’ lending to green companies can reduce risk and create more innovative green projects, and refusing to lend to highly polluting industries can also reduce risk and improve banks' reputation (Fatica et al., 2021; Gangi et al., 2019). Highly profitable commercial banks have a strong awareness of social responsibility and actively develop green credit (Yin et al., 2021). Mésonnier (2022) investigates whether and how banks align green behavior in terms of credit allocation to carbon-intensive industries in France. Banking institutions with a high share of high pollution and emissions in their credit business are given more attention and scrutiny by relevant stakeholders and regulators during external audits and regulatory inspections on the transformation risks of the companies they support (Andersson et al., 2016). In order to comply with the policy requirements, banks have to use the extra credit balance to increase the proportion of green credit by reducing the interest rate of green credit and thus attracting more green loans (Dikau & Volz, 2021). As Bătae et al. (2021), banks often provide green financial products and services, such as green funds, to improve their competitiveness, reputation, customer loyalty, and profitability.
In summary, research on climate risk on the pricing, supply, and transformation of bank credit has been well-established. Based on the previous studies, the objectives of this study can be explained in two folds. Firstly, in the face of climate change, many countries worldwide, from developed to developing countries struggle to reduce the negative impact of climate risks (Abid et al., 2022; Nga, 2022). The technically advanced countries have attained sustainable development goals through green innovation and green finance, such as China, Japan, and South Korea (Tolliver et al., 2021). The developed countries also respond to climate change to promote high productivity low-carbon projects (Hosono et al., 2016; Mésonnier, 2022). At the same time, developing countries become aware of the climate risk and take some actions (Aftab et al., 2022; Dougherty et al., 2020; Khan et al., 2022; Sun et al., 2019). Global climate change has threatened economic growth and financial development in developed and developing countries (Tol, 2009). However, to the best of our knowledge, little academic research adds insight for both countries to study the climate risk and credit supply. Consequently, it is crucial to consider the impact of climate risk on credit supply from an international perspective.
Second, private sector credit as a percentage of GDP is usually employed as the indicator to measure the credit supply (Batabyal & Chowdhury, 2015; Chen & Chang, 2021; Denizer et al., 2000; Levine et al., 2000; Samargandi et al., 2015). As well as private sector credit, we believe that public sector credit is also an important part of the credit supply. Although a lot of literature studies the differences between the private and public sectors (Chan et al., 2011; Goodwin, 2004; Lyons et al., 2006), there is currently less attention on the impact of climate risk on public sector credit, especially the different impacts to private and public sectors. To address this, this paper empirically investigates the impact of climate risk on the private sector and public sector credit supply based on panel data for 174 countries from 2000 to 2019, particularly focusing on the heterogeneous effect of climate risk on the different sectors.
This paper contributes to the literature in three important ways at least. First, it contributes to the growing literature investigating the impact of climate risk on credit supply (Campbell & Slack, 2011; Levine et al., 2018). A common argument is that serious natural disasters will lead to the unbalance of the financial system and impact the banks’ credit service (Brei et al., 2019; Cortés & Strahan, 2017; Ivanov et al., 2020). Expanding this argument, we contribute to this growing literature by presenting that the regular climate risks instead of the extreme climate events have been recognized by the banks and induced the changes in credit supply.
Second, we divide bank credit supply to the private sector and public sector, and study the influences of the climate risks on the credit supply of the private sector and public sector, respectively. Joo and Chung (2014) compare the characteristics of private and public sectors, especially in objective and organizational culture. Considering the impact of climate risks, the private sector and public sector take different responses to climate change (Victor, 2012; Koh & McCarthy, 2018; Barry & Adeyemi, 2022). Based on the previous studies, there may be different mechanisms of the impact of climate risk on credit supply to the private sector and public sector. Therefore, we analyze the impacts of climate risk on the credit supply of private and public sectors and compare the differences.
Third, by providing an international comparison among 174 countries, we consider the heterogeneity of income level and analyze the influences of climate risks on credit supply in high-income countries and low-income countries. It manifests that climate risk in high-income countries has a greater negative impact on private sector credit supply and a greater positive impact on the supply of public sector credit supply.
The rest of this paper is arranged as follows: Sect. 2 is the theoretical analysis and hypothesis; Sect. 3 illustrates the data and methodology; Sect. 4 presents the empirical results; Sect. 5 argues the treatment of endogeneity and conducts the robustness checks. Section 6 discusses the results. Section 7 concludes.
Theoretical analysis and hypotheses
Climate risk affects the economic and financial system through two main channels: physical risk and transition risk (Monnin, 2018; Margherita et al., 2019; Allen et al., 2020; Nehrebecka, 2021). Physical risk is mainly caused by the impact of extreme weather events and long-term changes in climate patterns, while transition risk refers mainly to the uncertainties that may arise from low-carbon socio-economic transitions, such as policy changes and shifts in market preferences (Batten et al., 2020). On the one hand, physical risk and transition risk can directly affect banks' credit business. Sudden climatic events are likely to cause drastic fluctuations in commodity prices, increase uncertainty faced by the macroeconomy, increase market interest rate volatility, increase market risk exposure faced by banks, and reduce banks' willingness to provide credit services (Mulwa et al., 2017), while banks will hoard more liquid assets to cope with potential liquidity risks, thus reducing the supply of credit. Driven by the policy of low-carbon economic transformation, banks' credit strategies will again be subject to intervention from the government. The government will support banks' credit resources to state-owned enterprises (SOEs) by intervening to support SOEs to actively cope with climate risks and promote the low-carbon transformation of the state-owned economy.
On the other hand, physical and transformation risks indirectly impact banks' credit business by affecting the development of the real economy. Extreme climate events of physical risk lead to the shrinkage of a large number of collateral assets of enterprises, causing extensive damage to physical assets such as land and equipment, generating huge construction and maintenance costs, reducing the productivity of the real economy sector through bank financing channels, which in turn affects banks' credit business (Monnin, 2018). The transition to the low-carbon economy will limit the future use of fossil fuel energy, leading to a reduction in revenue capacity for the high-carbon energy sector. At the same time, the implementation of the carbon emissions trading market and carbon tax policies will increase the operating costs faced by the high-carbon sector (Grippa et al., 2019).
Impact of climate risk on private sector credit supply
The private sector refers to business enterprise organizations that are market-regulated and aim to maximize organizational interests. When climate risk increases, the problem of information asymmetry will appear in the private sector. On the one hand, the private sector lacks of good climate risk information disclosure, income certificates, and asset certificates, which makes banks face a higher risk of adverse selection (Cameron et al., 2018; Adhikari & Chalkasra, 2021). On the other hand, when exposed to climate risk, the private sector especially the small private sector is motivated to take more risks (Xu et al., 2022), which makes banks face a greater risk of moral hazards. Banks are usually averse to the uncertainty of information asymmetry; therefore, they have more incentive to overestimate the losses and reduce the credit supply. Hence, increased information asymmetry might lead banks to decrease credit supply to the private sector.
Banks are concerned with the repayment ability of lenders when making credit decisions, while the borrowers’ repayment ability decline because of the decrease in profitability, solvency, and operation capacity (Atta-Mensah, 2016; Dafermos et al., 2018; Huang et al., 2018; Olovsson, 2018). Thus, the profitability, liquidity, and operating costs of lenders become their critical indicators in credit. The climate risk mainly affects the private sector through the following three channels: first, climate risk reduces the revenues and profit of firms (Huang et al., 2018). When climate risks increase, equipment damage and weather restrictions can affect the normal production of the private sector, causing a decline in revenue. Climate change also has an impact on the cost of raw materials. For example, highly-polluted suppliers face strict environmental regulatory policies, which will lead to higher and more volatile raw material costs under supply uncertainty. The decline of revenue and the increase of costs impair the profitability of the private sector (Sakhel, 2017; Natalia, 2021); second, when climate risk increases, a large number of collateral assets of private sector enterprises shrink, resulting in the depreciation of collateral such as land and equipment, and the reduction of collateral asset value. The reduction in the value of collateral assets means that the borrower's solvency decreases (Graff Zivin & Neidell, 2014); third, when climate risk increases, higher carbon emission standards, and environmental requirements will seriously increase the operating costs. The private sector spends more costs on adjusting their production activities to meet environmental standards, such as replacing equipment, using clean energy, and applying carbon taxes. Climate change leads to higher operation and maintenance costs due to the shortened life span of equipment or infrastructure. Meanwhile, the promotion of technological alternation and industrial upgrading results in the stranding or impairment of outdated technologies and the increase of operating costs in replacing equipment (Pankratz et al., 2019).
In summary, climate risk impairs the profitability, solvency, and operation capacity of the private sector, which increases banks' credit risk and reduces their credit supply to the private sector; at the same time, since banks have serious "ownership preferences" and "large enterprise preferences" when allocating financial resources, these preferences are more unfavorable when climate risk increases. Based on the above analysis, this paper proposes hypothesis 1.
Hypothesis 1
Climate risk has a negative impact on private sector credit supply.
Impact of climate risk on public sector credit supply
The public sector refers to organizations such as governments and state-owned enterprises that aim to achieve the public interest of society. Many public sector enterprises are in industries that are natural monopolies, such as the water, electricity, oil, and gas industries are well-known examples. For the public sector, the impact of climate risk on profitability, solvency, and operation capacity also appears in the public sector. However, compared to the private sector, the public sector has a more transparent corporate governance structure and more open information, and the influence of information asymmetry is less (Javadi & Masum, 2021). Furthermore, the public sector generally has a large scale and strong organizational structure. So public sector is more resilient to risks than the private sector. We mainly focus on the impact of climate risk on public sector credit supply from a government perspective for two reasons: first, government ownership of banks and regulation of credit markets are common throughout the world (La Porta et al., 2002), As Calomiris and Haber (2015) states, “banking system is an outcome of political deal making.” It is universal for the regulation of credit allocation; second, the public sector plays an important role in facilitating climate finance, for example by leading the development of a strong climate information architecture to further improve decision-making and risk pricing (Georgieva & Adrian, 2022). Thus, the public sector is more likely to receive government attention and has more affected by government intervention.
Driven by the policy of low-carbon economy transition, banks' credit strategy to the public sector will be subject to intervention from the government (Switzer & Wang, 2013). On the one hand, the government will directly interfere with banks' financial resource allocation behavior by means of administrative-style orders. When climate risk increases, the government will directly intervene to push banks' credit resources toward public sector enterprises, support state-owned enterprises to actively cope with climate risks, and promote the low-carbon transformation development of the state-owned economy. D'Orazio (2022) discovers that the government and regulators take green credit allocation measures to support sustainable development, such as concessional loans and green lending quotas. On the other hand, the government may indirectly influence banks' credit resource allocation behavior by distorting the risk-return characteristics of some of the enterprises it prefers or supports through direct or "invisible" subsidies or guarantees. When climate risk increases, the government's strong support for state-owned enterprises, through subsidies for public sector credit and financial products or the establishment of lending incentives, promotes banks to increase their credit allocation to public sector enterprises. Lamperti et al. (2019) find that green credit guarantees reduce carbon dioxide emissions and contribute to sustainable economic growth.
In summary, with the development of green finance and low-carbon transition economy, the increase of climate risk makes the government prompt banks to increase the supply of credit to public sector enterprises, directing banks' resources to state-owned enterprises and promoting the low-carbon transition of public sector enterprises. Based on the above analysis, this paper proposes hypothesis 2.
Hypothesis 2
Climate risk has a positive impact on the supply of credit to the public sector.
Data and methodology
Data
This study uses the annual data over the period of 2000–2019 period. The main reasons of period selection are presented as follows: first, since the beginning of the twenty-first century, countries around the world have been paying more and more attention to the impact of climate change on economic development. Since 2000, human carbon dioxide emissions have been increasing at a rate of more than 2% per year, while the amount of carbon dioxide that can be absorbed by natural ecosystems has been decreasing (see Fig. 1). Wang et al. (2020) state that carbon emissions can impair financial growth. Thus, we select 2000 as the beginning of the period. Second, according to Feyen et al. (2021), the macro-financial shock caused by the COVID-19 pandemic precipitated a global economic recession and put severe pressure on bank balance performance. In order to avoid the effect of COVID-19, we exclude data from 2020 and beyond. Therefore, we choose 2000–2019 as the sample period.Fig. 1 The carbon dioxide emissions of the world.
Source: Climate Watch. 2020. GHG Emissions. Washington, DC: World Resources Institute. Available at: climatewatchdata.org/ghg-emissions
In the selection of the sample countries, we collect all countries with climate risk and bank credit data and delete some countries based on two considerations: first, the countries deleted are small economy sized and are not representative in our study; second, the current sample includes sufficient countries and covers all representative countries. Therefore, we believe that the data process can support us to draw common conclusions.
Given this background, this paper proposes to select data on climate risk and bank credit from 174 countries over the period 2000–2019. All data in this paper are obtained from the University of Notre Dame public database, WDI, and GFDD databases. The climate risk index is from the University of Notre Dame public database, the macro variables at the country level are from the WDI database, and the microvariables at the bank level are from the GFDD database.
Variable construction
Dependent variables
The University of Notre Dame-Global Adaptation Index (ND-Gains), an emerging, country-level, leading indicator for predicting climate change issues and the adaptive capacity of countries, was chosen to measure climate risk. Since 1995, the University of Notre Dame has ranked countries annually on their resilience to natural hazards and their ability to adapt to changes in natural hazards. The ND-Gains are calculated based on the following formula.1 ND-Gains score=(Readiness score-Vulnerability score+1)×50
The vulnerability index is calculated from 36 indicators, including the proportion of imported cereals to domestic cereals, the rate of freshwater extraction, the number of deaths due to disease caused by climate change, changes in biodiversity (MC1), the proportion of vulnerable people (under 14 or over 65 years old), and the number of flood disasters. The readiness index is calculated from 9 indicators, including infrastructure resilience, quality of government regulation, higher education enrollment rate, and the number of patent applications per capita.
As can be seen from the formula, the ND-Gains index is a negative indicator of climate risk, so Gains are taken as a proxy for climate risk. The greater Gains, the higher the climate risk.
Core independent variables
The supply of credit in this paper includes both private sector and public sector credit supply and the corresponding explanatory variables are: private sector credit as a percentage of GDP (PriCredit) and public sector credit as a percentage of GDP (PulCredit). Batabyal and Chowdhury (2015) state that private sector credit as a percentage of domestic GDP as a percentage of GDP is usually used as an indicator of the banking system; Samargandi et al. (2015) also argue that the private sector share of GDP can measure the development of the banking system; Levine et al. (2000) argue that private sector credit has a positive relationship with the development of the banking system. Thus, private sector credit as a percentage of GDP can be used as a proxy variable to measure the supply of bank credit to the private sector. Similarly, in order to study the difference in the supply of bank credit to the private and public sectors, the ratio of public sector credit to GDP is chosen as a proxy variable for the supply of bank credit to the public sector (Table 1).Table 1 Variable names, symbols and definitions
Variables Symbols Definitions
Independent variable
Climate risk index Gains The Gains measure the country's vulnerability and preparedness for climate risks
Dependent variables
Private sector credit PriCredit Private sector credit as a percentage of GDP
Public sector credit PulCredit Public sector credit as a percentage of GDP
Control variables
Economic growth Gdpg GDP growth rate
Inflation lnCPI Logarithm of the Consumer Price Index
Import and export trade Trade Total import/export trade as a percentage of GDP
Bank earnings Return Net income after taxes of the banking sector as a percentage of average annual equity
Non-performing loan rate Npl Non-performing loans in the banking sector as a percentage of total loans
Bank deposits Deposit Deposits in the banking sector as a percentage of GDP
Control variables
Based on existing studies (Bordo et al., 2016; Ward & Shively, 2017; Laséen et al., 2017; Niepmann & Schmidt-Eisenlohr, 2017; Korri & Baskara, 2019; Yin, 2019; Nguyen et al., 2020; Phan et al., 2021; Chen & Chang, 2021; Rusdiyanto et al., 2020; Demir, 2021), this paper selects control variables at the country level and the bank level that prior studies suggest being associated with credit supply.GDP growth rate (Gdpg), which measures economic growth. As richer countries have better infrastructures and more mature financial markets, which may be a determinant of credit supply in the effect of climate risk (Chen & Chang, 2021).
Logarithm of the consumer price index (lnCPI), which measures the level of inflation, is selected. Ikpepsu (2021) points out that bank credit can be hindered by inflation. Meanwhile, in order to mitigate the adverse effects caused by possible heteroskedasticity, the CPI data are smoothed by taking the natural logarithm of the CPI and the lnCPI is used to measure the level of inflation in this paper;
Total import and export trade as a percentage of GDP (Trade), which measures the level of trade and the degree of openness of the country. Niepmann and Schmidt-Eisenlohr (2017) studies the relationship between international trade level and band credit. Referring to Chen and Chang (2021), we choose the total import and export trade as a percentage of GDP as the proxy of trade level.
The ratio of net income after tax to average annual equity (Return), which measures the profitability of the banking industry; Ruziqa (2013) and Beck et al. (2013) find the adverse relationship between bank performance and credit. Ruziqa (2013) concludes that higher profitability contributes to lower bank credit risk. Return on equity (ROE) and return on total assets (ROA) are usually used as proxies for the performance of banks (Ekinci & Poyraz, 2019). Compared to ROA, ROE illustrates the profitability of the banks’ net assets, which considers the leverage and capital structure of banks. As most banks maintain highly leveraged operations, ROE is more appropriate to measure bank financial performances.
The ratio of non-performing loans to total loans (Npl), which measures the stability of the banking industry; It estimates the quality and safety of the bank credit and allows us to assess the sustainability of bank credit risk (Caby et al., 2022; Mohaddes et al., 2017). Thus we choose Npl as an indicator of the stability of banks.
The ratio of deposits to GDP (Deposit), which measures the size of the banking industry, is selected. Yin (2019) reveals a strong relationship between the ratio of deposits to GDP and bank credit supply. If a country has a higher ratio of bank deposits to GDP, the banking system's role in providing credit to the economy is more important. Phan et al. (2021) illustrate that the ratio of deposits to GDP is usually used as proxies for the deposit level of a country. Therefore, deposits should be considered in our analysis.
Model construction
This paper selects panel data for 174 countries from 2000 to 2019 and develops the following econometric model.2 Credit=β0+β1Gainsit+β2Gdpgit+β3lnCPIit+β4Tradeit+β5Returnit+β6Nplit+β7Depositit+uit
In Eq. (2), credit is divided into two categories, PriCredit for private sector credit supply and PulCredit for public sector credit supply. β0 is a constant term; β1 is the coefficient of climate risk, by estimating this coefficient, the impact of climate risk on credit supply can be known; β2, β3 and β4 are the coefficients of country-level control variables Gdpg, lnCPI, and Trade, respectively. Gdpg denotes the country's level of economic growth; lnCPI denotes the country's level of inflation; Trade denotes the country's level of import and export trade; and are the coefficients of the bank-level control variables Return, Npl, and Deposit, respectively; Return denotes the profitability of the banking sector; Npl denotes the credit quality of the banking sector and Deposit denotes the size. i and t denote country and year, respectively; uit are error terms.
Empirical findings
Descriptive statistics
Table 2 shows the descriptive statistical results for the main variables. It can be seen that the maximum value of private sector credit (PriCredit) is 986.1, the minimum value is 0.391, and the standard deviation is 51.06, indicating that the private sector credit of each country fluctuates greatly during the sample period in this paper. The maximum value, minimum value and standard deviation of public sector credit (PulCredit) are 75, 0.003 and 10.46, indicating that there are also great differences among public sector credit of different countries. Gains also showed significant differences in the maximum value of − 26.99, the minimum value of − 77.83, the standard deviation of 11.07, and these differences prompted further studies of the heterogeneity of climate risk effects.Table 2 Descriptive statistical results
Variables Observations Mean SD Minimum Maximum
PriCredit 3212 47.95 51.06 0.391 986.1
PulCredit 3130 10.42 10.46 0.003 75
Gains 3480 − 48.53 11.07 − 77.83 − 26.99
Gdpg 3432 3.849 5.229 − 62.08 123.1
lnCPI 3236 4.551 0.379 1.068 7.916
Trade 3220 86.43 49.99 0.175 437.3
Return 2703 12.86 14.19 − 132.6 259
Deposit 3169 50.77 48.15 0.61 770.3
Npl 2108 6.922 7.443 0 74.1
Baseline regression
In this paper, we select gains as a proxy variable for climate risk and empirically test the effect of climate risk on private sector credit supply and public sector credit supply. Based on Eq. (2), F-test and Hausman test are conducted to determine the specific form of the panel regression model by combining the sample data. The results show that all p-values of the F-test are less than 0.1, so the mixed-effects model is not selected. All p-values of the Hausman test are less than 0.05, so the random-effects model is not selected. In summary, this paper chooses a two-way fixed effects model, i.e., controlling for country and time effects, and conducts hypothesis tests for private sector credit supply and public sector credit supply, respectively.
Columns (1) and (2) of Table 3 show the regression results of climate risk on the credit supply of the private sector and public sector, respectively, and it can be seen that the coefficients of climate risk on private sector credit supply and public sector credit supply are − 0.7253 and 0.1848, respectively, and both are statistically significant at 1% level. The results indicate that climate risk has a significant negative relationship with private sector credit and a significant positive relationship with public sector credit. For the private sector, when climate risk increases, the profitability and solvency decrease, operation costs increases, which makes banks face more credit risk and thus reduce the supply of credit to the private sector; for the public sector, when climate risk increases, the government influences the credit resource allocation behavior of banks through direct or indirect interventions to promote the low-carbon transformation of public sector enterprises development, resulting in a credit bias of bank credit to public sector enterprises.Table 3 Baseline regression results
(1) (2)
PriCredit PulCredit
Gains − 0.7253*** 0.1848***
(− 4.7393) (2.9329)
Gdpg − 0.9453*** − 0.1279***
(− 9.1291) (− 2.9815)
lnCPI 3.4077** 0.6821
(2.0573) (1.0024)
Trade − 0.0858*** − 0.0102
(− 4.2534) (− 1.2154)
Return − 0.0606*** − 0.0201**
(− 2.7589) (− 2.2326)
Deposit 0.7044*** 0.0229**
(25.2242) (1.9788)
Npl − 0.0297 0.0945***
(− 0.5056) (3.9152)
_cons − 25.0591** 15.9286***
(− 2.1800) (3.3751)
N 1704 1683
R2 0.4745 0.1406
Robust t-statistics in parentheses; ***p < 0.01, **p < 0.05, *p < 0.1
Considering the influence of control variables, in the regression of climate risk on private sector credit supply, GDP growth rate, international trade, banking sector profitability Return and banking sector deposit level are significantly negative at 1% level, the coefficient of Deposit is significantly positive at 1% level, and the price level lnCPI is significantly positive at 5% level; in the regression of climate risk on public sector credit supply regressions, GDP growth rate and banking sector profitability Return are significantly negative at 1% and 10% levels, respectively, and banking sector deposit level Deposit and non-performing loan ratio Npl are significantly positive at the 5% and 1% levels, respectively, i.e., rising price level has a positive impact on both credit supply, and an increase in bank deposits as an indicator of GDP Deposit has a positive impact on private sector credit and the public sector have a positive impact, and the findings are in line with theoretical expectations.
Endogeneity
As described by Giusy et al. (2020), there may be a bidirectional effect between climate risk and credit supply, and the p-values of both regressions are less than 0.05 by Hausman's test, indicating that the benchmark regression does have the problem of estimation bias due to endogeneity. Therefore, this paper adopts an instrumental variable approach to mitigate the endogeneity problem, drawing on Demir (2021) by using bank-level control variables as endogenous variables and using the lagged terms of the endogenous variables as instrumental variables, choosing the first-order lags of bank earnings Return, bank deposits Deposit, and non-performing loan ratio Npl as instrumental variables for the regressions.
The regression results for private sector credit supply indicate that the explanatory variables remain significantly negative at the 1% level. In the identification test, the Anderson LM statistic is 62.492, with a p-value less than 0.01 indicating that the original hypothesis of “underidentified instrumental variables” is significantly rejected at the 1% level; in the weak instrumental variables test, the Cragg–Donald Wald F-statistic is 21.405, which is greater than the In the weak instrumental variables test, the Cragg-Donald Wald F-statistic is 21.405, which is greater than the 5% threshold, indicating that there are no weak instrumental variables. The results of the instrumental variables regression for public sector credit supply indicate that the explanatory variables remain significantly positive at the 1% level. In the identification test, the Anderson LM statistic is 61.623 with a p-value less than 0.01 indicating that the original hypothesis of “underidentified instrumental variables” is significantly rejected at 1% level; in the weak instrumental variables test, the Cragg-Donald Wald F-statistic is 21.101, which is greater than the In the weak instrumental variable test, the Cragg-Donald Wald F-statistic is 21.101, which is greater than the 5% threshold, indicating that there is no weak instrumental variable problem.
The results in Table 4 show that after mitigating the endogeneity problem, climate risk has a significant negative impact on private sector credit supply and a significant positive impact on public sector credit supply, and the results of the instrumental variables regression are generally consistent with the results of the benchmark regression.Table 4 Regression results of instrument variable method
(1) (2)
PriCredit PulCredit
Gains − 0.6746*** 0.1863***
(− 4.2625) (2.7775)
Gdpg − 1.0608*** − 0.0034
(− 7.3173) (− 0.0553)
lnCPI 3.0559 1.0022
(1.6374) (1.2679)
Trade − 0.0940*** − 0.0197**
(− 4.3901) (− 2.1415)
Return − 0.0486 − 0.1281***
(− 0.4581) (− 2.8511)
Deposit 0.7842*** 0.0241
(19.3373) (1.3888)
Npl − 0.3002*** 0.1143***
(− 3.7292) (3.3617)
N 1538 1521
R2 0.4515 0.0518
Robust t-statistics in parentheses; ***p < 0.01, **p < 0.05, *p < 0.1
Additional robustness checks
Using an alternative proxy variable
Following Demir (2021), the lagged term of the explanatory variable Gains is used as a proxy variable, and the results from columns (1) and (2) of Table 5 show that replacing the explanatory variables, the climate risk index has a significant negative effect on private sector credit supply and a significant positive effect on public sector credit supply, in line with the results of the benchmark regression.Table 5 Robustness checks
(1) (2) (3) (4) (5) (6) (7) (8)
PriCredit PulCredit PriCredit PulCredit PriCredit PulCredit PriCredit PulCredit
L. Gains − 0.6727*** 0.2296***
(− 4.3961) (3.6670)
Gains − 0.8096*** 0.2076*** − 0.7253*** 0.1848** − 0.2730** 0.1706***
(− 5.0702) (3.0111) (− 3.0305) (2.5002) (− 2.4305) (2.9883)
Gdpg − 0.9479*** − 0.1381*** − 0.9010*** − 0.1318** − 0.9453*** − 0.1279* − 0.3622*** − 0.0939**
(− 9.1454) (− 3.2342) (− 7.3026) (− 2.4749) (− 8.3055) (− 1.9534) (− 4.6095) (− 2.3598)
lnCPI 2.0771 0.9432 4.4567*** 0.3343 3.4077* 0.6821 − 4.3778*** 2.1747***
(1.1921) (1.3250) (2.6106) (0.4542) (1.9675) (1.0955) (− 3.4900) (3.4249)
Trade − 0.0983*** − 0.0103 − 0.0788*** − 0.0257*** − 0.0858*** − 0.0102 − 0.0344* 0.0211**
(− 4.8386) (− 1.2294) (− 3.7567) (− 2.7739) (− 3.1225) (− 0.7282) (− 1.9079) (2.3090)
Return − 0.0602*** − 0.0207** − 0.0800*** − 0.0386*** − 0.0606** − 0.0201* − 0.0777*** 0.0120
(− 2.7370) (− 2.3007) (− 2.7555) (− 3.0798) (− 2.4411) (− 1.9179) (− 4.2132) (1.2865)
Deposit 0.6811*** 0.0219* 0.7147*** 0.0237* 0.7044*** 0.0229* 0.9146*** 0.0652***
(24.3163) (1.9031) (23.6582) (1.8021) (9.4718) (2.0495) (34.9359) (4.9081)
Npl − 0.0191 0.0917*** − 0.0517 0.1058*** − 0.0297 0.0945*** − 0.0458 0.0810***
(− 0.3177) (3.7260) (− 0.8559) (4.0648) (− 0.2445) (4.8666) (− 1.0483) (3.6684)
Reserve − 0.3046*** − 0.0877***
(− 11.4177) (− 6.4814)
FDI 0.0820* − 0.0341
(1.9232) (− 1.5838)
Urban 0.0517 − 0.0613
(0.4400) (− 1.0261)
_cons − 16.0681 21.0344*** − 34.5979*** 19.9219*** − 25.0591 15.9286** 18.2673 10.9813*
(− 1.2099) (3.8827) (− 2.8726) (3.8406) (− 1.6337) (2.5612) (1.4950) (1.7697)
N 1651 1632 1428 1413 1704 1683 1192 1185
R2 0.4669 0.1460 0.4922 0.1410 0.6957 0.2645
Robust t-statistics in parentheses; ***p < 0.01, **p < 0.05, *p < 0.1
Adjusting sample period
Considering the impact of the global financial crisis on credit supply in 2008, the sample of the year of the event is removed from the paper. The data from 2008 to 2010 are excluded and thus regressed again. Columns (3) and (4) in Table 5 show the regression results. The results show that a 1-unit increase in the climate risk index would reduce private credit supply by 0.8096% and increase public sector credit by 0.2076%, supporting hypotheses 1 and 2, indicating that the results are robust.
Altering models
As the panel data in this paper has the characteristic of “long N short T,” it may cause the heteroscedasticity problem. In this paper, the method of Driscoll and Kraay (1998) was adopted to solve the heteroscedasticity problem of panel data. As Driscoll and Kraay (1998), the error structure is set as the autoregression of heteroscedasticity and specific order. When the time dimension increases gradually, the standard error is robust to the cross-section correlation and time correlation of the general form. Because this Driscoll and Kraay (1998) estimation approach uses the nonparametric technique to estimate the standard error, the number of sections is not limited, so when the number of sections N is much larger than the period number T, the estimation will not be greatly affected. The results of column (5) and column (6) are basically consistent with the baseline regression results, which proves the robustness of the results.
Adding controls
To mitigate the endogeneity of missing variables, we also add a series of controls by following recent studies (Carmignani et al., 2021; Emefiele et al., 2022; Sugimoto & Enya, 2022). The ratio of bank liquid reserves to bank assets (Reserve), which reflects the bank reserves level of a country. Emefiele et al. (2022) suggest that there is a significant effect of bank reserves on bank credits. Lower bank reserve ratio will enhance the credit supply. The net inflows of foreign direct investment as a percentage of GDP (FDI), which measures the ability of attracting foreign investment of a country. Foreign capital flows into banks in the form of direct investment increases the bank credit supply (Sugimoto & Enya, 2022). The ratio of the urban population to the total population (Urban), which reflects the level of urbanization. Carmignani et al. (2021) show that the level of urbanization has a positive impact on access to credit. Consequently, the above three variables (Reserve, FDI, and Urban) should be included as controls for this study. The results from columns (7) and (8) of Table 5 show that adding Reserve, FDI, and Urban as controls. Comparing the results with the results in Table 3, the estimations provide similar results.
Heterogeneity
Considering that there may be heterogeneity in national income level in the impact of climate risk on credit supply of private and public sectors, the samples are grouped and returned according to the World Bank standard by income level. The World Bank divides national income level into: High-income countries, upper-middle-income countries, lower-middle-income countries, and low-income countries. In this paper, considering the sample size when grouping, both high-income and upper-middle-income are classified into the high-income group, and both lower-middle-income and low-income are classified into the low-income group, and excluding 2 countries without ratings, there are 100 countries in the high-income group and 72 countries in the low-income group, and then grouped for regression, and the results are shown in Table 6.Table 6 Heterogeneous effect
(1) High-income (2) Low-income (3) High-income (4) Low-income
PriCredit PriCredit PulCredit PulCredit
Gains − 0.7911*** − 0.2309** 0.2512*** 0.1419**
(− 3.4956) (− 1.9826) (2.6101) (2.1423)
Gdpg − 1.2392*** − 0.2336** − 0.1311** − 0.1219**
(− 9.3434) (− 2.4078) (− 2.3058) (− 2.2098)
lnCPI 8.2538*** − 2.3343 − 1.2140 3.9262***
(3.4041) (− 1.3672) (− 1.1830) (4.0434)
Trade − 0.1194*** 0.0447** − 0.0323*** 0.0558***
(− 4.8676) (2.0499) (− 3.0501) (4.4691)
Return − 0.0430* − 0.1755*** − 0.0221** 0.0185
(− 1.6979) (− 5.4047) (− 2.0597) (1.0017)
Deposit 0.4833*** 1.0943*** 0.0255 0.0211
(13.2143) (45.1597) (1.6287) (1.5318)
Npl 0.0949 − 0.2453*** 0.1168*** 0.0752***
(1.0331) (− 5.6617) (2.9942) (3.0496)
_cons − 33.6446** 1.8133 31.4742*** − 8.9910*
(− 2.0065) (0.1987) (4.4346) (− 1.7319)
N 1209 495 1190 493
R2 0.4283 0.8664 0.1332 0.3054
Robust t-statistics in parentheses; ***p < 0.01, **p < 0.05, *p < 0.1
Table 6 shows that for private sector credit supply, private sector credit supply is more strongly affected by climate risk in high-income countries than in low-income countries, probably because of the faster development of inclusive finance and micro and small credit in high-income countries and thus a larger share of private sector credit, with a ratio of private sector credit to public sector credit of 35.02:1 in high-income countries compared to 5.41:1 in low-income countries. The higher proportion of private sector credit implies that private sector credit is more vulnerable to climate risk in high-income countries. Therefore, when climate risk increases, climate risk has a greater impact on the supply of private sector credit in high-income countries.
For public sector credit supply, the impact of climate risk on public sector credit supply is more dramatic in high-income countries than in low-income countries, probably because the government plays a more important role in the allocation of bank credit resources due to the improved infrastructure development and financial system in high-income countries, and the government promotes the transition to a low-carbon economy in the public sector through bank credit, thus promoting banks to increase credit allocation to the public sector. Therefore, when climate risk increases, the impact of climate risk on public sector credit supply is greater in high-income countries.
Discussion
This study empirically investigates the impact of climate risk on credit supply by using a sample of 174 countries during 2000–2019 from the perspective of the difference between private and public sectors. We present our main findings as follows: first, climate risk has a significant negative impact on credit supply to the private sector and a significant positive impact on the public sector. When climate risk increases, the private sector's profitability, and solvency decrease, while operation costs increase, making banks more vulnerable to credit risk and decreasing the supply of credit to the private sector. This finding is consistent with Hosono et al. (2016) and Islam and Wheatley (2021). When climate risk increases, the government directs or indirectly intervenes in banks' credit resource allocation behavior to encourage the public sector's low-carbon transformation, resulting in a credit supply heterogeneity of banks to the public sector. It is consistent with Lamperti et al. (2019) and D'Orazio (2022).
Second, both private and public sector credit supply are more strongly affected by climate risk in high-income countries than in low-income countries. For the private sector, climate risk has a more significant impact on the supply of private sector credit in high-income countries, mainly due to a larger share of private sector credit in high-income countries. Thus, private sector credit is more vulnerable to climate risk in high-income countries. For the public sector, government plays a more important role in the allocation of bank credit resources due to the well-developed infrastructure and better quality of governance in high-income countries, the impact of climate risk on public sector credit supply is greater in high-income countries. Our study provides some interesting evidence that may not be consistent with other scholars (Chen & Chang, 2021; Lee et al., 2022): The complete infrastructure construction and financial system have two folds in high-income countries. On the one hand, complete infrastructure construction and better quality of governance facilitate the role of government in credit allocation in high-income countries and promote the green transformation of the public sector. On the other hand, mature financial systems creates a higher proportion of private sector credit and the more convenient risk contagion in high-income countries, which results in the vulnerability to climate risks of the high-income countries.
Limitations of this study and directions for further research: this study reveals the impact of climate risk on bank credit supply to the private sector and public sector from an international perspective. Compared to firm-level or industry-level research in this field, this study focuses on the comparisons from a macro perspective, which inevitably leads to the neglect of some micro influences. The limitations in this study need further research and broader research scope.
Our investigation suggests the following future directions in this field as well: first, the features of credit should be taken into account when studying the impact of climate risk on the credit supply, such as the maturity of credit, the interest rate of credit, and so on. Firms exposed to climate risk are more likely to use long-term credit than short-term credit (Huang et al., 2018; Islam & Wheatley, 2021). Nguyen et al. (2020) find that banks charge higher interest rates on credit for firms exposed to climate risk. Therefore, investigating the maturity and cost of credit may generate discrepant findings which are also significant. Second, the industry of borrowers is also an important factor of credit supply. For example, it is obvious that firms operating in agriculture are more sensitive to climate change than other industries. Banks are more cautious about the credit supply to firms in agriculture. Third, the features of banks may be determinants of credit supply under the impact of climate risk. Yin et al. (2021) argue that compared to non-state-owned banks, state-owned banks have leading positions in green credit supply. Hence, the ownership of banks affects the credit supply to private and public sectors in the face of climate risks. In addition, the geographical location of the bank should be regarded as a determinant of the effect of the climate risks.
Conclusions and implications
This paper has investigated the impact of climate risk on credit supply by using panel data of 174 countries during 2000–2019. We have conducted a heterogeneity analysis of climate risk effects on private and public sectors’ bank credit for these countries. The results show that climate risk has a significant negative impact on credit supply to the private sector and a significant positive impact on credit supply to the public sector. Further, both private and public sector credit supply are more strongly affected by climate risk in high-income countries than in low-income countries.
Academic implications: these findings together provide some important academic implications. Firstly, the existent and common argument is that serious natural disasters will lead to the unbalance of the financial system and impact the banks’ credit service (Brei et al., 2019; Cortés & Strahan, 2017; Ivanov et al., 2020). Climate risk is an important component of natural disasters. Our findings confirm the previous studies of natural disasters to a certain extent and further deepen the research on the mechanism of the impact of climate risk on bank credit supply. Secondly, this study focuses on the heterogeneous effect of climate risk to private and public sectors and investigates the different mechanisms of impact of climate risk on credit supply, which fill the gap in existent research. The heterogeneous effects mainly come from the differences in objectives, organizational structure, and organizational culture between the private and public sectors. Thirdly, we study the impact of climate risk on bank credit supply from the international perspective and obtain common conclusions from a macro view. We also provide new evidence about the amplifying effect of climate risk in high-income countries compared to other scholars. While other scholars have noted that well-established infrastructure in high-income countries improves resilience to risk and national governance in credit allocation to the private sector, this study also indicates that the mature financial systems and the more convenient risk contagion in high-income countries lead to a higher vulnerability of the private sector's credit to the climate risk.
Managerial implications: according to the findings above, there are some managerial implications as follows. For the private sector, climate risk brings new changes to the profitability, solvency, and operational capacity of the private sector. In the face of climate risk, the private sector should raise awareness of climate risk, make corporate strategies, optimize organizational structure, and improve climate risk information disclosure to enhance climate risk management capabilities. For the public sector, it should make full use of credit provision and accelerate its own low-carbon transition. At the same time, the public sector can cooperate closely with policymakers, regulators, local governments, and enterprises to enhance the synergies of low-carbon transition. For banks, climate risk has impacts on risk assessment and capital management. In terms of risk assessment, banks should attach great importance to climate risk, fully consider the links and transmission pathways between climate risk and other risks, and incorporate climate risk into bank comprehensive risk management systems. In terms of capital management, climate risk should be regarded as an important consideration in credit decisions, and promote innovation in green financial products.
Policy recommendations: based on our findings, the following policy recommendations are proposed to cope with the current complex context of climate change: first, governors should enhance the quality of information disclosure, since the current pricing of climate risk is too low, mainly due to insufficient information disclosure requirements, resulting in the failure of capital market to identify the climate risk. The climate risk aggravates the information asymmetry in the market and impairs the efficiency of capital allocation. Therefore, the government should improve climate risk management and construct a complete information disclosure system of climate risk. Second, the climate risk should be incorporated into banks' credit policies. Especially for the private sector in high-income countries, with the development of inclusive finance, the private sector credit is more vulnerable to climate risk. For banks, specific credit supply strategies should be designed for high-climate-risk industries to manage climate risk. By developing quantitative and stereotypical tools to assess portfolio exposures in geographic regions and industries with high-climate risk. Particularly, the impact of climate risk on enterprises should be considered to avoid the physical and transition risks of climate change from exacerbating adverse impacts on bank customers when supplying credit to the private sector. Third, the complete infrastructure development and economic system are beneficial to prevent climate risk. For public sector credit, in high-income countries, a complete infrastructure construction and financial system is conducive to the government's promotion of low-carbon economic transformation in the public sector through bank credit and increased support for the low-carbon economic transformation of the public sector. Therefore, governors should devote to improving production technology and raising income levels, while stimulating R&D development to strengthen risk control capabilities.
Acknowledgements
None.
Data availability
The data would be available from the authors.
Publisher's Note
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| 0 | PMC9744666 | NO-CC CODE | 2022-12-15 00:01:51 | no | Environ Dev Sustain. 2022 Dec 13;:1-23 | utf-8 | Environ Dev Sustain | 2,022 | 10.1007/s10668-022-02827-0 | oa_other |
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Microb Ecol
Microb Ecol
Microbial Ecology
0095-3628
1432-184X
Springer US New York
36509943
2148
10.1007/s00248-022-02148-9
Human Microbiome
The Upper Respiratory Tract Microbiome Network Impacted by SARS-CoV-2
Li Wendy 12
Ma Zhanshan (Sam) [email protected]
134
1 grid.419010.d 0000 0004 1792 7072 Computational Biology and Medical Ecology Lab, State Key Laboratory for Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
2 grid.443576.7 0000 0004 1799 3256 College of Biological Sciences and Technology, Taiyuan Normal University, Taiyuan, China
3 grid.9227.e 0000000119573309 Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223 China
4 grid.410726.6 0000 0004 1797 8419 Kunming College of Life Sciences, University of Chinese Academy of Sciences, Kunming, China
13 12 2022
110
24 5 2022
12 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
The microbiome of upper respiratory tract (URT) acts as a gatekeeper to respiratory health of the host. However, little is still known about the impacts of SARS-CoV-2 infection on the microbial species composition and co-occurrence correlations of the URT microbiome, especially the relationships between SARS-CoV-2 and other microbes. Here, we characterized the URT microbiome based on RNA metagenomic-sequencing datasets from 1737 nasopharyngeal samples collected from COVID-19 patients. The URT-microbiome network consisting of bacteria, archaea, and RNA viruses was built and analyzed from aspects of core/periphery species, cluster composition, and balance between positive and negative interactions. It is discovered that the URT microbiome in the COVID-19 patients is enriched with Enterobacteriaceae, a gut associated family containing many pathogens. These pathogens formed a dense cooperative guild that seemed to suppress beneficial microbes collectively. Besides bacteria and archaea, 72 eukaryotic RNA viruses were identified in the URT microbiome of COVID-19 patients. Only five of these viruses were present in more than 10% of all samples, including SARS-CoV-2 and a bat coronavirus (i.e., BatCoV BM48-31) not detected in humans by routine means. SARS-CoV-2 was inhibited by a cooperative alliance of 89 species, but seems to cooperate with BatCoV BM48-31 given their statistically significant, positive correlations. The presence of cooperative bat-coronavirus partner of SARS-CoV-2 (BatCoV BM48-31), which was previously discovered in bat but not in humans to the best of our knowledge, is puzzling and deserves further investigation given their obvious implications. Possible microbial translocation mechanism from gut to URT also deserves future studies.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00248-022-02148-9.
Keywords
COVID-19
Upper respiratory tract (URT) microbiome
Enterobacteriaceae
Bat coronavirus
Network analysis
==== Body
pmcIntroduction
Since 2019, the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has triggered a massive global health crisis, claiming more than six millions of lives (e.g., [30, 31]. Numerous studies have shown that there is a wide variation in clinical severity in SARS-CoV-2 infection, which is related to many factors, including age, sex, body mass index, hormone secretion levels, and genetic factors [13, 38]. The microbial community (microbiome) plays an important role in the pathogenesis and progression of many respiratory diseases [5, 7, 15, 16]. Exploring the affect of COVID-19 on the respiratory microbiome may help research into disease progression and the appearance of certain symptoms.
Some studies have explored the relationships between SARS-CoV-2 infection and respiratory microbiome. In terms of microbial diversity, COVID-19 may cause a decrease in the upper respiratory tract (including the oral, nose, throat, oropharynx, nasopharynx) and an increase in the lung [14, 52–54]. The diversity of respiratory microbiome may be negatively correlated with the severity of COVID-19 [37, 39, 54]. The impact of COVID-19 on microbial composition is mainly reflected in the increased species abundance of pathogens. The pathogens enriched in the respiratory tract of COVID-19 patients included Klebsiella, Acinetobacter, Serratia, Pseudomonas, Veillonella, Megasphaera, Prevotella, Peptoniphilus, and Anaerococcus [14, 26, 39, 41, 42, 52, 53]. However, it is also possible that these changes in respiratory microbiome of COVID-19 patients may be more closely related to ICU stay, oxygen support type, antibiotic use, and other factors than SARS-CoV-2 infection [23]. Most studies focus on bacterial communities, but ignore viral communities. Currently, research on viral community in the upper respiratory tract (URT) of COVID-19 patients is still limited [14, 37].
Here, we investigate the characteristics of URT microbiome impacted by COVID-19 by re-analyzing RNA metagenomic-sequencing datasets of 1737 nasopharyngeal samples collected from COVID-19 patients. We applied complex network analysis approach to investigate core/periphery nodes and strong clusters of URT microbiome network, aiming to shed lights on the possible interactions between SARS-CoV-2 and other microbes including bacteria, archaea, and RNA viruses. The comprehensive network analysis revealed the enrichment of gut-associated bacteria, many of which are opportunistic pathogens for URT, in the URT microbiome, possibly translocated from gut triggered by COVID infections. Furthermore, we found a “cooperative alliance” consisting of 89 microbes against SARS-CoV-2, which might play an important role in the disease progression. A somewhat puzzling discovery is the presence of a bat coronavirus (i.e., Bat coronavirus BM48-31/BGR/2008, BatCoV BM48-31), which was previously discovered in bat [10], but, to the best of our knowledge, not yet in humans, seems to be the only “ally” of SARS-CoV-2 in the URT microbiome network of COVID-19 patients.
Materials and Methods
Dataset of Upper Respiratory Tract Microbiome
URT microbiome dataset used for this study were from 1903 nasopharyngeal (NP) swab samples tested positive for SARS-CoV-2 by RT-qPCR, whose total RNA was extracted and processed with RNA sequencing-based metagenomics [19]. Metagenomic sequencing data and genome assemblies are publicly available at NCBI’s GenBank and SRA databases under BioProject PRJNA622837. Metagenomic data were classified to the species-level using Kraken 2 v2.1.2 against the reference sequence databases [50, 51]. The reference sequence databases were built based on the complete bacterial, archaeal, and viral genomes, the GRCh38 human genome, and UniVec Core database accessed from NCBI RefSeq on June 3, 2021. After taxonomic classification, the species abundance was estimated using Bracken v2.6 [24, 25]. Samples not annotated with severe acute respiratory syndrome-related coronavirus (SARSr-CoV) were removed, and the microbiomes of the remaining 1737 samples were used for subsequent analyses.
Co-occurrence Network Analysis
To ensure the reliability of correlation calculation, species present in less than 1% of the samples were excluded for correlation calculation. FastSpar, an efficient and parallelizable implementation of the SparCC algorithm, was used to construct network based on the true abundance of taxon (Friedman et al. 2012, Watts et al. 2019). Correlation relationships with a p value ≤ 0.01 after false discovery rate (FDR) adjustment and absolute coefficient > 0.1 were used to construct the co-occurrence network. The properties of network were calculated using the iGraph R-package. The P/N (positive to negative links) ratio estimated in this study is a network property that was introduced by Ma [27]. Cytoscape v2.8.3 was used for the visualization of the network. The MCODE (molecular complex detection) algorithm was used to detect network clusters.
The core/periphery network (CPN) analysis was used to detect the core/periphery structure in the network, which consists of two types of nodes: dense cohesive core nodes and sparse connected periphery nodes. An ideal CPN consists of core nodes that are fully linked to each other and periphery nodes that are fully linked only to the core [6]. Formally, let G = (V, E) be an undirected, unweighted graph with n nodes and m links, and let A = (aij) be the adjacency matrix of G. If node i and node j are linked, then aij = 1, otherwise aij = 0. Let δ be a vector of length n consisting of 1 and 0, where 1 represents the core node and 0 represents the periphery node. Let P = (pij) be the adjacency matrix of the ideal CPN of n nodes and m links. The detection of the core-periphery structure is an optimization problem to find vector δ, such that the objective function (ρ) achieves its maximum based on the following expression:1 ρ=∑i,jAijPij
With vector δ, it is then easy to classify nodes as either core or periphery. We implemented the CPN analysis in Python using code provided by Ma and Ellison [28].
Results
Composition of the URT Microbiomes in COVID-19 Patients
We identified 6049 species, including 5754 bacteria, 147 archaea, 72 eukaryotic RNA viruses, and 76 prokaryotic RNA viruses, from the 1737 URT metagenomic samples of COVID-19 patients. In addition to severe acute respiratory syndrome-related coronavirus (SARSr-CoV, a species-level taxon including subspecies of SARS-CoV-2), these eukaryotic RNA viruses identified also included some other respiratory pathogens, such as Human coronavirus NL63, Human coronavirus HKU, Human metapneumovirus, Enterovirus, and Rotavirus, but most of them were present in less than 10 samples (Supplementary Tables S1). It suggested that some COVID-19 patients have developed co-infections with other viruses. We also identified two bat viruses in the URT of COVID-19 patients, BatCoV BM48-31 and Bat sapelovirus, of which BatCoV BM48-31 was present in 178 samples and Bat sapelovirus in one sample (Supplementary Tables S1). Possible explanations for the presence of bat viruses in humans have been discussed in later section.
The most abundant phylum across all samples was the Proteobacteria (68% of total abundance), followed by the Pisuviricota (24%), Firmicutes (4.6%), Actinobacteria (1.4%), and Uroviricota (1.4%). The 1737 microbial communities can be roughly divided into two categories, one dominated by bacteria of the family Enterobacteriaceae and the other dominated by virus of the family Coronaviridae. The relative abundance of Enterobacteriaceae decreased with the increase of Coronaviridae (Fig. 1a). The most widely species was severe acute respiratory syndrome-related coronavirus (a species-level taxon including subspecies of SARS-CoV-2), which was present in all samples, followed by Staphylococcus aureus (99.8%), Escherichia coli (99.8%), Klebsiella pneumoniae (99.4%), and Salmonella enterica (99%). These five species accounted for 88% of the relative abundance of the total microbiomes (Fig. 1b).Fig. 1 Composition of upper respiratory tract microbiome: a at family level and b at species level of COVID-19 patients: X-axis is 1737 URT samples and y-axis is relative abundance
Co-occurrence Network Analysis for COVID-19-URT Microbiomes
The co-occurrence network of COVID-19-URT microbiomes was constructed based on the species that were present in 1% or more of the samples. Out of the 6104 species identified, 32.6% were present in 1% or more of the samples, including 1956 bacteria, 23 archaea, 5 eukaryotic viruses, and 9 prokaryotic viruses. After removing the links (correlations) with insignificant p values (p > 0.01) or weak correlation coefficients (|R|≤ 0.1), 1840 nodes (species) and 135,105 links remained in the network (Fig. 2). The basic network properties are listed in Supplementary Table S2.Fig. 2 Network of upper respiratory tract microbiome in COVID-19 patients: links in cyan are positive correlation; links in orange are negative correlations; circles represent core species; triangles represent periphery species; nodes are colored differently in terms of their phylum identity. See supplementary Table S10 for the details of links
We divided the species in the network into core and periphery groups by using CPN analysis, of which 938 species belonged to core and 902 to periphery (Supplementary Tables S3 & S4). It is worth noting that all 5 eukaryotic viruses in the network belonged to the core: SARSr-CoV, BatCoV BM48-31, Murine leukemia virus, Adeno-associated dependoparvovirus A (AAV), and Megavirus chiliensis.
The Strongest Cluster (Guild) in the URT Microbiome Network of COVID-19 Patients
There were 28 clusters in the COVID-19-URT microbiome network (supplementary Table S5), of which the strongest cluster consisted of 277 nodes (15% of the total nodes) and 28,657 links (21% of the total links). The strongest cluster contains two parts, one was a cooperative sub-cluster dominated by Proteobacteria (129/185), in which one-third (50/185) of the species were from Enterobacteriaceae; another was composed of species that were antagonistic or competitive this sub-cluster (Fig. 3). The interactive patterns within each of these two parts were positive, but almost all correlations between them were negative. In the following, we refer to this Proteobacteria-dominated sub-cluster as PDSC for short. Supplementary Table S6 lists the species composition of the top three strongest clusters in the network.Fig. 3 The strongest cluster in the URT microbiome network of COVID-19 patients: links in cyan are positive correlation; links in orange are negative correlations; circles represent core species; triangles represent periphery species; nodes are colored differently in terms of their phylum identity. Specific species information is listed in supplementary Table S6
Ratio of Positive to Negative Interactions in the COVID-19-URT Microbiome
Previous studies by our team found that most human microbiome networks were predominantly mutualistic, and diseases might even lead to a reduction in antagonistic interactions [20, 21, 22, 27, 29]. However, the ratio of positive to negative links (P/N ratio) in the network is 0.677, that is, the negative links are 1.477 times of the positive links (Supplementary Table S7, Fig. 4), indicating that the COVID-19-URT microbiome was not a mutualistic community. Bacteria, especially Proteobacteria species, held most of the negative links (Supplementary Table S7).Fig. 4 Ratios of positive to negative links (P/N ratios) in the URT microbiome network of COVID-19 patients: a the P/N ratio in the whole networks, and the ratios within and between kingdoms. b The P/N ratios within and between main bacteria phyla. F, Firmicutes; P, Proteobacteria; B, Bacteroidetes; A, Actinobacteria
The interactions between archaea, between viruses, and between archaea and viruses were mainly positive [log10(P/N ratio) > 0, Fig. 4a]. There were more negative interactions than positive between bacteria, between bacteria and archaea, and between bacteria and viruses [log10(P/N ratio) < 0, Fig. 4a]. The interactions between viruses are very few and mostly positive (Supplementary Table S7). Prokaryotic viruses hold 88% of the interactions between viruses and bacteria. Both eukaryotic and prokaryotic viruses have more negative interactions with bacteria than positive ones. For bacteria, the P/N ratios of intra-phyla were all greater than 1 [log10(P/N ratio) > 0], and the P/N ratios of inter-phyla were all less than 1 [log10(P/N ratio) < 0, Fig. 4b].
Niche overlap is one of the important reasons for competition or antagonism (negative interaction) among species. These results suggest that niche overlap within URT microbiome of COVID-19 patients occurs mainly within bacteria as well as between bacteria and archaea and viruses. More specifically, niche competition within bacterial community mainly occurred intra-Proteobacteria and between Proteobacteria and other phyla.
Sub-networks Associated with SARSr-CoV and Other Eukaryotic Viruses
In the COVID-19-URT microbiome network, SARSr-CoV was suppressed by a cooperative alliance of 89 species and was in a cooperative relationship with only one species, i.e., BatCoV BM48-31 (Fig. 5). The reason why it is called cooperative alliance is that the relationships between these 89 species were positive or cooperative. All species but four bacteria in the anti-SARSr-CoV cooperative alliance were the members of PDSC in the strongest cluster, including 1 prokaryotic virus (Enterobacteria phage fd), 1 archaea (Sulfolobus acidocaldarius), and 83 bacteria (including 58 Proteobacteria, 12 Firmicutes, 8 Actinobacteria). Specific species information is listed in supplementary Table S7. Much like SARSr-CoV, BatCoV BM48-31 was also jointly inhibited by a group of species and was positively linked only to SARSr-CoV (supplementary Fig. S1, Table S8). All 129 species negatively linked to BatCoV BM48-31 were from PDSC, and more than 4/5 of them also inhibited SARSr-CoV (supplementary Table S8).Fig. 5 Sub-network associated with SARSr-CoV in the URT microbiome network of COVID-19 patients: links in cyan are positive correlation; links in orange are negative correlations; circles represent core species; triangles represent periphery species; nodes are colored differently in terms of their phylum identity
The network also contains three other eukaryotic viruses, Adeno-associated dependoparvovirus A (AAV), Murine leukemia virus, and Megavirus chiliensis. AAV was positively correlated with 42 species, and the correlations within these 42 species were positive (supplementary Fig. S2A). Murine leukemia virus held negative links with three bacteria, and Megavirus chiliensis held positive link with a bacteria (supplementary Figs. S2B & S2C).
Discussion and Conclusion
The URT is the initial site of entry and replication of SARS-CoV-2, and its colonization of microbial community is closely related to respiratory health. However, a limited number of studies have examined the signatures of the URT microbiome infected by SARS-CoV-2. The purpose of this study was to understand the impact of COVID-19 on URT microbiome including bacteria, archaea, and viruses from two aspects of species composition and interspecies interactions.
In terms of species composition, we found that COVID-19 leads to the predominance of gut-associated bacteria (i.e., Enterobacteriaceae) in the URT microbiomes of patients. The normal URT microbiomes are dominant by Corynebacterium, Staphylococcus, Streptococcus, Dolosigranulum, and Moraxella, and the species abundance of Enterobacteriaceae is low [1, 18, 32]. However, the URT microbiomes of many patients were enriched with Enterobacteriaceae, especially pathogens, E. coli, K. pneumoniae, and S. enterica.
One explanation for this phenomenon is the uncontrolled overgrowth of these gut-associated bacteria, which were present in low abundance in the URT before infection. The infection of SARS-CoV-2 may first destroy the cooperative relationships between the normal URT species and the inhibitions of the normal bacteria to opportunistic pathogens. This gives pathogens the opportunity to proliferate and establish their own guilds to compete for resources. The strongest cluster (guild) found in the COVID-19-URT microbiome network may confirm this progress. Network module analysis can be used to study the guild in ecology, which refers to a group of species exploiting the same kinds of resources in similar ways [20, 21, 46, 52, 53]. The strongest guild in the COVID-19-URT microbiome consists of two parts: PDSC, a highly dense cooperative sub-guild dominated by Enterobacteriaceae, and the species that antagonize PDSC. PDSC had a high network density, in which interactions were all cooperative. However, interactions between the PDSC-antagonistic species were sparse, with even 25 species negatively correlated only with PDSC and not interacting with the rest of species in this group. The interactions between PDSC and PDSC-antagonistic species were almost entirely competitive or antagonistic. It illustrates a common phenomenon in ecological guilds, where the two groups are competing for the same resources. The 13 out of 92 species exploited by the PDSC were belonged to Corynebacterium. Corynebacterium spp. are closely related to respiratory health and have been considered as potential keystone species in the URT microbiome, as they play an important role in the exclusion of potential pathogens [3, 18, 32, 48]. Therefore, we speculated that although Enterobacteriaceae pathogens exist in URT of healthy people, they are inhibited by probiotics such as Corynebacterium and maintain a very low abundance. Infection with SARS-COV-2 results in strong interference of URT microbiome by internal and external factors, thus destroying this inhibition effect. Another possible explanation for the dominance of gut-associated bacteria in COVID-19 URT is that SARS-CoV-2 infection, like HIV infection, triggers translocation of the gut microbiome.
URT microbiome, as gatekeeper of the respiratory system, is one of the most important sources of lower respiratory tract and lung microbiome [2, 32, 35, 45]. The gut-associated bacteria in URT may enter the lung and alter the composition of the lung microbiome. Enrichment of the lung microbiome with gut-associated bacteria may propel alveolar inflammation and injury, which may lead to the aggravation or even deterioration of the disease [8, 9, 40]. In addition, a study has shown that the decrease of odor identification might be related to the increase of Enterobacteriaceae in URT [17]. One possible explanation is that Enterobacteriaceae are capable of producing butyrate, whose unpleasant smell might interfere with olfactory performance [18]. During the COVID-19 outbreak, an increasing number of patients have reported a disorder of the sense of smell [47, 49, 55]. Olfactory dysfunction has been one of the symptoms and sequelae of COVID-19. The increase of gut-associated bacteria in URT may be one of the causes of olfactory dysfunction, and controlling these bacteria may improve this symptom.
We also found through co-occurrence network analysis that SARSr-CoV and BatCoV BM48-31 were inhibited by a cooperative alliance in which most of species were members of the PDSC. Moreover, SARSr-CoV and BatCoV BM48-3 were the each other’s only cooperators in the microbiome. This result suggested that SARSr-CoV and its “friend” are common enemies of both normal and dysbiosis URT microbiome. Although PDSC, the high-density cooperative guild dominated by gut-associated pathogens, seized resources and suppresses beneficial microbes collectively, it also played the most important role in warding off these two viruses. What roles that the cooperative alliance consisting of species against SARS-CoV-2 play in clinical progression, severity, and recovery of COVID-19 will need to be addressed in future studies.
Another point of note is the cooperative interaction between SARSr-CoV and BatCoV BM48-31. BatCoV BM48-31 was identified from Rhinolophus blasii bat collected in Bulgaria in 2008 and belongs to lineage B betacoronaviruses, together with SARS-CoV-2 and SARS-CoV from SARSr-CoV [10]. Sequences of this virus are similar to those of SARS-CoV-2 and SARS-CoV, but there is still some phylogenetic distance between them [58], Boni et al. 2020, [43]. Although it has been shown that some bat SARS-like coronavirus viruses have the ability to infect human cells, they do not include BatCoV BM48-31 [11, 33, 34, 43]. Therefore, we should emphasize that the presence of BatCoV BM48-31 in the URT microbiome is somewhat puzzling. More cautiously, we cannot exclude the small probabilities of errors, from arguably exhaustive three sources: possible mis-annotation from using Kraken 2 software pipeline, possible contamination of the original samples, and/or data handling/storage errors in the databases from which we obtained the raw datasets for reanalysis. A mis-annotation could mean that the annotated BatCoV BM48-31 and SARS-CoV-2 could just be the same virus or a close variant, as suggested by one of the anonymous expert reviewers. In terms of species level annotation, compared with other methods, Kraken 2 has a relatively low false positive rate, and the accuracy is relatively high [44, 36]. Kraken 2 has also been used in many studies to identify viruses from metagenomic sequencing data (e.g., [4, 56, 57]. Although BatCoV BM48-31 belongs to the same lineage B betacoronaviruses with SARS-CoV-2, there is still a considerable amount of phylogenetic distance between them. In other words, there is still a large difference between the sequences of BatCoV BM48-31 and SARS-CoV-2. The results of Kraken 2 should be robust as long as the difference between the two virus sequences is greater than Kraken 2’s error rate, which seems to be the case from existing applications of Kraken 2 [12].
Finally, if the previous three small probability events are unnecessarily cautioned, i.e., the presence of BatCoV BM48-31 in the URT microbiome is truly positive, then further investigations on the infection mechanisms of BatCoV BM48-31, in particular, its possible cooperative infection action with SARS-CoV-2, should have important implications for understanding the origin of SARS-CoV-2. Given that BatCoV BM48-31 was discovered more than a decade ago, its co-presence SARS-CoV-2 in humans a decade later during the COVID-19 pandemic is puzzling and certainly worthy of further investigations.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 1677 KB)
Supplementary file2 (XLSX 2867 KB)
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant Number: 31970116 and 72274192). We appreciate Miss WM Xiao of the Chinese Academy of Sciences for her computational support to this study.
Author Contribution
WL performed the study and wrote the manuscript. ZSM designed and performed interpretations. All authors read and approved the final manuscript.
Data Availability
The dataset used in this study was downloaded from NCBI Sequence Read Archive (SRA) database (accession no. PRJNA622837).
Declarations
Ethics Approval
Ethics approval was not required for this study.
Conflict of Interest
The authors declare no competing interests.
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Original Research Article
How Does the Public Evaluate Vaccines for Low-Incidence, Severe-Outcome Diseases? A General-Population Choice Experiment
http://orcid.org/0000-0002-7572-2150
Johnson F. Reed [email protected]
1
Fairchild Angelyn 2
Whittington Dale 34
Srivastava Amit K. 58
Gonzalez Juan Marcos 6
Huan Liping 7
1 grid.26009.3d 0000 0004 1936 7961 Duke Clinical Research Institute, Duke University, 300 West Morgan Street, Durham, NC 27701 USA
2 grid.410711.2 0000 0001 1034 1720 Angelyn Fairchild Kenan-Flagler School of Business, University of North Carolina, Chapel Hill, NC USA
3 grid.410711.2 0000 0001 1034 1720 Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC USA
4 grid.5379.8 0000000121662407 Global Development Institute, University of Manchester, Manchester, UK
5 grid.410513.2 0000 0000 8800 7493 Medical Development and Scientific Clinical Affairs, Pfizer Vaccines, Collegeville, PA USA
6 grid.26009.3d 0000 0004 1936 7961 Duke Clinical Research Institute, Duke University, Durham, NC USA
7 grid.410513.2 0000 0000 8800 7493 Health Economics and Outcomes Research, Pfizer Inc., Collegeville, PA USA
8 Orbital Therapeutics, Cambridge, MA, USA
13 12 2022
113
20 9 2022
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Background
Because immunizing large numbers of healthy people could be required to reduce a relatively small number of infections, disease incidence has a large impact on cost effectiveness, even if the infection is associated with very serious health outcomes. In addition to cost effectiveness, the US Advisory Committee on Immunization Practices requires evidence of stakeholders’ values and preferences to help inform vaccine recommendations. This study quantified general-population preferences for vaccine trade-offs among disease severity, disease incidence, and other vaccine features.
Methods
We developed a best-practice discrete choice experiment survey and administered it to 1185 parents of children aged 12–23 years and 1203 young adults aged 18–25 years from a national opt-in consumer panel. The data were analyzed using exploded-logit latent-class analysis.
Results
Latent-class analysis identified two classes with similar relative-importance weights in both samples. One of the two classes represented about half the samples and had preferences consistent with well-structured, logically ordered, and acceptably precise stated-preference utility. Preferences for the other half of the samples were poorly defined over the ranges of vaccine and disease attributes evaluated. Both parents and young adults in the first class evaluated protection from a disease with 1 in 100 incidence and full recovery at home as having statistically the same preference utility as a disease with 1 in 1 million incidence requiring hospitalization and resulting in permanent deafness.
Conclusions
The results suggest that vaccines that protect against low-incidence, severe-outcome diseases, provide ‘peace of mind’ benefits not captured by standard health-outcome metrics. The fact that half the respondents had poorly defined vaccine preferences is a reminder of the challenges of implementing patient-centric vaccine decision making.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40271-022-00602-x.
http://dx.doi.org/10.13039/100004319 Pfizer
==== Body
pmcKey Points for Decision Makers
The value of low-incidence, severe-outcome diseases for about half of a large sample of the US public was found to be much larger than typically is indicated in cost-effectiveness assessments.
The value of vaccines to protect against low-incidence, severe-outcome diseases is at least as large as vaccines against high-incidence, less severe-outcome diseases.
About half of the same sample had unexpectedly ordered and imprecise vaccine preferences. This result is consistent with the well-known problematic state of vaccine knowledge and vaccination decision making among a substantial portion of the US public.
Introduction
In the United States (US) the Advisory Committee on Immunization Practices (ACIP) provides expert external advice and guidance to the Centers for Disease Control (CDC) on controlling vaccine-preventable diseases. Key factors considered in developing recommendations include the balance of benefits and harms, type of evidence, and health-economic analyses [1]. The ACIP also requires evidence of stakeholders’ values and preferences for the purpose of informing vaccine recommendations [2].
The evaluation framework requires that the evidence includes a ‘summary of findings of cost-effectiveness analyses (CEAs) of the vaccine in the target population’. CEA compares the costs of providing immunizations with the health benefits of reducing infection incidence. Even if the infection is associated with very serious health outcomes, including death, sufficiently small incidence will result in a vaccine having such a high cost per case avoided that it would fail a conventional cost-effectiveness test.
An international panel of clinical and health economic experts concluded that “the currently prevailing logic of cost-effectiveness … was considered deficient as it does not capture well-established social preferences regarding health care resource allocation” [3]. Erickson and colleagues proposed a comprehensive framework that went beyond cost effectiveness for evaluating new vaccines [4]. To be useful, such a framework should provide guidance on how to compare diseases with low incidence but high fatality and severe-sequelae rates with diseases with high incidence, low fatality rates, and mild sequelae. The authors suggest that evaluations of immunization programs should include acceptability as indicated by ‘public perception of disease risk, severity, fear, and demand for disease control’.
Such public perceptions of value can be significantly different than those obtained with conventional CEA methods. For example, Prosser et al. [5] found that US parents and other adults would pay $500 to reduce the risk of pneumococcal meningitis from 21 per 100,000 to 6 per 100,000, which is equivalent to approximately $3.3 million per case avoided, orders of magnitude larger than conventional cost-effectiveness thresholds.
This study aimed to better understand and quantify the patient and population benefit-risk trade-off preferences among vaccine attributes, particularly with regard to disease incidence and sequelae severity. A secondary interest of this study is to compare vaccination preferences of parents of teen-age and college-age children with the preferences of college-age individuals themselves for certain infectious diseases for which college-age individuals are at elevated risks.
Materials and Methods
Study Design
An online survey used a discrete choice experiment to elicit respondents’ evaluations of tradeoffs among vaccine attributes [6, 7]. The study design followed good research practices for health-related choice-experiment studies [8]. Vaccine attributes and levels were identified and defined in consultation with clinical experts and pretested in face-to-face interviews with 18 adult parents of at least one child between the ages of 16 and 25 years, and seven young adults between the ages of 18 and 25 years. All pretest interviews were conducted by at least two experienced interviewers using a think-aloud protocol in which respondents were asked to read the survey instrument aloud and were encouraged to express their thoughts related to survey information materials and questions. Details on the pretest interviews are contained in Appendix A in the electronic supplementary material (ESM).
The final web-enabled survey instrument included choice questions that required respondents to evaluate constructed vaccines, which were defined by five attributes. Three of these attributes related to the disease that the vaccine is protective against:Effect of the disease (Effect)
How many people get the disease each year (Rate)
How the disease spreads (Mode)
The remaining two attributes describe the vaccine itself:How long the vaccine lasts (Duration)
Cost to you (Cost)
Each of these five attributes can assume one of three or more levels, which are shown in Table 1. Each unique vaccine profile in the choice questions was described based on the level assigned for each attribute.Table 1 Attributes and attribute levels used in the discrete choice experiment
Attribute Levels
Effect of the disease Moderately ill—full recovery at home: People feel moderately ill for about 1 week but can recover at home. They will not have any long-term problems because of the disease
Severely ill—full recovery after hospital stay: People feel severely ill and spend 2 weeks in hospital. They will not have any long-term problems because of the disease
Total deafness: People become severely ill and spend 2 weeks in hospital. Even after receiving the best interventions, people become permanently deaf. They cannot hear at all in any situation and hearing aids do not work
Lose both legs: People become severely ill and spend 2 weeks in hospital. Even after receiving the best interventions, the infection damages people’s legs so badly that they must be amputated
Permanent brain damage: People become severely ill and spend 2 weeks in hospital. Even after receiving the best interventions, people have permanent brain damage and depend on others for feeding, toileting, dressing, and walking
Death: People become severely ill and spend 2 weeks in hospital. Even after receiving the best intervention, people die from the disease
How many people get the disease and its effects each year 1 in 100 (1 person in a neighborhood)
1 in 1000 (1 person in a village)
1 in 10,000 (1 person in a small town)
1 in 100,000 (1 person in a medium-sized city)
1 in 1,000,000 (1 person in a large city)
Mode of exposure Airborne: People could get the disease if they breathe air containing germs after an infected person coughs or sneezes
Casual contact: Some germs are spread through casual contact with doorknobs, desks, toys, or railings that an infected person has touched
Personal contact: Some germs can only spread through personal contact such as kissing, or sharing straws, drinks, or eating utensils with an infected person
How long the vaccine lasts 1 year
5 years
10 years
Cost to you $50
$100
$300
$500
Because our goal is to understand respondents’ willingness to accept tradeoffs between disease severity and incidence, we do not name any diseases in the direct choice-experiment questions. Respondents could have reactions to disease labels that would confound the experiment. However, various combinations of disease attribute levels can describe a wide range of vaccine-preventable diseases, such as seasonal influenza, invasive meningococcal disease, pertussis, and herpes zoster.
Experimentally constructed vaccine profiles were arranged in pairs, and respondents were asked to choose one of four options: (1) a vaccine to protect against disease A; (2) a vaccine to protect against disease B; (3) vaccines to protect against both disease A and disease B; or (4) neither vaccine. If ‘Both’ or ‘Neither’ was selected, respondents were asked which vaccine they thought was more important. Thus, the response data consist of three possibilities: one vaccine is preferred to both another vaccine and to no vaccine, no vaccine is preferred to either of two vaccines, or both vaccines are preferred to no vaccine with an indication of which vaccine is more important. The last case provides a complete ordering of the three alternatives. Figure 1 shows an example choice question.Fig. 1 Example choice question
An experimental design determined how attribute levels were combined to describe disease profiles and profile pairings in each choice question. The experimental design was generated using SAS software version 9.4 (SAS Institute, Inc., Cary, NC, USA) to optimize D-efficiency and maximize the statistical power available to estimate the preference or utility weight for each attribute level. Research on experimental subdesigns has found gains in efficiency from using multiple designs in the same study [9]. We developed two flat-prior designs, one of which optimized on main effects and one of which accommodated an interaction between disease severity and incidence rate. Each design contained 32 subsets of three unique choice questions each. Respondents were randomly assigned to two subsets, one from each group. This procedure resulted in six trade-off questions for each respondent. SAS code used to generate the experimental design is contained in Appendix B in the ESM.
The final web-enabled survey instrument included several important features in addition to the preference elicitation and treatment experience questions, which were designed to both aid respondents in interpreting the survey and to provide indications of respondent comprehension and consistency. These additional features included informed consent, detailed attribute descriptions that could be recalled in pop-up windows by mousing over attribute labels, comprehension and reflection questions, a risk tutorial, and practice choice questions. The final web-enabled survey also collected respondents’ demographic information, perceptions of risk of infectious disease with different degrees of severity and risk, attitudes and behaviors toward vaccines, and judgments about the value of receiving MenB vaccine-related information directly from a physician. This study received approval from a major research university Institutional Review Board.
Data Collection
The final version of the survey instrument was programmed by IPSOS, a market research company, for web-enabled administration. Members of the IPSOS national opt-in consumer panel were invited, via email or via their personalized online portal, to participate in the online survey. Panelists were eligible for the study if they met a basic set of inclusion criteria, i.e. ability to read and understand English, and being either a young adult aged 18–25 years or a parent of at least one child aged 12–25 years. Survey responses were collected during three phases. Two soft launches collected data in July and August 2019. After each soft launch, these preliminary data were assessed to check that randomization processes were working properly and that attribute ranges were wide enough to induce tradeoffs among all the attributes. IPSOS fielded the final survey between 22 August and 2 October 2019. Demographics for the soft-launch samples can be found in Table S1 of the ESM.
Statistical Analysis
We performed recommended internal-validity tests on the data to assess data quality [10]. We identified respondents who always chose the alternative with the better level of a single attribute, always chose the vaccine alternative in the same position (either A or B) or provided incorrect responses to quiz questions testing respondent comprehension of the attributes included in the choice questions [10]. Any of these response patterns can indicate that respondents were inattentive, did not understand the survey, or were using simplifying heuristics to avoid evaluating each choice question in detail. Additionally, we identified respondents who always selected either the ‘Neither vaccine’ or ‘Both vaccines’ alternative in every choice question. While this pattern of responses might be caused by inattention, it can also be an expression of very strong preferences for or against vaccines in general. We used probit models to test for systematic relationships between these strongly vaccine-hesitant or pro-vaccine choice patterns and respondent characteristics.
The main analysis evaluated the responses to the vaccine choice questions. Logit models were used to understand how respondents’ choices between vaccines (including ‘Both’ and ‘Neither’) were associated with the characteristics of each vaccine option. Results from these models indicate the effect that changes in disease and vaccine characteristics would have on respondents’ choices; thus, they are considered a measure of relative importance or utility of specific attribute levels in the questions. Latent-class, log-odds parameter estimates can be interpreted as relative utility weights. The utility specification used in the analysis is shown in Eq. 1:1 Uij=βijEffectEffect+βijRatelnRate+βijRate×EffectlnRate×Effect+βijDurationDuration+βijModeMode+βijCostCost+γiZ
where i indexes individuals with class-i preferences and j indexes vaccine profiles. Variable names are defined above. All vaccine variables are categorical vectors except for Rate, and continuous Rate is interacted with the Effect categories. Z is a vector of individual covariates.
Only differences in preference estimates between levels of the same attribute are interpretable and represent that specific change’s relative importance in determining observed choices. Because choice-model preference estimates are confounded with a model-specific scale factor, raw utility weights cannot be directly compared between models [11]. However, utility weights can be rescaled relative to a consistent set of attribute differences; this normalizes cross-model scale differences and facilitates comparison and interpretation.
Because choice alternatives not only included ‘Vaccine A’, ‘Vaccine B’, or ‘Neither vaccine’ but also the option of choosing ‘Both vaccines’, the standard choice model requires modification. Appendix C in the ESM shows how sequential or ‘exploded’ logit was adapted for this question format. There are likely to be scale differences among the A/B vaccine alternatives and the ‘Both’ and ‘Neither’ alternatives. Furthermore, it is likely there are scale differences between the A/B alternatives in the first question and the A/B alternatives in the second question generated from the ‘Both’ and ‘Neither’ choices. To account for heteroskedasticity in the two-stage question format, we obtained random-parameter estimates for alternative-specific constants corresponding to choosing one of the two vaccine alternatives, ‘Both alternatives’, and ‘Neither alternative’. Hensher et al. [12] derived a formula for converting the random-parameter standard-deviation estimates to corresponding scale values. We also estimated scale controls for ‘Both’ and ‘Neither’ variants of the second question. After controlling for scale in the first question, the second-question scale estimates were not significantly different from 1, which is the normalized scale for the A/B alternatives in the first question. Hence, we report scale results only for the scale-adjusted first question.
The model specification assumed that observed respondent choices were the result of differences in the levels of each disease and vaccine attribute that define each choice alternative, and that were experimentally controlled. Furthermore, the models were structured to allow the importance of disease incidence to vary with the effects of the vaccine-preventable diseases. Furthermore, each class of respondents in the latent-class model was allowed to have unique importance weights. Because we quantified the values of vaccines that protect against diseases with different exposure risks and severity in a common preference-utility metric, we were able to identify combinations of risk and disease severity that yield similar vaccine preference values for respondents within each class. The resulting similar-utility bands enable comparisons between values for vaccines against high-incidence/low-severity diseases versus low-incidence/high-severity diseases.
In accordance with good-practice guidance to account for heterogeneity in respondents’ preferences, we used latent-class analysis to estimate relative importance weights for each attribute level [13]. Latent-class analysis identifies classes of respondents with similar preferences; results give both the relative importance of the vaccine attributes within each class as well as the probability that each respondent is assigned to a given class. The number of latent classes included in the final models is based on several criteria, including the Bayesian information criterion (BIC), interpretability of results, and model parsimony.
We estimated 2-, 3-, 4-, and 5-class models with the same specification. The 3-class model had the smallest BIC, but as noted, BIC should not be the only criterion for selecting a latent-class specification. Class 1 in the 3-class model is essentially the same as Class 1 in the 2-class model. The second class in the 2-class model is split into two classes in the 3-class model. The larger of those classes is similar to Class 2 in the 2-class model. The third class is much smaller. It is not as strongly disordered but all the severities have similar importance. Thus, the 3-class model provides no quantitative or qualitative insights that are not shown in the 2-class model.
Relationships among class-membership probabilities and respondent characteristics were estimated with preference parameters and included sociodemographic, vaccine attitude, vaccination history, and internal validity variables. Data from the young-adult and parent samples were analyzed separately. Analyses used Stata SE version 16 (StataCorp LLC, College Station, TX, USA) and Latent GOLD version 5.1 (Statistical Innovations, Arlington, MA, USA).
Results
Sample and Validity Tests
We obtained observations from 1185 parents and 1203 young adults. Table 2 contains selected demographic and attitude characteristics of the samples. For reference, Table 2 also contains basic demographic data for the US population for the relevant age bands, according to the US Census Bureau. In general, the parent sample was older, oversampled White non-minority people and contained a lower proportion of high-income (<$100,000 annual income) respondents compared with the general US population. The young-adult sample contained more women and more people with 4-year college degrees than the general population.Table 2 Selected demographic and attitude variables, survey respondents, compared with the US population
Characteristic Parents (n = 1185) US population Young adults (n = 1203) US population
Age, years 58.4 45.7 21.8 20.6
Female (%) 50.1 50.0 76.1 49.5
Minority (%) 10.6 25.4 22.7 26.8
4 years of college or more (%) 47.3 39.1 26.3 8.8
Income < $25,000 (%) 11.3 12.1 25.9 24.3
Income > $100,000 (%) 24.0 42.7 10.9 15.1
Vaccines are necessary to protect health (% agree or strongly agree) 3.9 6.9
People receive too many vaccines (% agree or strongly agree) 12.8 18.9
Get the flu shot every, or nearly every, year (%) 61.8 43.4
US population statistics are provided for reference only and are drawn from Census.gov
Overall, the sample contained very few inconsistencies in the validity tests. In the parent sample, 2.3% of respondents failed all of the comprehension questions, 2% always selected the same alternative (either A or B) in the vaccine choice questions, and 28.5% always selected the vaccine with the better level of a single attribute. In the young-adult sample, 4.8% of respondents answered all the comprehension questions incorrectly, 2.1% always selected the same alternative (either A or B) in the vaccine choice questions, and 27.8% always selected the vaccine with the better level of a single attribute.
Vaccine Hesitancy and Pro-Vaccine Correlates
Only about 3% of the sample (69 respondents) indicated strongly vaccine-hesitant preferences by selecting the ‘Neither vaccine’ alternative in every question, while 19% (453 respondents) indicated strongly pro-vaccine preferences by always choosing ‘Both vaccines’. Table 3 contains results of probit analysis that evaluates relationships between respondent demographic characteristics and non-variant responses; while an extensive list of possible covariates was included in the model, only significant covariates are included in Table 3 because of space constraints. Parents under age 65 years, parents whose children were older, and lower-income parents and young adults were more likely to select the ‘Neither vaccine’ alternative in every question. On the other hand, lower-income respondents and those who selected White as their race were also more likely to always select ‘Both vaccines’. Vaccine-hesitant respondents were more likely to say that they did not need a doctor to help make vaccine decisions, while pro-vaccine respondents were more likely to say they did need such help. Finally, in terms of survey mechanics, vaccine-hesitant respondents were more likely to incorrectly answer a quiz question on their understanding of a probability graphic, and pro-vaccine respondents were less likely to rush through the survey in less than 7 min.Table 3 Probit analysis of vaccine-hesitant and pro-vaccine respondents. Statistically significant determinants of likelihood of always choosing the ‘No vaccine’ alternative (vaccine-hesitant, 3% of the sample) or always choosing the ‘Both vaccines’ alternative (pro-vaccine, 19% of the sample) in every question
Variable Vaccine-hesitant Pro-vaccine
Coefficient p value Coefficient p value
Constant − 2.189 0.00 − 1.0331 0.00
Parent 0.732 0.00 0.288 0.00
Children aged < 18 years − 0.380 0.02
Age > 65 years − 0.458 0.01
Income − 0.411 0.00
Income < $70,000 0.170 0.005
Minority − 0.158 0.049
Do not need doctor to help make vaccine decisions 0.331 0.02 − 0.205 0.033
Fail probability quiz 0.365 0.00
Survey duration < 7 min − 0.588 0.007
n = 2386 n = 2386
Latent Classes and Attribute Importance
For subsequent analysis, we dropped the 47 parents and 22 young adults who chose ‘Neither vaccine’ in all choice questions, giving us analysis samples of n = 1138 and n = 1181, respectively. Based on the criteria described above, models with two classes provided the most appropriate fit for the choice data. Estimated class-membership proportions for Class 1 and Class 2 were 65% and 35%, respectively, for parents, and 55% and 45%, respectively, for young adults.
Table 4 compares covariate analysis of latent-class membership probabilities for the parent and young-adult samples. In both samples, respondents who completed the survey in less than 10 min were less likely to be grouped in Class 1. Younger parents and parents with adult children were more likely to be grouped into Class 1. Limited educational attainment and minority status were significantly correlated with Class 1 membership for young adults, but minority status was uncorrelated with Class 1 membership for parents. Those who more frequently chose the ‘Both vaccines’ option were more likely to have Class 1 preferences.Table 4 Covariate analysis of class 1 latent-class membership probabilitiesa
Covariate Parent sample (n = 1138) Young-adult sample (n = 1181)
Coefficient p value Coefficient p value
Age > 55 years − 0.847 0.00 – –
Parent with child aged < 18 years − 0.847 0.00 – –
Minority 0.292 0.22 − 0.692 0.00
High school education or less − 1.598 0.00 − 1.153 0.00
Reported having discussion with doctor about MenB vaccines − 0.775 0.00 − 1.004 0.00
Concerned (4 or more on a 7-point feeling scale ranging from ‘unconcerned’ to ‘angry’) if the doctor does not discuss MenB vaccines 0.380 0.00 0.538 0.00
Accepted specified cost to pay for additional time to discuss the vaccine with the doctor − 0.411 0.00 − 0.165 0.02
Accepted specified cost to pay for MenB vaccine 0.696 0.000 0.481 0.00
Spent less than 10 min taking the survey − 2.034 0.010 − 1.612 0.00
aAll covariates are 0/1 indicator variables
Finally, class membership was also related to respondents’ perception of the value of vaccine information provided by physicians. In both samples, respondents who placed greater value on receiving information about vaccines from their doctor were more likely to have Class 1 preferences. Similarly, respondents who had not discussed a MenB vaccine with their doctors and those who expressed higher concern about physicians not discussing a MenB vaccine were also more likely to have Class 1 preferences. In the young-adult sample, respondents with Class 1 preferences were more likely to agree to pay for more time with their physician to discuss a MenB vaccine.
The two latent classes had distinct preference patterns that were similar between the parent and young-adult samples. Figure 2a and b compare the 2-class relative utility weights and 95% confidence intervals for parent (Fig. 2a) and young-adult (Fig. 2b) samples. These figures compare three disease effects: recover fully at home in 1 week with moderate illness (Home), recover fully in hospital in 2 weeks with serious illness (Hospital), and die in hospital after 2 weeks with serious illness (Death). Three levels—total deafness, lose both legs, and permanent brain damage—are omitted from Fig. 2 due to space constraints; preference weights for all levels are included in ESM Tables S2a and S2b and in Fig. 3. The results reported here were obtained by rescaling the log-odds relative utility weights from each class and population, such that preferences for a 1 in 1 million chance of recovery at home had a weight of zero, and a 1 in 100 chance of death had a weight of 10. All other weights were scaled proportionately in relation to this difference to preserve the relative importance of changes in the attributes. Table 1 in the ESM contains all of the raw coefficient estimates.Fig. 2 a Latent-class estimates, parent sample (95% confidence intervals). Preference estimates for Class 1 incidence preferences are logically ordered with good precision, however Class 2 incidence preferences are not logically ordered and imprecise. Pro-vaccine preferences are much weaker for Class 2. The large negative value for the ‘Neither’ (no vaccine choice) option indicates strong pro-vaccine preferences. The alternative-specific constant for choosing both vaccines in the first question is insignificantly different than choosing one of the two vaccines for both classes. The endpoints for the confidence interval for ‘Both’ in Class 2 is ± 137. b Latent-class estimates, young-adult sample (95% confidence intervals). Results are qualitatively similar to that of the parent sample. Precision of the ‘Both vaccines’ parameter is very poor for both classes. ‘Neither vaccine’ is significant and strongly negative for both classes relative to choosing one of the two vaccines in the first question. The endpoints for the confidence interval for ‘Both’ in Class 2 is ± 177
Fig. 3 a Constant-utility bands for severity-incidence combinations, parent sample Class 1. The charts show bands of similar utility or value of protection. Combination A describes a vaccine for an infection with high incidence and low severity, such as the annual influenza virus. Combination B describes a vaccine for an infection with very low incidence but very serious sequelae. Both A and B lie on the same similar-utility band. Points within bands are not statistically significantly different. b Constant-utility bands for severity-incidence combinations, young-adult sample Class 1
Class 1 estimates for both parent and young-adult samples are well-ordered for severity-incidence interactions. Vaccines that prevent higher-incidence diseases with more severe effects are preferred to vaccines that prevent lower-incidence diseases with less severe effects. Duration of protection, mode of transmission, and cost are relatively unimportant compared with severity-incidence interactions. For example, for young adults evaluating a vaccine against a disease from which most people will recover at home, the importance of obtaining protection against the disease would increase by about 1.89 if the disease incidence increased to 1 in 10,000 from 1 in 1 million. By contrast, the importance of obtaining protection from a disease spread through personal contact increases by 0.72 if the disease was airborne. Thus, young adults considered the importance of the change in incidence from 1 in 1 million to 1 in 10,000 to be 2.6 times more important than the difference between transmission through personal contact and airborne contact. For parents, the same increase in incidence is about 1.35 times more important than airborne contact (weight 1.16 vs. 0.86). For both samples, the importance weight for the ‘Neither vaccine’ is strongly negative, indicating that the mean vaccine shown in the study design was strongly preferred to no vaccine. Estimate precision was similar in both samples for severity-incidence interactions, but parent-sample confidence intervals are much wider for other attributes compared with the very precise young-adult estimates.
Figure 3 provides an alternative way to visualize preferences for vaccines for diseases with varying combinations of severity and incidence, again divided for the parent (Fig. 3a) and young-adult (Fig. 3b) samples with Class 1 preferences. In Fig. 3, disease incidence ranging from lowest to highest is plotted on the vertical axis, while disease severity based on the five qualitative categories included in the survey is plotted on the horizontal axis. Preferences for each combination included in the survey are plotted in the two-dimensional space in a contour map, with less-preferred vaccines (for diseases with low severity and low incidence) closer to the lower left-hand corner and the most-preferred vaccines closer to the upper right-hand corner. Thus, moving progressively to the right or upward indicates higher preference-utility ‘elevations’. Utility weights in this space are grouped into constant-utility curves or bands, which are graded by color and indicate the sets of severity-incidence combinations that are of similar preference utility. While differences in utility levels within each band are not statistically significant, differences in utility levels close to each other in different bands could also be statistically insignificant. For both figures, the bands do not cross, indicating that, given a specific severity, respondents consistently prefer protection against higher-incidence diseases, and given a specific incidence, respondents prefer protection against diseases with more serious long-term effects. The bands also slope downward, indicating that respondents would accept trade-offs involving increases in disease incidence only if they are paired by decreases in disease-outcome severity. However, the bands are steeper for the young-adult sample, indicating they would accept larger increases in incidence for a given reduction in severity than the parent sample. This pattern indicates young-adult respondents were more tolerant of contagion risks than parent respondents.
Point A in each figure corresponds to the utility of a vaccine against a disease with 1 in 100 incidence and an expectation of full recovery after 1 week at home, a profile similar to the seasonal influenza virus. Point B corresponds to the utility of a vaccine against a disease with 1 in 1 million incidence resulting in permanent deafness. For the parent sample, the high-incidence/low-severity vaccine lies on the same constant-utility band as the low-incidence/high-severity vaccine. Points A and B for the young-adult sample have higher utility levels than the corresponding points for the parent sample. For young adults, a vaccine protecting against a condition resulting in deafness lies on a higher constant-utility band than a vaccine protecting against a condition such as the seasonal influenza virus. Several other specific preference-utility values for disease incidence and severity combinations are also included in the figure for reference.
In contrast to the well-ordered Class 1 preferences, Class 2 preferences exhibit unexpected ordering for some severity-incidence combinations and wide confidence intervals for these attributes. For example, for the approximately 45% of young adults with Class 2 preferences, none of the disease severity-incidence combinations are statistically significantly different from one another. Hence, for respondents with Class 2 preferences, we cannot quantify the difference in value for obtaining protection from diseases that result in death and those resulting in full recovery at home, or on diseases that occur in 1 in 100 people and 1 in 1 million. Consequently, it is not useful to display the Class 2 results in a figure analogous to Fig. 3.
The ‘Neither vaccine’ alternative, while still negative, was of a much smaller magnitude in Class 2 compared with Class 1. However, it was not statistically significantly different from zero in any of the models. Interestingly, although the duration, mode, and cost attributes have lower average-preference utility for Class 2 than Class 1, the confidence intervals are generally smaller in Class 1, particularly in the young-adult sample.
Discussion
Policy Implications
The findings from this research suggest three lessons about public preferences for vaccines for low-incidence, severe-outcome diseases in the US, all of which are important for how the ACIP interprets evidence on stakeholders’ perspectives. First, the US public wants vaccines to protect against low-incidence, severe-outcome diseases and values these vaccines at least as much as vaccines against high-incidence but less-severe diseases. This preference-based finding stands in contrast to analyses based on conventional QALY frameworks. For many respondents, vaccinations against severe but low-incidence diseases have a value comparable with vaccines against common but less consequential diseases. One interpretation of this result is that vaccines that protect against low-incidence, severe-outcome diseases provide ‘peace of mind’ benefits that are not captured by standard health-outcome metrics.
Second, our latent-class analysis illustrates the difficulties in evaluating and interpreting preferences among a heterogeneous population. While only a small minority of respondents failed our built-in logical consistency checks, approximately 35–45% of our samples had Class 2 preference patterns, which featured unexpected ordering and imprecise vaccine preferences. This result appears to be consistent with the well-known problematic state of vaccine knowledge and vaccination decision making among a substantial portion of the US public. In contrast, Class 1 preferences indicate that 55–65% of our samples placed a well-defined value on vaccines much larger than is typically indicated in CEA assessments.
Third, our findings suggest that an ACIP recommendation for shared clinical decision making may not be successful, especially for people with Class 2 preferences. The observed response patterns imply that changes in CDC vaccine messaging and shared decision-making approaches may be necessary to help many people make informed vaccination decisions.
Limitations
Hypothetical choices do not have the same emotional and financial consequences as real choices. Thus, there is always potential for hypothetical bias in choice-experiment studies. This study adhered to best practices for limiting hypothetical bias by framing the preference elicitation in a realistic context, defining vaccine attributes carefully, and minimizing the cognitive effort required to evaluate vaccine alternatives.
Because this study was conducted prior to the coronavirus disease 2019 (COVID-19) pandemic and increased awareness of vaccine development, testing, and approval procedures, we must acknowledge the possibility that people’s current attitudes toward vaccines could be different from the attitudes expressed in this survey. Moreover, it is not clear what impact population-wide increases in pandemic-related stress and anxiety, alongside greater awareness of public-health policies and programs, might have on the public’s overall assessment of vaccine-preventable diseases.
Based on general opinion surveys about vaccine attitudes, we expected to find a larger proportion of vaccine-hesitant respondents. While we observed only about 3% of respondents rejected all the vaccine alternatives, we found that about half of both the parent and young-adult samples had implausible, uninformative preferences for vaccine-attribute trade-offs. This result is consistent with much of the population’s known ambiguous attitudes toward vaccines [14–16].
Our sample sizes are considerably larger than most published choice-experiment studies [7, 17]. While our samples were proportionately similar to the general population on several dimensions, members of large consumer panels are not necessarily representative of the general US population. Nevertheless, the large sample sizes facilitated identifying statistically significant personal-characteristic covariates that help explain class-membership probabilities and preference patterns.
Conclusions
This study demonstrates the value that a large sample of respondents places on achieving protection against vaccine-preventable diseases with varying incidence and disease-severity characteristics. It demonstrates that many respondents place considerable value on achieving protection against low-incidence but severe diseases. These population preferences could be relevant for informing vaccine recommendations to better align with the public’s desire to access vaccines against rare but serious diseases.
Supplementary Information
Below is the link to the electronic supplementary material.Appendix A: Pretest Report (DOCX 50 KB)
Appendix B: SAS Code for Experimental Design (DOCX 19 KB)
Appendix C: Adaptation of Sequential Logit (DOCX 18 KB)
Demographics by Soft-Launch Source (DOCX 21 KB)
Vaccine Utility - Parents (DOCX 18 KB)
Vaccine Utility – Young Adults (DOCX 21 KB)
Author Contributions
All authors made substantial contributions to the conception or design of the work; the acquisition, analysis, or interpretation of data; and drafting or revising the manuscript critically for important intellectual content. All authors also provided final approval of the version to be published and agreed to be accountable for all aspects of the work.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Data used in this study can be accessed at https://github.com/ekonom7836/Preference-Research/find/main.
Declarations
Funding
Financial support for this study was provided entirely by a research agreement with Pfizer, Inc. The funding agreement ensured the authors’ independence in designing the study, interpreting the data, and writing and publishing the results.
Conflicts of interest
Amit K. Srivastava and Liping Huan are employed by the sponsor. F. Reed Johnson, Angelyn Fairchild, Dale Whittington, and Juan Marcos Gonzalez report no conflicts of interest.
Ethics Approval
Research protocol Pro00092441 was approved by the Duke University Institutional Review Board.
Consent to participate
The study obtained ethics approval and consent to participate by the Duke University Institutional Review Board.
Consent to publish
Not Applicable. No personal data were collected.
Code availability
Code provided in Appendix B in the supplementary material.
Amit K. Srivastava was employed by Pfizer Vaccines at the time of this study.
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| 36509960 | PMC9744670 | NO-CC CODE | 2022-12-15 00:01:52 | no | Patient. 2022 Dec 13;:1-13 | utf-8 | Patient | 2,022 | 10.1007/s40271-022-00602-x | oa_other |
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Mamm Biol
Mamm Biol
Mammalian Biology = Zeitschrift Fur Saugetierkunde
1616-5047
1618-1476
Springer International Publishing Cham
309
10.1007/s42991-022-00309-4
Review
The value of individual identification in studies of free-living hyenas and aardwolves
Spagnuolo Olivia S. B. [email protected]
1
Lemerle Marie A. [email protected]
2
Holekamp Kay E. [email protected]
1
Wiesel Ingrid [email protected]
2
1 grid.17088.36 0000 0001 2150 1785 Michigan State University, East Lansing, MI 48824 USA
2 Brown Hyena Research Project, Lüderitz, 9000 Namibia
13 12 2022
124
31 12 2020
9 9 2022
© The Author(s) under exclusive licence to Deutsche Gesellschaft für Säugetierkunde 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
From population estimates to social evolution, much of our understanding of the family Hyaenidae is drawn from studies of known individuals. The extant species in this family (spotted hyenas, Crocuta crocuta, brown hyenas, Parahyaena brunnea, striped hyenas, Hyaena hyaena, and aardwolves, Proteles cristata) are behaviorally diverse, presenting an equally diverse set of logistical constraints on capturing and marking individuals. All these species are individually identifiable by their coat patterns, providing a useful alternative to man-made markings. Many studies have demonstrated the utility of this method in answering a wide range of research questions across all four species, with some employing a creative fusion of techniques. Despite its pervasiveness in basic research on hyenas and aardwolves, individual identification has rarely been applied to the conservation and management of these species. We argue that individual identification using naturally occurring markings in applied research could prove immensely helpful, as this could further improve accuracy of density estimates, reveal characteristics of suitable habitat, identify threats to population persistence, and help to identify individual problem animals.
Supplementary Information
The online version contains supplementary material available at 10.1007/s42991-022-00309-4.
Keywords
Aardwolf
Camera traps
Carnivores
Hyena
Individual identification
Mark-recapture
http://dx.doi.org/10.13039/501100008982 National Science Foundation OISE1853934 IOS1755089 Holekamp Kay E. Namdeb Diamond Corporation
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pmcIntroduction
Our understanding of the biology of many mammals, including mammalian carnivores, has been greatly enhanced by studies of individually recognizable animals (Clutton-Brock and Sheldon 2010; Schneider et al. 2019; Karczmarski et al. 2022a, b). Such studies have shed light on demography, natural selection, life histories, ontogeny, social behavior, and intrapopulation variation in diverse species and populations (Clutton-Brock and Sheldon 2010). In free-living populations, however, capturing and marking individuals (Mills 1982a, 1983a, b) may be impractical due to limited funds, difficulty obtaining permits, rarity or elusiveness of subjects, or—in some group-living species—a large number of subjects, making it impractical to capture every individual in the study population. Individual identification using naturally occurring markings is a practical, cheap, and noninvasive alternative to capturing and marking wild animals (Powell and Proulx 2003; Mendoza et al. 2011; Kelly et al. 2012; Schneider et al. 2019). This method has been applied to various mammalian carnivores with unique pelage patterns (Karanth and Nichols 1998; Heilbrun et al. 2003; Harihar et al. 2010). Even in more subtly marked species, individuals can be consistently differentiated using whisker patterns (Anderson et al. 2007; Osterrieder et al. 2015; Elliot and Gopalaswamy 2017), coloration, facial markings, leg and tail markings, body and tail structure or carriage, kinks in tails, ear nicks, or scars (Trolle et al. 2006; Kelly et al. 2008; Sarmento et al. 2009; Zheng et al. 2016). Natural markings are used to identify individual animals both in direct observations (Smith et al. 2017) and during use of camera traps (Dheer et al. 2022).
Studies of individually known members of the family Hyaenidae have proven particularly fruitful. This family contains only four extant species, but these species exhibit impressive diversity in morphology, diet, and social organization. The three bone-cracking hyena species include spotted (Crocuta crocuta), brown (Parahyaena brunnea), and striped (Hyaena hyaena) hyenas. Although spotted hyenas kill most of their own prey, the other two bone-cracking forms live mainly on carrion. In contrast, aardwolves (Proteles cristata) feed almost exclusively on termites. These species span a wide spectrum of social behavior, from aardwolves, which are solitary except when breeding, to spotted hyenas, which sometimes live in the largest groups of any terrestrial carnivore (Green et al. 2018). The diversity within this family makes these species excellent models for basic research. Furthermore, human–hyena conflict and the Near Threatened status of brown and striped hyenas (AbiSaid and Dloniak 2015; Wiesel 2015) suggest that further study of these animals should facilitate their conservation and management.
In this review, we briefly describe the morphology and ecology of each extant species in the family Hyaenidae and describe how best to distinguish individuals based on their unique markings. We then highlight studies of demographic and socioecological processes that illustrate the utility of individual identification in studies of free-living hyaenids. Finally, we discuss previous applied work using individual identification, and identify important gaps in our knowledge of hyaenids that could be filled using the identification methods we describe.
The four extant hyaenid species
Spotted hyenas are large, gregarious carnivores that occur throughout much of sub-Saharan Africa. Adults typically weigh roughly 55.00 kg and stand 0.77–0.80 m tall at the shoulder, with females being about 10% larger than males (Swanson et al. 2013), making spotted hyenas the largest of the extant hyaenids. Their fur ranges in color from sandy to grey or brown, with dark spots on their flanks, backs, rumps, and legs (Holekamp and Kolowski 2009). The spotted hyena is the only extant hyaenid whose post-cranial anatomy is adapted for cursorial hunting of medium- and large-sized herbivores, and 65–95% of their diet consists of prey they kill themselves (Holekamp and Dloniak 2010). Spotted hyenas exhibit social behavior convergent with that of cercopithecine primates. They live in stable, fission–fusion social groups, called “clans,” that may contain up to 126 individuals (Green et al. 2018). Each clan is structured by a linear dominance hierarchy in which adult females outrank most breeding males. Although they are experiencing global decline, spotted hyenas are still abundant throughout sub-Saharan Africa, and are listed as a species of Least Concern by the International Union for Conservation of Nature (IUCN; Bohm and Höner 2015).
Brown hyenas occur in southern Africa, where they are widespread throughout Botswana (Winterbach et al. 2017) and most of Namibia (Wiesel 2015). They also occur in Angola, Zimbabwe, and South Africa. Body size varies regionally, with adults weighing 28.00–47.50 kg, and typically standing around 0.74 (females) or 0.79 (males) m tall at the shoulder (Holekamp and Kolowski 2009). Their long, shaggy fur is dark or reddish brown on their torsos and has a lighter tawny color on their necks and shoulders. The face is covered with short, dark hair, and their front and hind legs are striped. They are opportunistic foragers, feeding mainly on vertebrate remains. Hunting plays a minor role in this species, although brown hyenas living along the southern Namib Desert coast regularly kill Cape fur seal (Arctocephalus pusillus pusillus) pups at mainland seal colonies (Wiesel 2010). Brown hyenas live in small clans of 4 to 14 individuals, within which females sometimes breed cooperatively (Mills 1982b, 1990). Males either remain in their natal clan, disperse to a new clan to breed, or become nomadic breeders. The IUCN lists this species as Near Threatened, with a population estimate of fewer than 10,000 mature individuals (Wiesel 2015).
Striped hyenas have the largest geographic range of the extant hyaenids, stretching from the northwestern coast of Africa and as far south as Tanzania, through the Middle East and the southern Caucasus, and eastward through much of India (AbiSaid and Dloniak 2015) and into Nepal (Bhandari et al. 2020). They are smaller than spotted or brown hyenas, typically weighing 26.00–41.00 kg and standing 0.66–0.75 m tall at the shoulder. Striped hyenas have a somewhat shaggy appearance, a bushy tail, and the most prominent mane of any hyaenid. They have black muzzles, black throat patches, and black or brown stripes on lighter colored fur (Holekamp and Kolowski 2009). These hyenas are omnivorous scavengers that hunt infrequently and opportunistically (Kruuk 1976; Holekamp and Kolowski 2009). Despite their expansive range and ecological importance (Beasley et al. 2015), they remain poorly understood. This void in information is likely due to their low density, nocturnality, elusiveness, the rough terrain they sometimes inhabit, and confusion with spotted hyenas where the two species co-occur (Kruuk 1976; Holekamp and Kolowski 2009). Traditionally, striped hyenas have been considered solitary (Kruuk 1976), but recent research suggests that this is not the case for all populations (Wagner et al. 2008; Califf et al. 2020; Tichon et al. 2020). The striped hyena has been extirpated from many parts of its range, and populations continue to decline globally. Conservation of this Near Threatened species requires further research on its behavior and demography (Mills and Hofer 1998; Holekamp and Kolowski 2009; AbiSaid and Dloniak 2015).
Aardwolves occur in East and southern Africa (Green 2015). As the smallest member of the hyena family, they typically weigh 8.00–12.00 kg and stand 0.45–0.50 m tall at the shoulder (Holekamp and Kolowski 2009). Aardwolves feed predominantly on termites (Trinervitermes spp.; Kruuk and Sands 1972; Koehler and Richardson 1990; Anderson 2013; Green 2015). They are primarily nocturnal and forage alone (Smithers 1983; Koehler and Richardson 1990; Anderson 2013). During the breeding season, mated pairs of aardwolves occupy a territory with their youngest offspring (Koehler and Richardson 1990; Richardson 1991). The conservation status of aardwolves is listed as Least Concern, and their global population is considered stable (Green 2015).
Individual identification by naturally occurring markings
All four hyena species have unique coat patterns that are consistent throughout the animals’ lives. Individuals can be distinguished using these markings and any other unique characteristics, such as scars or ear damage. To avoid misidentification, reference photographs must be maintained for each study population, preferably including high-quality reference photos of the left and right sides of each animal, as the markings on the two sides differ. Such images can be obtained easily by taking video footage of both sides of an individual animal as it moves around, freezing the frames in which left- and right-side markings are clearest, and printing those images. If photographs of each individual’s left and right side cannot be matched for any reason, two separate sets of records should be kept, one for the right-side images and one for left-side images (Karanth 1995), and they should be analyzed separately (Gupta et al. 2009; Harihar et al. 2010; Kent and Hill 2013; Dheer et al. 2022). Identification relies on distinctive patterning of the coat in all four species, so images need not be in color; in fact, converting photographs to black and white and increasing the contrast may be helpful for maximizing clarity of coat patterns. Images may be annotated with other useful, unique physical characteristics. These databases require upkeep as new individuals are born or immigrate and existing hyenas develop new scars or injuries, emigrate, or die. Digital reference photographs of known individuals may be most useful for identifying animals in camera trap images, as they allow the observer to zoom in on individual body parts (Henschel and Ray 2003). Although future technological advances may lead to digital devices that are practical for field identification, in general, hard copies of reference photos are currently necessary for identification during direct observations. Hard copies of reference photos also serve as invaluable backup records. If time allows, photographs can be taken of individuals in the field and immediately compared to the reference photos to confirm identities. It is important that the observer uses spots or stripes from multiple body parts whenever possible to confirm an identity. Before they can identify individuals without their work being checked by an expert, observers need a substantial period of training. An expert should observe their work and decide when new observers are ready to work independently. Ideally, two or more independent observers will confirm each identity.
Spotted hyenas
Long-term (1979 to present, Holekamp and Strauss 2020; 1987 to present, Hofer and East 1993) and shorter term (Henschel and Skinner 1990) studies of spotted hyenas demand that observers be able to recognize each hyena individually based on its unique spot patterns, ear damage, and other permanent markings (e.g., missing tail, significant scars). Fortunately, except after mud-bathing, individuals are recognizable, as they have unique, permanent spot patterns that vary among individuals (Fig. 1). The Mara Hyena Project (Kenya) maintains a photo album for each of its study clans showing left- and right-side spot patterns of each clan member (Fig. 2a). Photo albums for all nearby study clans are also carried in each research vehicle during data collection. Position and shape of ear damage (e.g., cut, notch, missing ear; Fig. 2b), when present, also aids in individual identification, but examining spot patterns in reference photos is critical to confirm identities, even for highly experienced observers. Different age-sex classes (i.e., cub, subadult, adult female, adult male) have different body-shape profiles (Johnson-Ulrich et al. 2018), so organizing photos by age-sex class reduces the number of spot patterns one must check for confirmation. Further dividing adult hyenas into residents and “aliens” can further facilitate the process of individual identification. Hyenas that are seen passing through the territory of a study hyena clan that are not members of that particular clan are considered “aliens”; these are often dispersing males. Thus, we recommend organizing each photo album into five sections: cubs, subadults, resident adult females, resident adult males, and “aliens”.Fig. 1 Photographs of two different hyenas in the Maasai Mara National Reserve, captured on different occasions. These photographs were all taken manually by observers in the field, using digital cameras. Contrast, brightness, and sharpness were edited to enhance visibility of spots. Shown here are reference photographs of the right (a, c) and left (b, d) sides of a female hyena named Pike. Spotted hyenas’ spots are not bilaterally symmetrical, so reference photographs should ideally show both sides. Her identity may be confirmed by comparison of her spot patterns on her right and/or left shoulder(s), flank(s), hip(s), and legs. Spots from multiple body parts should be used, but the specific parts used may depend on visibility (e.g., whether grass is in the way, whether the hyena is muddy, or depending on the animal’s posture or the angle from which the animal is seen). The right (e) and left (f) sides of a different hyena, a male named Kaikura, are quite distinct from Pike’s
Fig. 2 a A photo album of one of the Mara Hyena Project’s study clans in the Mara Triangle, Kenya. The photo album is organized by age–sex class. For each subject, photos of the left and right sides are shown together and oriented in the same fashion to facilitate comparison across subjects. These photos are updated throughout the hyenas’ lifetimes, and each photo is marked with the date taken. Photos are edited to increase contrast, so that spots are clearly visible. The position and shape of each hyena’s ear damage, if present, are noted on reference photos. Whereas a hyena’s spots never change, ear damage often varies over a hyena’s lifetime. Therefore, ear damage should be used to narrow the list of likely candidates, but final confirmation should always rely on examination of spot patterns. b Ears of eight different spotted hyenas in the Mara Triangle, Kenya. Ear damage is acquired while fighting with conspecifics or other large carnivores. Clearly, ear damage among individuals can be quite variable and distinctive, from a small nick to a missing ear. Photo credit for (a) to Erin Person
Spotted hyena cubs are seldom seen aboveground before they are a few weeks old. They are born with solid dark brown or black natal coats, and, upon first seeing them, their age can be estimated to within 7 days based on their pelage, size, and other features (Pournelle 1965; Holekamp et al. 1996). Although cubs are often difficult to tell apart before replacement of the natal coat, this can sometimes be done based on slight differences in fur color, size differences, patterns of abrasion on the skin covering the carpal bones, small nicks in the ears (often inflicted during the early fighting between litter-mates; Frank et al. 1991; Fig. 3), and differential patterns of scarring on cubs’ backs, necks, and shoulders. Although female spotted hyenas have male-like genitalia, one can determine the sex of each cub older than a few weeks by using the dimorphic morphology of the glans of the erect phallus (Frank et al. 1990; Drea et al. 1999; Cunha et al. 2003; McCormick et al. 2021; Dheer et al. 2022). Cubs change somewhat in appearance as they grow, mainly due to having fur of variable length and texture between consecutive molts, but, once the spot pattern appears, it never changes. The spots typically begin to fade by the time a hyena reaches its mid-teens and continue fading as the hyena ages. The oldest hyenas recorded by the Mara Hyena Project were 26 years old at the time of their deaths.Fig. 3 Distinct ear damage on a spotted hyena cub with its natal coat. This cub, Black Bear, was the only cub at this communal den with a slit on this part of its ear (indicated by white arrow), so he could be clearly distinguished from the other cubs, including his littermate. This allowed researchers to identify Black Bear before he shed his black natal coat and developed spots
There is a lack of consistent criteria to define age-sex classes of spotted hyenas, and definitions of the age classes used are project-specific (e.g., Trinkel et al. 2004; Höner et al. 2005; Belton et al. 2018). For example, Holekamp et al. (2012) consider hyenas to be subadults once they are no longer dependent on the communal den, which typically happens at 9–12 months of age, whereas Kruuk (1972) defines subadults based on a specific range of tooth-wear values. Similarly, females may be considered adults when they are first known to conceive litters, when their teeth are worn down to a certain degree, or when they reach a specific age.
Brown hyenas
Before the advances of digital photography and camera trap technologies, triangular ear notches were cut into brown hyenas’ ears for quick individual identification (Mills 1982a, 1983a, b). However, because man-made and natural ear notches may change over time (Fig. 4), they are not a reliable stand-alone method of identification. Instead, the Brown Hyena Research Project (Namibia) distinguishes individuals by the unique stripe patterns on their fore- and hindlegs. Brown hyena cubs have no solid natal coat, and their leg stripes are faintly visible from birth, and become clearer as the hyenas grow. These stripes are permanent over the course of a hyena’s lifetime (Fig. 5), but their appearance is greatly influenced by the viewing angle (Fig. 6). The stripes are often indistinct, due to the small and round surface area of the legs, and the sometimes-changing directional position of the hair. Therefore, the combined use of stripes on the anterior, lateral, and medial surfaces of the forelegs, stripes on the lateral surfaces of the hindlegs, and any ear notches result in the highest likelihood of correct identification. Photographs of the anterior surfaces of the forelegs as well as the left and right sides of the body should be maintained for identification purposes. Unlike spotted hyenas, female brown hyenas do not have masculinized genitalia, but external morphology is otherwise similar between sexes and they are generally considered to be sexually monomorphic (Mills 1982a; Butler-Valverde et al. 2015; Dheer et al. 2022). As a result, it is generally not possible to distinguish between males and females in the field without capture.Fig. 4 A natural ear notch on the right ear of the same brown hyena at the ages of five (a) and 15 years (b). The shape of the original notch has changed, and new smaller notches have appeared over time
Fig. 5 The top row (a–c) shows the anterior surfaces of the forelegs of a male brown hyena named Kai-Alex, and the bottom row (d–f) shows those of a second male, Lloyd. Kai-Alex’s leg stripes are the same at six months (a) and 2.5 years of age (right foreleg, b; left foreleg, c). Similarly, Lloyd’s foreleg stripes are consistent from cubhood (d) to adulthood (right foreleg, e; left foreleg, f). Photos of leg stripes at 2.5 years of age were taken while hyenas were anesthetized
Fig. 6 A single female brown hyena, Alaika, is shown at the ages of five, eight, and 12 years. The first frame (a) shows the lateral view of Alaika’s right foreleg at five (left), eight (center), and 12 (right) years of age. We can see that the stripes are consistent over her lifetime. In the second frame (b), we see that the anterior view of the right foreleg looks quite different from the lateral view of the same leg, but, again, the stripes are consistent throughout her lifetime (5 years of age, left; 8 years, center; 12 years, right). Photographs in a and b were taken while Alaika was anesthetized for handling on three different occasions. c Remote camera trap images of Alaika with sufficient clarity to identify her using lateral stripes of right foreleg (left, center), and insufficient clarity for confident identification (right)
Striped hyenas
Striped hyenas have vertical stripes on their flanks, and diagonal and horizontal stripes on all four limbs (Holekamp and Kolowski 2009). They have no natal coat and, instead, are born sporting clear, conspicuous stripes (Rieger 1979; Bothma and Walker 1999). The position and shape of these stripes are consistent throughout a hyena’s lifetime, although they may become distorted with seasonal variation in coat length or fade slightly with age (Rieger 1979; Jhala 2013). Striped hyenas can be individually identified by the patterns of stripes and dots on their shoulders, flanks, hips, forelimbs, and hindlimbs, as well as by any other conspicuous features (e.g., ear notches, scars; Fig. 7). Stripes on the hind- (hip and upper hindleg) and forequarters (shoulder and foreleg) are the most useful, as they are prominent and vary between individuals (Singh 2008; Harihar et al. 2010), while stripes on the flank may be distorted by shaggy fur. One should use stripe patterns from multiple body parts to confirm individual identification (Gupta et al. 2009). Determination of sex is difficult without capture (Dheer et al. 2022) but may be possible for females that have dependent cubs, for example, if they are visibly lactating or being followed by their cubs (Alam 2011; Tichon et al. 2020).Fig. 7 Left sides of two known striped hyenas in a population near Shompole, Kenya. a, b Two images of the same individual, male M113, captured on different occasions. M113’s mane is erect in a, revealing some stripes on his left flank, but is not erect in b, thus partially covering and distorting these stripes. The stripes and spots on the fore- and hindquarters are more useful than the flanks or ears for identification of striped hyenas. c, d Two images of a second individual, male M114, captured on different occasions. In (c), M114’s legs are partially obscured by grass. Leg stripes may certainly be useful when visible, but they are more likely to be out of view than the shoulders and hips, which also have similarly variable and prominent markings. In this population, many hyenas have a single solid stripe over a double stripe on their left hip (white boxes; a, c). As an observer becomes more experienced identifying subjects in a given population, they should recognize interindividual similarities such as this and focus on more variable features (e.g., left thigh stripes, shoulder stripes). Therefore, slight similarities among hyenas should not necessarily lead to a reduction in accuracy, particularly if observers use patterns from multiple body parts to confirm each identification. Images captured by handheld digital camera (a) and remote digital camera traps (b–d) by Aaron Wagner
Aardwolves
The coats of aardwolves are yellowish in color and the face and throat are grayer than the rest of the body. They have three or more vertical black stripes on each flank, and one or two diagonal stripes across their fore- and hindquarters. Irregular horizontal stripes run across the legs, and are darkest near their feet. Stripes and spots are sometimes present on the neck (Smithers 1983; Koehler and Richardson 1990). Individuals can be distinguished using their stripe and spot patterns (Richardson 1991; Silwa 1996; O’Brien and Kinnaird 2011; Rich et al. 2019; Fig. 8). Coat patterns can also be paired with natural scars and ear nicks, if present (Richardson 1991; Silwa 1996). Natural features have also been supplemented with reflective collars and man-made ear notches to aid in recognition (Richardson 1987a, b, 1990, 1991; Silwa 1996). Visual determination of sex is unlikely to be feasible without capture (Dheer et al. 2022).Fig. 8 Incidental photographic captures of aardwolves by remote camera traps used by the Brown Hyena Research Project in Namibia. a, b Two captures of the same individual, viewed from different angles. c A second individual. These two individuals can be easily distinguished by the stripes on their shoulders. While individuals can often be recognized even when viewed from different angles, applying bait or taking advantage of natural or man-made trails can help position animals relative to the camera lens for optimal visibility
Past and present use in basic research
Our knowledge of the ecology of the four hyaenid species has been acquired, in large part, from studies taking advantage of natural markings. Here we describe findings from selected studies that have used this method to address a wide array of research questions about hyaenids. This body of literature is vast, particularly for spotted hyenas, and this is by no means intended to represent a comprehensive overview of the literature. Rather, the studies highlighted here are meant to serve as examples of the diversity of past and present applications of this method and to demonstrate its value in basic research.
Individual recognition of wild hyaenids has greatly improved the accuracy with which we can assess their demography. Most large carnivores, including hyaenids, are rare, elusive, primarily nocturnal, or maintain large home ranges, making them difficult to detect (Cozzi et al. 2013; Chutipong et al. 2014; Green et al. 2020). Low detection probability renders common methods for estimating density of large terrestrial mammals, such as aerial transects and line surveys, inappropriate for these carnivores (Cozzi et al. 2013). Instead, density estimates for some large carnivores were historically based on call-in (also known as call-up) station surveys and sign surveys (most commonly track counts), which are demonstrably unreliable (Karanth and Nichols 1998; Kelly et al. 2012; Vissia et al. 2021). Photographic capture–recapture analyses of individually identifiable animals in camera trap images represents a substantial methodological advance over call-in station and sign surveys. Since its first application to estimating tiger (Panthera tigris) abundance and density in India (Karanth 1995; Karanth and Nichols 1998), photographic capture–recapture has emerged as a powerful method for quantifying population characteristics of elusive carnivores (Treves et al. 2010; Kelly et al. 2012; Johansson et al. 2020). Camera traps were deployed in the field by 2007 for brown hyenas (Thorn et al. 2009), 2007–2008 for striped hyenas (Gupta et al. 2009; Harihar et al. 2010; Singh et al. 2010; Athreya et al. 2013), and 2008 for aardwolves (O’Brien and Kinnaird 2011). Photographic capture–recapture has been used to estimate the density of spotted hyenas in many countries throughout their geographic range, such as Congo (Henschel et al. 2014; Bohm 2015), Uganda (Braczkowski et al. 2022), Kenya (O’Brien and Kinnaird 2011), Botswana (Rich et al. 2019; Vitale et al. 2020), Namibia (Stratford et al. 2020), and South Africa (de Blocq 2014). In rare cases in which all study animals were known from extensive long-term direct observations, researchers derived precise counts of spotted hyenas within their study area (rather than using capture–recapture methods to estimate abundance; Watts and Holekamp 2009; Green et al. 2018), but extensive direct observations yield a better return-on-investment for behavioral studies than for population estimation (de Blocq 2014). In addition to population size, studies of known individuals have yielded estimates of other demographic parameters, such as population growth rate (Benhaiem et al. 2018; Green et al. 2018; Mandal 2018), mortality rate (White 2005; Watts and Holekamp 2009; Höner et al. 2012; Mandal 2018), birth rate (Holekamp and Smale 1995; Watts and Holekamp 2009), and sex ratio (Holekamp and Smale 1995).
Incorporation of environmental data into models of spatial or temporal variation in demographic parameters can reveal processes underlying population ecology. For example, the past decade has revealed several ecological correlates of striped hyena population characteristics. Singh et al. (2010, 2014) found that, unlike in other parts of their geographic range, striped hyenas in Rajasthan, India occurred at higher densities closer to human settlements than farther away. They posited that this high density was supported by the availability of unexploited livestock carcasses near settlements. They also found rugged terrain and forest cover to be important components of suitable habitats for striped hyenas in India, likely because they provide undisturbed den sites and daytime refugia where hyenas can rest undetected by humans and domestic dogs (Singh et al. 2010, 2014). In another Indian population of striped hyenas, vehicular traffic regulation had tremendous effects on rates of survival and population growth (Mandal 2018).
Studies of spatial and temporal variation in population size have aimed to illuminate ecological drivers of demography in spotted hyenas as well. In the Maasai Mara National Reserve, Kenya, the Talek hyena clan, which became known as the Talek West clan after a permanent clan fission event in 2000, has been studied from 1988 to present. Observers know each hyena by its unique natural markings and opportunistically collect biological samples (for genetic, dietary, hormonal, and other analyses) and fit hyenas with collars (VHF and/or GPS). The size of the Talek clan remained remarkably stable between 1989 and 1995 (Fig. 9; Green et al. 2018), given that outbreaks of rabies (1989–1991) and canine distemper (1994–1995) decimated sympatric populations of African wild dogs (Lycaon pictus; Macdonald 1992; Alexander and Appel 1994; Kat et al. 1995) and lions (Panthera leo; Roelke-Parker et al. 1996; Kock et al. 1998), respectively. The slight reduction in hyena clan size in 1989 (Fig. 9; Green et al. 2018) was due to emigration rather than increased mortality. This is consistent with previous findings documenting strong resistance of spotted hyenas to diseases that substantially increase mortality among sympatric carnivore species (Alexander et al., 2015; East et al. 2001; 2004; Watts and Holekamp 2009). However, disease-induced mortality has certainly been recorded for spotted hyenas (Roelke-Parker et al. 1996), including a Streptococcus outbreak that correlated with a 78% increase in mortality and slight population decline for 2 years in a spotted hyena population in the Ngorongoro Crater, Tanzania (Höner et al. 2006; 2012). Trends in the size of the Talek West clan (Kenya) between 2008 and 2013 reflected the top-down effects of human disturbance on spotted hyenas. During this time period (2008–2013), livestock grazing inside the Reserve increased more than sixfold, resulting in significantly fewer sightings of lions, which are the top competitor and mortality source of spotted hyenas, after humans. Meanwhile, the Talek West clan increased in size by 95%, eventually reaching 126 individuals and making it the largest spotted hyena clan ever documented (Fig. 9; Green et al. 2018).Fig. 9 Variation over time in the sizes of six study clans in the Maasai Mara National Reserve, Kenya. For each time point, the annual mean clan size is shown (with standard error bars when multiple population counts were performed within the given year). Data for each of six study clans, represented by symbols indicated in the key at the top left, were included from the first year each was studied through 2013. The Talek West clan split into two daughter clans in both 1989 and 2000, indicated by horizontal black bars over the data points. Each of these two clan fissions resulted in a reduction in size of the parent clan, as a subset of this clan’s members left to form a new clan in each case.
Reproduced from Green et al. (2018) with permission from Biodiversity and Conservation
Several studies have investigated ecological correlates of brown hyena density. The highest published densities to date were found in enclosed reserves (Welch and Parker 2016; Edwards et al. 2019), but a substantial proportion of the global population may live outside of protected areas (Kent and Hill 2013). Some studies have documented suppression of brown hyena density by sympatric apex carnivores (e.g., spotted hyenas) through competition (Williams et al. 2021), while others have found brown hyenas and apex carnivores to co-occur at high densities. Co-occurrence could be due to high prey density and divergent foraging strategies (hunting vs. scavenging; Vissia et al. 2021), or because the hunting activity of apex predators creates additional scavenging opportunities for brown hyenas (Yarnell et al. 2013). More work is needed to disentangle the environmental drivers of brown hyena density.
Behavioral studies of individually recognizable hyaenas have allowed researchers to investigate dispersal as well as its potential functions. Spotted hyenas exhibit male-biased dispersal (Höner et al. 2007), but dispersal processes and patterns may vary in different environments. In the Maasai Mara National Reserve, Kenya, most males disperse to new clans from their natal ones, and dispersers seem to experience greater mortality than non-dispersers (Smale et al. 1997), but also more mating opportunities. The reproductive success was compared between philopatric males (i.e., adult natal males who had not yet dispersed) and immigrant males by pairing observational data with genetic samples of known individuals from this study population (Engh et al. 2002; Van Horn et al. 2004; Watts et al. 2011). Engh et al. (2002) reported that, although 20% of the adult males in their study clan were philopatric males, they sired only 3% of cubs born. Thus, the immigrant males had much higher reproductive success than philopatric males who had not dispersed. Engh et al. (2002) also found that immigrant males’ reproductive success increased with their length of tenure within the new clan. However, spotted hyenas in the Ngorongoro Crater, Tanzania, exhibited quite a different pattern of dispersal. While the majority of males there dispersed, dispersers and philopatric adult males distributed themselves similarly across clans, electing to join clans with the highest number of potential mates, and attained similar fitness (Davidian et al. 2016). The difference in patterns between these two study sites may reflect either variation in constraints on dispersal or variation in the underlying processes of males’ decisions to disperse or not, but further work on known individuals using consistent methodology across study sites is needed to address these hypotheses (Davidian et al. 2016). Collectively, studies of individually recognizable spotted hyenas have revealed that female mate choice drives male-biased dispersal (Smale et al. 1997; Engh et al. 2002; East et al. 2003; Höner et al. 2007; Davidian et al. 2016).
Striped hyenas also seem to be plastic in their dispersal behavior. Califf et al. (2020) compared space use of known individuals between populations of striped hyenas in central (Laikipia) and southern Kenya (Shompole). Whereas food resources in Laikipia were relatively scarce, they were plentiful in Shompole. Striped hyenas in these two populations showed very different dispersal patterns, with Laikipia females dispersing (Califf et al. 2020), while Shompole females were philopatric (Califf et al. 2020). Females in central Laikipia may have dispersed to avoid competing with close kin for food, whereas the high density of prey in Shompole allowed females to remain near their natal home range (Califf et al. 2020).
Individual identification is particularly critical in studies of social behavior (spotted hyenas, Frank 1986; brown hyenas, Mills 1983a; striped hyenas, Califf et al. 2020; aardwolves, Richardson 1987b, 1991). Repeated behavioral observations of individually recognizable spotted hyenas allow researchers to determine each individual’s precise social rank in its clan, and to track ontogenetic changes in individuals’ social ranks (Smale et al. 1993; Strauss and Holekamp 2019a). Like many juvenile primates, young spotted hyenas learn their ranks in the clan’s dominance hierarchy early in life through a process known as “maternal rank inheritance,” where they acquire ranks immediately below those of their mothers, and above those of their older siblings (Holekamp and Smale 1991; Engh et al. 2000). Despite variability in the timing of rank acquisition among juveniles, most young hyenas come to attain the precise rank predicted by the rules of maternal rank inheritance. Nevertheless, transient variation in early-life rank acquisition is associated with long-term fitness consequences; juveniles that “underperformed” at acquiring their expected ranks show reduced survival and lower lifetime reproductive success than better performing peers, and this relationship was independent of both maternal rank and rank achieved in adulthood (Strauss et al. 2020). In adulthood, rank changes often occur due to passive processes (e.g., births, emigration), but, on rare occasions, they arise from active processes (e.g., rank reversals; Strauss and Holekamp 2019b). That is, individual adult females who repeatedly form coalitions with their top allies may improve their position in the clan’s hierarchy, suggesting that social alliances facilitate revolutionary social change. Using lifetime reproductive success as a fitness measure, Strauss and Holekamp (2019b) demonstrated that these status changes can have major fitness consequences. Furthermore, these fitness consequences may increase over multiple generations (Fig. 10), as small differences in social rank become amplified over time. Thus, knowing each hyena individually allows investigation of rank changes within individuals’ lifetimes, as well as the fitness consequences that unfold over many generations.Fig. 10 Representation among adult female spotted hyenas of the Talek clan at decade-long intervals (Holekamp and Strauss 2020) of descendants of the original 19 adult females studied by Frank (1983).
Reproduced from Holekamp and Strauss (2020) with permission from Integrative and Comparative Biology
Camera trapping has scarcely been used to study spotted hyena sociality, but a recent pioneering study (Stratford et al. 2020) suggests that camera traps can be used to shed light on the diversity in group composition and dynamics within this species. Clan size of spotted hyenas is highly variable, ranging from six to over a hundred individuals (Kruuk 1972; Green et al. 2018), depending on environmental factors (Stratford et al. 2020). Extensive direct observations have been used to study the social structures of several large clans of spotted hyenas in grassland ecosystems (Hofer and East 1993; Holekamp and Strauss 2020), where relatively high visibility makes such observations possible. However, direct observations are challenging in dense forests and rugged terrain, so little is known about the social structure of spotted hyenas living in smaller clans in these environments (Stratford et al. 2020). Stratford et al. (2020) demonstrated the utility of camera traps to fill this gap in knowledge using individual identification. They deployed camera traps at waterholes in a Namibian game reserve to capture images of resident hyenas. They used the photographic captures to estimate clan size, assign clan membership, and estimate individuals’ connectedness within their clan (Stratford et al. 2020).
Studies of known individual striped hyenas have recently revealed that these animals are not strictly solitary, as previously thought, and that their social behavior varies greatly among populations under different ecological conditions. For example, Califf et al. (2020) found that females in the resource-rich Shompole region exhibited high home range overlap, particularly between kin, whereas those in the resource-poor Laikipia region exhibited no home range overlap. In the Laikipia population, most females’ territories were occupied by at least one male (Wagner et al. 2008). In fact, although striped hyenas typically forage solitarily, many studies have observed social aggregations (Wagner 2006; Tichon et al. 2020), particularly at active dens. Alam (2011) observed groups of three to eight striped hyenas gathering at a single den, and cubs from previous litters often helping to rear their younger siblings, sometimes even provisioning them with food (Alam 2011; Mandal 2018). Recently, den-sharing by a pair of closely related female striped hyenas was documented in Shompole (Spagnuolo 2016; Califf et al. 2020).
Future directions in basic research
There are countless potential future directions for the role of individual identification in basic research on wild hyenas and aardwolves. Camera traps could be used to expand our knowledge of brown hyenas, striped hyenas, and aardwolves, as well as spotted hyenas inhabiting dense forests and rugged terrain; these are currently poorly understood, especially compared to our knowledge base about the spotted hyena populations inhabiting grassland ecosystems (Dheer et al. 2022). For example, camera traps can be effective at collecting data on the two most elusive hyaenids, striped hyenas and aardwolves, the basic biology of which remain poorly understood. Striped hyenas and aardwolves are nocturnal, persist at low densities, and inhabit rugged terrain, making them difficult to detect. In areas thought to be occupied by residents of these species—based on reported sightings, presence of spoor or scat, or by-catch data from camera trap studies of other species—camera traps can be strategically placed to capture images of striped hyenas or aardwolves (Schuette et al. 2013). That is, camera traps can be systematically distributed on a grid (optionally baited with an attractant) or placed at points of interest, such as waterholes, artificial or natural trails, known dens, or locations where spoor, scat, or direct sightings have been reported recently. If sufficient data can be obtained, then density, space use, movement, and activity patterns could be assessed. For striped hyenas, if the goal is to investigate social group size and composition, fission–fusion dynamics, or social networks, camera traps will likely need to be stationed at active dens, because this species typically forages solitarily but sometimes convenes at dens. These camera traps should be equipped to capture short videos, because higher quality behavioral data can be extracted from videos than from still images alone.
For all four hyaenid species, more work is needed to delineate ecological drivers of demography and behavior. Studies should collectively cover the diversity of habitats and geographic range of each species. We recommend camera traps for data collection, as these can be used even for elusive populations in dense vegetative cover or rough terrain (Treves et al. 2010; Kelly et al. 2012; Johansson et al. 2020). Similar methods must be used across different studies, so that the findings can be compared or, ideally, eventually incorporated into meta-analyses. These methods can be adapted as needed for the given species or study area, or to meet additional objectives of the research project.
This review presents examples of studies of known individual hyaenids across diverse disciplines, and the possible future directions are equally diverse. We presented several examples of interesting avenues for future research, but the possibilities certainly are not limited to those presented here. Hyena biologists with research foci other than those touched on herein should certainly seek applications that fit their own area of research in the literature, or consider new applications to their interests.
Past and present use in conservation and management
Individual identification of hyaenids facilitates research that informs conservation and management of free-living populations. First, individual identification has been employed to develop methods for density estimation that are far superior to traditional methods (Karanth and Nichols 1998; Treves et al. 2010; Kelly et al. 2012; Green et al. 2020; Vissia et al. 2021). Population density is critical information needed for wildlife conservation (Rich et al. 2019), and the IUCN has identified estimation of population size as a top research priority for conservation of all four hyaenid species (AbiSaid and Dloniak 2015; Bohm and Höner 2015; Green 2015; Wiesel 2015). Photographic capture–recapture methods have been used to estimate density of hyaenid populations, even for rare or elusive hyaenids (O’Brien and Kinnaird 2011; Alam et al. 2015; Edwards et al. 2019; Vitale et al. 2020; Braczkowski et al. 2022) and those occupying areas only accessible to researchers on foot (Henschel et al. 2014). Accurate estimates of density are important as this allows for better estimation of global population size and the designation of appropriate conservation status (Akçakaya et al. 2006).
Second, information on hyaenids’ social systems gleaned from studies of known individuals may also be useful in conservation planning. Camera trap (Mandal 2018; Tichon et al. 2020) and observational studies (Frank 1986) form the basis of much of our understanding of social grouping, which may inform density estimation. This body of research has also provided evidence of cooperative breeding in brown hyenas (Mills 1990) and, more recently, in striped hyenas (Alam 2011; Spagnuolo 2016; Mandal 2018; Califf et al. 2020). This knowledge may help to predict how reduced social group sizes (resulting from declines in population density) may affect reproductive success in cooperatively breeding populations (van der Meer et al. 2013; Tichon et al. 2020).
Our knowledge of population connectivity has benefited from direct observations of spotted hyenas bearing unique natural markings, sometimes paired with complementary data from radio collars, GPS collars, or genetic samples. The resultant findings have illuminated patterns of space use and movement, including natal dispersal (Smale et al., 1997; Boydston et al. 2005), and reproductive success in spotted hyenas (Engh et al. 2002; Watts et al. 2011). Gene flow among spotted hyena clans may have important implications for metapopulation persistence (McCullough 1996; Hanski and Simberloff 1997; Dolrenry et al. 2014).
Finally, individual identification of hyaenids can be used to investigate their role within the ecosystem, to the benefit of multiple species. Ongoing research into predictors of demographic parameters identifies components of suitable habitat and threats to hyaenid population persistence (Singh et al. 2010, 2014; Mandal 2018), which may be directly targeted by conservation efforts. Camera traps can be used to monitor multiple species within the same study area (Kelly et al. 2012; Green et al. 2020). Illumination of the dynamics within large carnivore guilds, as well as the ecological relationships among carnivores and their wild and domestic prey (Green et al. 2018), may enable scientists and practitioners to foresee the consequences of changes within one species or trophic level for other sympatric species. Spotted hyena movement may also shed light on impending shifts in the sympatric large carnivore community; Green et al. (2019) found that, within spotted hyena territories, the areas frequented by low-ranking (rather than high-ranking) hyenas and in which hyenas moved at the highest speeds exhibited declines in carnivore species richness in the following months. The spatial resolution of this analysis was small (200 × 200 m cells), much smaller than a large carnivore’s home range, so this may reflect changes in space use by sympatric carnivores rather than their density in the study area. More research is needed to explore this relationship, to unravel the underlying mechanisms, and to determine appropriate applications to conservation and management.
Future directions in conservation and management
Many practical applications of individual identification of hyaenids remain unexplored. One potential application is the identification of population sinks. Source–sink theory posits that average fitness varies across subpopulations within a metapopulation due to variable habitat quality. Subpopulations inhabiting patches of high-quality habitat (source populations) are expected to experience high fitness, thus producing a surplus of individuals, while subpopulations inhabiting poor-quality habitats (sink populations) experience low fitness, with mortality exceeding local recruitment, resulting in a population deficit (Pulliam 1988; Kristan 2003; van der Meer et al. 2015; Kelt et al. 2019). Population sinks are maintained by immigration from source populations (Pulliam 1988). A common example of source-sink dynamics in large carnivores is edge effects on populations in protected areas; that is, conflict with humans along the boundaries of protected areas often turns border areas into population sinks, with populations in core areas acting as sources (Woodroffe and Ginsberg 1998; Balme et al. 2010). Knowledge of edge effects have been used to improve conservation and management of leopards in South Africa, potentially to the benefit of other carnivores, including spotted hyenas (Balme et al. 2010). Several studies have found evidence of edge effects on probability of population persistence (Woodroffe and Ginsberg 1998) and mortality (Newmark 2008; Pangle and Holekamp 2010) of spotted hyenas, but there is still much work to do in this area.
More urgently, we encourage researchers to take advantage of hyaenids’ unique natural markings to identify ecological traps. An ecological trap represents an extreme case of a population sink, in which the animals actually prefer the sink to the source area (Gates and Gysel 1978; Delibes et al. 2001; Donovan and Thompson 2001). Under classical source-sink theory, it is assumed that animals can accurately assess habitat quality and therefore prefer source habitat, only immigrating to sink habitat when the source habitat is already occupied. When vacancies become available in the source area, individuals should emigrate from the sink to the source (Kristan 2003; Kelt et al. 2019). Through continuous density-dependent immigration, sources and sinks can persist. In fact, sink patches may contribute to the persistence of the metapopulation as a whole (Pulliam 1988; Howe et al. 1991; Kelt et al. 2019). However, when environmental cues are uncoupled from true habitat quality—most often through anthropogenic disturbance—a population sink may become more attractive to animals than nearby source areas, representing an ecological trap (Gates and Gysel 1978; Delibes et al. 2001; Donovan and Thompson 2001). Elevated mortality rates in ecological traps create vacancies that invite immigration from nearby source populations, creating a “vacuum effect” that can lead to extirpation of the entire metapopulation over time (Balme et al. 2010). Occupancy and density data alone are insufficient to identify population sinks and ecological traps (Kelt et al. 2019). Rather, the relationship between habitat preference and habitat quality must be delineated, for example, using data on fecundity, mortality, and dispersal over time (Pulliam 1988; Kelt et al. 2019). Empirical evidence of ecological traps has been found for other large carnivores (van der Meer et al. 2013, 2015; Lamb et al. 2017), but we are unaware of any research on ecological traps for hyaenids specifically. In the face of continuing anthropogenic change, ecological traps may become increasingly widespread threats to the persistence of large carnivore populations (Balme et al. 2010). This could certainly be the case for hyenas, which could potentially be attracted to human settlements (e.g., by livestock, crops, or refuse; Kruuk 1976; Kolowski and Holekamp 2008; Kissui et al. 2019). Conservation planning should incorporate identification of and differentiation between conventional population sinks and ecological traps (van der Meer et al. 2015).
Increasing anthropogenic disturbance presents many natural opportunities to assess the responses of hyaenids to human activity. Monitoring efforts should be initiated in areas subject to imminent increases in anthropogenic activity, such as livestock grazing or tourist visitation, to provide baseline data. These efforts—whether direct behavioral observations or camera trap studies—can run continuously or be repeated at future time points using the same methods each time to quantify demographic or behavioral changes that occur alongside changing levels of human disturbance. This same process could also be applied to sites targeted for restoration or at which prohibitions against human activities are newly enforced to assess resilience of hyaenid populations. The COVID-19 pandemic presented another natural “experiment,” because travel restrictions interrupted ecotourism. In many countries, pre-pandemic data could be compared to data collected after the imposition of travel restrictions to investigate effects of tourism on hyaenids. Anthropogenic removal of sympatric carnivores or natural prey could allow researchers to delineate demographic and behavioral responses to reduction of apex carnivores (Green et al. 2018), mesocarnivores, or prey.
Identification of problem animals (Linnell et al. 1999) represents another potential future direction for applied research on individually identifiable spotted hyenas. Livestock depredation imposes a financial burden on affected households and can prompt retaliatory killings of hyenas and sympatric carnivores (Kissui 2008). Although we are unaware of any studies that sought to determine whether livestock depredation is attributable to a subset of problem animals, previous research on intrapopulation variation in hyaenid behavior suggests that this is likely. First, socioecological conditions affect space use in spotted hyenas, putting some individuals at higher risk of conflict with humans. In the Maasai Mara National Reserve, Kenya, low-ranking females without den-dependent cubs maintain the largest home ranges of any adult females, particularly in times of prey scarcity (Boydston et al. 2003; Green et al. 2019). Upon reaching puberty, males begin making exploratory forays beyond the boundaries of their territory, and adult males maintain larger home ranges than their female clanmates, venturing three to four times as far from the center of their territory as females (Boydston et al. 2005). Thus, males and low-ranking females may be more likely to venture into human-disturbed landscapes than high-ranking females, and thus experience an elevated risk of human-caused mortality.
Second, hyena personalities may affect individuals’ likelihoods of engaging in conflict with humans. Animal personality refers to individual variation in behavioral traits such as boldness, neophobia, and exploration that is consistent across time and context (Yoshida et al. 2016; Greenberg and Holekamp 2017; Turner et al. 2020). Individual personalities converge to affect population responses to novel environmental conditions, such as human disturbance (Merrick and Koprowski 2017). Greenberg and Holekamp (2017) and Turner et al. (2020) found that spotted hyenas from highly human-disturbed areas were less bold, less neophobic, and more exploratory than those in areas of low human disturbance. Boldness was negatively correlated with survivorship to adulthood in populations exposed to both low and high human disturbance. The relationships among intrapopulation variation in behavioral traits (personality) and space use have yet to be empirically studied in the context of human–hyena conflict.
If livestock depredation varies among individual spotted hyenas, one would also expect to observe intrapopulation variation in selection of native prey. Currently, the strength of individual diet specialization is poorly understood in hyaenids. This could be investigated through behavioral observations of hunting and feeding of known individuals or by analyzing tissue samples or repeat scat samples from known individuals. However, most published studies of scat analyses in hyenas used scat from unknown individuals (Henschel and Skinner 1990; Abay et al. 2011; Yirga et al. 2013), hindering the study of dietary specialization in hyaenids.
Intrapopulation variation in encounter rates with livestock affects livestock depredation risk and represents another exciting frontier in human–hyena conflict mitigation. For example, a camera trap grid could be placed to cover a mosaic of areas of livestock use (e.g., livestock corrals) and non-use, large enough to encapsulate at least one entire spotted hyena clan territory. Network analyses can be used to identify clans (Vitale et al. 2020), and clan membership can be paired with locations of photographic capture events to delineate territory boundaries. The camera trap data could be analyzed in a spatially explicit capture–recapture framework to estimate the size of a clan whose entire territory is included within the camera trap array and encompasses livestock corrals. Observers could then determine the number of visits to livestock corrals by each individual hyena. Variation in corral visit frequency would likely reveal differences in individuals’ tendencies to pass through these areas, representing individual-level differences in encounter rate with livestock. We are unaware of any camera trap studies at livestock corrals or grazing areas that differentiate among individual hyenas. In fact, we are only aware of one study in which camera traps were deployed at livestock corrals (Hoffmann et al. 2022). In this study, Hoffmann et al. (2022) used camera trap data to quantify encounter and attack rates at the species level but did not distinguish among individuals of each species. Innovative research methods are worthy of exploration, as are analytical applications to investigate human–hyena interactions and dynamics in shared landscapes.
Resources for conflict mitigation are limited, so identification of high-conflict areas is essential. Hyenas who frequent human settlements are likely at a higher risk of human-induced mortality (e.g., spearing, poison, snares) than others, regardless of their interactions with livestock. Individual-level space use and mortality data from known hyenas could be useful in identifying age-sex class and rank of hyenas at the highest risk of human-caused mortality. Furthermore, by identifying which high-use areas are correlated with the highest hyena mortality rates, efforts to reduce human–hyena conflict could be concentrated where they are most needed.
Current limitations
Despite its advantages, there are some drawbacks to individual identification using natural markings. To demonstrate these points, we draw from examples of hyaenids. There are certainly limitations of other methods discussed herein, such as camera trapping (Green et al. 2020; Dheer et al. 2022), but here we specifically focus on the limitations of individual identification of hyaenids in both camera trap studies and direct observations.
Using naturally occurring markings to identify individuals can be time-consuming and is not always reliable. For example, one study tested agreement among observers in individual identification of striped hyenas from camera trap images through a double-blind experiment in which three independent observers identified hyenas in 26 photographic captures (Harihar et al. 2010), following methods of Kelly et al. (2008). All three observers only agreed on the identity of the hyena for 76.80% of the capture events (Harihar et al. 2010).
According to Johansson et al. (2020), each time an attempt is made to identify an individual, there are five possible outcomes: correct identification, a splitting error, a combination error, a shifting error, or exclusion of the datum. A splitting error occurs when the focal individual is already present in the dataset but is mistakenly identified as a new individual. A combination error occurs when the focal individual has not yet been observed but is mistaken for a different animal that has already been observed. A shifting error occurs when the focal individual has already been observed and is mistaken for a different individual, who has also already been observed. Finally, a datum may be deemed unusable and excluded from the dataset either correctly (true exclusion) or erroneously (exclusion error). A true exclusion occurs when identification is truly infeasible, for example, due to poor lighting or blockage of the observer's view by features of the environment (e.g., tall grass) or another animal (Kelly et al. 2008; Harihar et al. 2010). An exclusion error occurs when sufficient information is available to make the identification, but the observer fails to identify the individual (Johansson et al. 2020).
Identification errors can skew the results of the studies in which they occur. In estimation of population size or density, splitting errors lead to overestimation, whereas combination errors lead to underestimation (Johansson et al. 2020). Shifting and exclusion errors do not necessarily bias the results of traditional capture–recapture analyses but shifting errors are problematic in spatially explicit capture–recapture analyses (Johansson et al. 2020). In a camera trap study of 16 snow leopards, photographic captures had an 8.70% probability of being excluded from the dataset. Of the remaining photographic captures, the probability of splitting errors (9.10%) was far higher than that of combination or shifting errors, leading to an overall misidentification rate of 12.50% (Johansson et al. 2020). The prevalence of splitting errors ultimately inflated the estimated population size by about one third (Johansson et al. 2020). Population estimates are central to conservation and management planning, and overestimation of population size may potentially undermine conservation efforts (Choo et al. 2020; Johansson et al. 2020). Splitting errors may be the most pervasive error type and are especially problematic in studies of threatened and endangered species, but more studies of identification error are needed to better understand the prevalence of error types across species with distinct individual natural markings. The other types of error (combination, shifting, and exclusion) also have the potential to bias estimates of demographic parameters, specifically if they are not randomly distributed across the population (Johansson et al. 2020), such as if some age-sex classes are more difficult to identify than others. For example, subadult spotted hyenas go through a phase in which they become very fluffy, making their spot patterns difficult to see. Additionally, ear damage and scars accumulate over a hyena’s lifetime, and are therefore relatively uncommon in young hyenas. On extremely old hyenas, on the other hand, spots may fade. For these reasons, it may be easier to identify middle-aged hyenas than those that are very young or very old. In addition to yielding erroneous population estimates (Johansson et al. 2020), misidentification can obscure the results of behavioral or genomic studies.
Standards for reporting methods and accuracy of individual identification are severely lacking. Most studies do not describe the methods they used to avoid misidentification, provide photographic evidence that individuals can be differentiated, or quantify the error rates of identification, thus precluding reviewers and readers from critically assessing the studies’ reliability and robustness (Choo et al. 2020). In summary, the methods by which data on known individuals are collected, analyzed, and reported certainly need further development. This is not to say that we should not use individual identification, but rather to stress the importance of quantifying, rectifying, and reporting errors, as well as refining methods for managing interobserver discrepancies and unclassifiable capture events (Choo et al. 2020; Johansson et al. 2020).
Future directions in methodology
Many of the current limitations of individual identification represent potential targets for methodological improvements. These include observer training, testing for errors, error prevention, transparency and accountability in reporting, and software to aid observers in identification. We also suggest methods by which the resultant data could be used to improve parameter estimation and answer novel questions.
More information is needed to determine what specific training or experience decreases observers’ misidentification rates. Virtual training tools, such as that recently produced for photographic identification of snow leopards (Johansson et al. 2020), may be helpful in improving training as well as in testing identification error. By testing rates of specific error types, targeted training approaches and identification methods can be identified to avoid the common error types (Choo et al. 2020; Johansson et al. 2020). Johansson et al. (2020) suggested prioritization of verification of new individuals, based on the prevalence of splitting errors. When feasible, multiple independent observers should identify individual animals, and methods for resolving disagreement among observers and management of images deemed unclassifiable should be carefully chosen (Choo et al. 2020; Johansson et al. 2020). Using multiple independent observers not only helps to detect and rectify identification errors but allows authors to report rates of interobserver agreement. Even when errors cannot be effectively rectified, quantification of error rates can allow for selection or development of modeling approaches that minimize the impacts of these errors on the results (Yoshizaki et al. 2009; Mendoza et al. 2011; Johansson et al., 2020). To achieve higher transparency and accountability in reporting, we recommend following the Individual Identification Reporting Checklist presented by Choo et al. (2020).
Software programs to automate individual identification have been successfully applied to multiple mammal species (Bolger et al. 2012; Crall et al. 2013; Schneider et al. 2019; Choo et al. 2020), and could potentially be applicable to hyaenids in the future. Computer vision has been used to assist manual identification by human observers in other carnivores with distinct coat patterns, such as cheetahs (Acinonyx jubatus; Kelly 2001), tigers (Hiby et al. 2009), and bobcats (Lynx rufus; Mendoza et al. 2011). A computer-aided approach relies on a human observer to confirm the final classification, but can reduce the man-hours needed to process large datasets (Kelly 2001) and reduce rates of misidentification (Hiby et al. 2009; Mendoza et al. 2011). Automated identification methods are currently underdeveloped and face many of the same challenges that human observers do (e.g., poor image quality, camera angle; Johansson et al. 2020). However, with further development, these methods could become highly effective and widely used in the future (Schneider et al. 2019). We are unaware of any studies that have used automatic methods to identify individual hyaenids, but suspect that this would be difficult, especially in species whose patterns are especially prone to distortion, such as by shifting position of long fur (spotted and striped hyenas) or due to camera angle (brown hyenas).
Data from individually identifiable animals can be applied to improve model parameter estimation. Counterintuitively, although studies of occupancy do not require differentiation of individuals, they could still benefit from examination of unique markings. Individual identity may be useful in determining whether or not the assumptions of spatial independence and population closure have been met (Edwards et al. 2018). Additionally, further research on personality may better inform estimates of detection probability for hyaenids. This research by definition requires individual hyaenids to be identified and studied across time and contexts.
New research questions may be addressable by combining multiple data types. Individually recognizable animals can be studied by pairing visual observations (direct or through photos) with data collected with either noninvasive (Table 1) or invasive (radio collars, Stratford et al. 2020; Edwards et al. 2020; biosamples, Engh et al. 2002; Van Horn et al. 2004; Watts et al. 2011) methods. Additionally, experts could visually identify individuals in geotagged photos of sufficient quality submitted by local people or tourists. There are also many large datasets of existing images produced by camera trap studies that could be used to answer new research questions. Thus, advances in methodology of individual hyaenid identification could facilitate citizen science and new collaborations.Table 1 Creative combinations of methods used with spotted hyenas have allowed researchers to collect biological samples noninvasively from known individuals to pair with direct observations. Here, we report methods paired with direct behavioral observations, the type of complementary data yielded by this method, and citations of researchers who have successfully employed this fusion
Method(s) Data type Citation(s)
Opportunistically pluck cubs’ hair Genetic Höner et al. (2007)
Necropsies of dead hyenas Genetic Höner et al. (2007)
Feces collection Genetic Watts et al. (2011)
Feces collection Hormones Dloniak et al. (2006)
Van Meter et al. (2008, 2009)
Sampling by saliva stick Hormones Montgomery et al. (2022)
Feces collection Microbiome Rojas et al. (2020)
The most vocal hyaenids, spotted hyenas, may be individually distinguishable not only through visual identification, but possibly through acoustic identification as well (Lehmann et al. 2022). Spotted hyenas’ loudest vocalizations, called “whoops,” are emitted in bouts and can be heard from up to five kilometres away (Kruuk 1972; East and Hofer 1991a). Whooping serves important functions, such as recruiting clanmates to cooperate in defense of a shared resource, and are used in various contexts to transmit information about the callers’ location, age, sex, affective state, and, importantly, identity (East and Hofer 1991a, b; Theis et al. 2007; Benson-Amram et al. 2011; Gersick et al. 2015; Lehmann 2020). Acoustic variation among different individuals (signal strength) and consistency of individuals’ acoustic signatures over time (signal stability) are necessary for acoustic identification of individuals (AIID; Linhart et al. 2022). If the acoustic variation quantified by Lehmann et al. (2022) proves to be consistent over time, as suggested by East and Hofer (1991a), then AIID could become a powerful tool for studying spotted hyenas.
Vocalizations may be collected through focal or passive recording. In focal recording, an observer typically uses a handheld microphone and digital recorder. In passive recording, vocalizations are captured by autonomous recording units (ARUs) placed in the animal’s environment. Focal recording has many benefits, such as yielding high-quality samples and allowing the observer to record the emitter’s identity, the emitter’s posture and orientation in relation to the microphone, the distance between the emitter and the microphone, and contextual information. However, focal recording is much more time consuming than passive recording. Using focal recordings for AIID in a capture–recapture framework is important for feature selection and external validation, and can be treated as a pilot study, with the ultimate goal of developing methods for AIID using passive recording (Linhart et al. 2022). We are unaware of any work that has identified individual hyenas based on passive recording, but this could be an interesting area for future exploration. Next steps should include developing software to perform AIID through machine learning and to externally validate the results. Additionally, the maximum distance at which a whoop can be correctly assigned to the emitter should be determined. These steps all require pilot data from focal recordings. If whoops can be recorded from kilometres away and the emitter accurately identified, then an ARU could potentially obtain much more data than a camera trap placed at the same location.
Conclusion
The unique markings of hyaenids are indispensable in ongoing research and have greatly enhanced our understanding of these species. We have highlighted several interesting studies that exemplify this, but this is by no means a comprehensive review of the literature built on individual identification of hyaenids. In addition to the fields discussed here, this method has facilitated studies of hyena cognition (Johnson-Ulrich et al. 2020), disease ecology (Höner et al. 2012; Gering et al. 2020), mate choice (Engh et al. 2002; Szykman et al. 2001), behavioral endocrinology (Dloniak et al. 2006; Montgomery et al. 2022), and microbiota (Theis et al. 2013; Rojas et al. 2020), among many others. Comparative work within the family Hyaenidae is especially useful, as the socioecological diversity within this family allows investigation of the evolution of various traits in closely related species and has been particularly useful in studies of social evolution and intelligence (Holekamp 2007; Holekamp et al. 2007; Holekamp and Benson-Amram 2017; Johnson-Ulrich 2017). Applied work with hyenas in situ is timely and important for protecting human livelihoods from crop raiding and livestock depredation, and for conserving rare striped and brown hyenas. Furthermore, results of such studies may help to inform conservation and management of other large mammalian carnivores or even whole ecosystems (Green et al. 2019).
Despite the wealth of knowledge about spotted hyenas, many unanswered questions remain, and relatively little is known about the other hyaenid species, especially striped hyenas. We have identified several of the many gaps in our current understanding that can be answered using studies of free-living, individually recognizable hyenas or aardwolves. Furthermore, identification by natural markings has been combined with other methods to generate novel datasets. For example, some studies have fitted subjects with collars to aid in visual identification or location of subjects for repeated behavioral observations, or to supplement data from direct observations with spatial data from GPS collars, while also using coat patterns to differentiate individuals (Richardson 1987a, b, 1991; Silwa 1996; Boydston et al. 2003; Califf et al. 2020). Individually known subjects may also be captured to obtain biosamples to complement behavioral data (Höner et al. 2007; Califf et al. 2020). Identification by natural markings has also been combined with various noninvasive methods (Table 1) to produce complementary datasets. Many possible combinations of methods have yet to be used for hyenas, such as pairing camera traps with hair snares or identifying prey hair or DNA in scat from known individuals to study individual diet variation and specialization (Larson et al. 2020). Noninvasive methods are unlikely to replace invasive methods completely, but they can be beneficial for minimizing stress and risk of injury to the animals, circumventing logistical limitations (including obtaining permits) and trap shyness, maximizing sample size, and detecting elusive species (Kelly et al. 2012).
Noninvasive individual identification has proven critical to building our understanding of the demography, social behavior, reproduction, and ecology of wild hyenas and aardwolves. The literature reviewed herein was selected to showcase the value of this method and to showcase the diversity of its applications, but we merely scratch the surface of this vast body of work. We encourage researchers and conservation practitioners to seek out papers that describe the use of this method in their own areas of interest and to consider how their current or future projects may benefit from incorporation of individual identification of study animals. Researchers already using individual identification should strive to meet the criteria specified in the Individual Identification Reporting Checklist (Choo et al. 2020). Besides the large body of published work to date, there are certainly many unexplored uses of individual identification. Researchers should consider new applications of this method to address basic research questions and methodological advances to address the limitations discussed above. Importantly, there are many avenues of applied research that have gone largely unpursued to date in hyenas, including identification of problem animals in livestock and crop damage. We encourage creative fusions of methods and the application of individual identification to basic and applied research questions. The methods we have discussed should be useful in future studies of wild hyaenids, as well as other mammalian carnivores, by facilitating new research, improving reliability and transparency of published work, and informing conservation and management strategies.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 170 kb)
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Acknowledgements
We thank all past and present members of the Mara Hyena Project for their work collecting and curating the data presented here. We thank the National Commission for Science, Technology and Innovation, the Kenya Wildlife Service, the Wildlife Research and Training Institute, the Narok County Government, the Government of Namibia, the Naboisho Conservancy, and the Mara Conservancy for permission to conduct research on spotted hyenas. We thank the Namdeb Diamond Corporation for allowing access to the study area for brown hyenas, and the Namibian Ministry of Environment, Forestry and Tourism for granting annual research permits to study brown hyenas. We thank Kenna Lehmann, Tracy Montgomery, Julie Jarvey, Lily Johnson-Ulrich, Eli Strauss, Jackie Spagnuolo, Darren Incorvaia, and both editors Scott Y.S. Chui and Leszek Karczmarski for their valuable feedback on this manuscript. We thank Sabrina Salome and Malit Ole Pioon for their help obtaining photographs of spotted hyenas.
Authors' contribution
O.S.B.S. and K.E.H. conceptualized this paper. O.S.B.S. conducted background research on each of the four hyaenid species. K.E.H. assisted in background research on spotted hyenas, I.W. did so for brown hyenas, and M.A.L. did so for aardwolves. Each author also found photos to illustrate points made about her species. Each author then submitted her text to O.S.B.S., who organized the manuscript and added figures and tables. O.S.B.S. and K.E.H. made manuscript revisions.
Funding
This work was supported by National Science Foundation (NSF) Grants OISE1853934 and IOS1755089 to KEH and the Namdeb Diamond Corporation funds granted to IW.
Declarations
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Handling editors: Scott Y.S. Chui and Leszek Karczmarski.
This article is a contribution to the special issue on “Individual Identification and Photographic Techniques in Mammalian Ecological and Behavioural Research – Part 2: Field Studies and Applications” — Editors: Leszek Karczmarski, Stephen C.Y. Chan, Scott Y.S. Chui and Elissa Z. Cameron.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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| 0 | PMC9744671 | NO-CC CODE | 2022-12-15 00:01:52 | no | Mamm Biol. 2022 Dec 13;:1-24 | utf-8 | Mamm Biol | 2,022 | 10.1007/s42991-022-00309-4 | oa_other |
==== Front
J Clin Virol Plus
J Clin Virol Plus
Journal of Clinical Virology plus
2667-0380
The Authors. Published by Elsevier Ltd.
S2667-0380(22)00068-0
10.1016/j.jcvp.2022.100129
100129
Article
Evaluation of STANDARDTM M10 SARS-CoV-2 assay as a diagnostic tool for SARS-CoV-2 in nasopharyngeal or oropharyngeal swab samples
Parakatselaki Maria-Eleni ⁎
Alexi Georgia
Zafiropoulos Alexandros
Sourvinos George
Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion, 71003, Crete, Greece
⁎ Corresponding author: Maria-Eleni Parakatselaki, Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion, 71003, Crete, Greece
13 12 2022
13 12 2022
10012910 8 2022
9 12 2022
12 12 2022
© 2022 The Authors. Published by Elsevier Ltd.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
The SARS-CoV-2 pandemic led to an urgent need for rapid diagnostic testing in order to inform timely patients’ management. This study aimed to assess the performance of the STANDARDTM M10 SARS-CoV-2 assay as a diagnostic tool for COVID-19. A total of 400 nasopharyngeal or oropharyngeal swabs were tested against a reference real-time RT-PCR, including 200 positive samples spanning the full range of observed Ct values. The sensitivity of the STANDARDTM M10 SARS-CoV-2 assay was 98.00% (95% CI 94.96% to 99.45%, 196/200), while the specificity was also estimated at 97.50% (95% CI 94.26% to 99.18%, 195/200). The assay proved highly efficient for the detection of SARS-CoV-2, even in samples with low viral load (Ct>25), presenting lower Ct values compared to the reference method. We concluded that the STANDARDTM M10 SARS-CoV-2 assay has a similar performance compared to the reference method and other molecular point-of-care assays and can be a valuable tool for rapid and accurate diagnosis.
Keywords
SARS-CoV-2
STANDARDTM M10 SARS-CoV-2 assay
molecular point-of-care test
COVID-19
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pmc1 INTRODUCTION
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) led to an outbreak of the Coronavirus Disease 2019 (COVID-19) [1]. Within a short period of time, SARS-CoV-2 has rapidly spread all over the world, therefore the COVID-19 outbreak was declared by World Health Organization (WHO) as a “pandemic” on March 11, 2020 [2]. The SARS-CoV-2 genome is composed of a positive-sense, single-stranded RNA of around 30kb in size [3]. This genome consists of two segments. The first segment is formed by two open reading frames (ORF1a and ORF1b), which are translated to two polyproteins, resulting in 16 non-structural proteins, one of which is the RNA-dependent RNA polymerase (RdRp). The second segment encodes for structural proteins, for instance the spike (S), the envelope (E), the membrane (M) and the nucleocapsid (N) [4]. Many of the above genes have been used as diagnostic targets in a variety of nucleic acid amplification-based tests, such as reverse-transcription polymerase chain reaction (RT-PCR) [5].
Currently, COVID-19 can be diagnosed by various methods, such as reverse transcription polymerase chain reaction (RT-PCR), virus culture and antigen or antibody tests [6]. In many cases, presence of the virus is confirmed by real-time RT-PCR, as it is still considered the gold-standard method for diagnosing both symptomatic and asymptomatic cases [7,8]. Regardless of its diagnostic value, real-time RT-PCR is not easily applicable at all cases, mainly due to its long turnaround times and the need for heavy equipment and skilled personnel to perform it [9,10]. Therefore, a great number of point-of-care (POC) methods have been developed, which include fluorescent rapid antigen-detecting (RADT) and rapid nucleic acid amplification (NAAT) tests [11,12]. RADTs are vastly used, since they are inexpensive and able to give the result in a few minutes, however they give a great percentage of false negative results, especially in cases where the viral load is low [11,13].
It is obvious that developing fast, accurate, molecular point-of-care tools for the detection of SARS-CoV-2 RNA is essential to control the pandemic. Various rapid NAATs have been developed and assessed for their use at point-of-care sites. The more frequently assessed rapid NAATs include the Xpert Xpress SARS-CoV-2 (Cepheid,Sunnyvale, CA, USA) and the ID Now SARS-CoV-2 (Abbott, Chicago, IL, USA). Overall, the above tests exhibited a sensitivity of 95.1% (95% CI 90.5% to 97.6%) and specificity of 98.8% (95% CI 98.3% to 99.2%), respectively [11]. Here, we report an evaluation of the STANDARDTM M10 SARS-CoV-2 assay (SD BIOSENSOR), which is a multiplex real-time RT-PCR test designed to detect SARS-CoV-2 RNA in upper respiratory specimens, such as nasopharyngeal or oropharyngeal swabs.
2 MATERIALS AND METHODS
The under evaluation STANDARDTM M10 SARS-CoV-2 assay is designed for use with the STANDARDTM M10 system (SD BIOSENSOR), which conducts sample preparation, nucleic acid extraction and amplification and detection of the target sequences, using the real-time RT-PCR as the test method. The system comprises of the M10 Console, which allows the user to import information about the sample, and the M10 module, which performs the assay. The assay requires single-use disposable cartridges that contain the RT-PCR reagents. Cross-contamination between samples is greatly limited, since the cartridges are self-contained. The assay is targeting two genes of the SARS-CoV-2, the ORF1ab gene and the E gene, and the human RNAse P as an internal control. The procedure lasts 60 minutes. At the end of each assay the result is shown with the corresponding Cycle Threshold (Ct) values on the M10 Console. The limit of detection (LoD) is 100 copies/ml, as reported by the manufacturer.
The reference method used to assess STANDARDTM M10 SARS-CoV-2 performance was TaqPath™ COVID 19 CE-IVD RT PCR kit (Applied Biosystems™), which targets three genes of SARS-CoV-2, the ORF1ab gene, the N gene and the S gene. PCR was carried out in a QuantStudio™ 5 Real-Time PCR System (Applied Biosystems™). According to the manufacturer, the LoD is 250 copies/ml. Ct values were collected from the accompanying software. RNA was extracted by 200μl sample with the KingFisher™ Flex Purification System (Thermo Scientific™) using the MagMAX™ Viral/Pathogen II (MVP II) Nucleic Acid Isolation Kit (Applied Biosystems™), according to manufacturer's instructions.
Totally, 200 negative and 200 positive for SARS-CoV-2 samples were chosen for analysis with the STANDARDTM M10 SARS-CoV-2 assay. More specifically, approximately half of the positive samples chosen, had a Ct value higher than 30, in order to test the assay in samples with low viral load, 25% had a Ct value ≥25 and ≤30 while the rest had a Ct value lower than 25. The assay was performed on 600μl sample, according to manufacturer's instructions. Besides positive and negative outcome of the test, there was also the possibility of presumptive positive as an outcome, in cases where only the E gene was detected. In case of discrepancy in comparison to the reference method, the assay was repeated two more times. The result detected more than 50% (two out of three times) was adopted as the final result and kept for the statistical analyses.
Estimates of the sensitivity and specificity of the STANDARDTM M10 SARS-CoV-2 assay were made according to Altman and Bland (1994). A two-sided alpha value of 0.05 was defined as the significance cut-off. The Ct values for the ORF1ab gene from the reference method were compared with the corresponding Ct values from the STANDARDTM M10 SARS-CoV-2 assay. Shapiro-Wilk test was used to test for normal distributions. Since the normality assumption was not met, Spearman's rank correlations and Wilcoxon signed-rank tests for paired data were used to analyze the above variables. Cabilio & Masaro symmetry tests were also conducted to check for the basic assumption of the Wilcoxon signed-rank test, which confirmed the null hypothesis. A p value less than 0.05 was considered statistically significant. The positive samples were also categorized in 3 groups according to the Ct values obtained from the reference method (<25, ≥25 and ≤30, >30) and Wilcoxon signed-rank tests were also performed in the groups. All statistical analyses and plots were performed in RStudio (v. 1.2.5042, RStudio Team, 2020).
3 RESULTS
Among the 400 samples examined, 12 gave discrepant results compared to the reference method and therefore, they were tested two more times with the STANDARDTM M10 SARS-CoV-2 assay (Supplementary Table 1). Of those, 7 were positive whereas 5 were negative by our reference method. After retesting the positive samples with the STANDARDTM M10 SARS-CoV-2 assay, 3 samples came out positive, 2 came out negative while 2 were presumptive positive. Retesting of the negative samples, resulted in 4 presumptive positive samples, respectively. The fifth negative sample gave all possible outcomes with the STANDARDTM M10 SARS-CoV-2 assay.
Conclusively, of the 200 positive specimens tested, 196 were identified as true positive, 2 as false negative and 2 as presumptive positive. The two presumptive samples had an ORF1ab Ct value by our reference method over 35. Regarding the 200 negative samples, 195 were identified as true negative, 0 as false positive and 4 as presumptive positive. For the calculation of specificity and sensitivity, we considered the 2 positive samples that were identified as presumptive positive from the STANDARDTM M10 SARS-CoV-2 assay as false negative and the 5 presumptive positive from the negative samples as false positive. The negative sample that gave all the possible outcomes was considered as false positive in downstream analyses. Sensitivity of the STANDARDTM M10 SARS-CoV-2 assay was estimated at 98.00% (95% CI 94.96% to 99.45%, 196/200), while specificity was estimated at 97.50% (95% CI 94.26% to 99.18%, 195/200).
Spearman's rank correlation was computed to assess the relationship between ORF1ab Ct values from the STANDARDTM M10 SARS-CoV-2 assay and the reference method. There was a very strong positive correlation between the two variables (r= 0.954, p value < .001, Figure 1 ). The Ct values obtained from the STANDARDTM M10 SARS-CoV-2 assay (median= 28.45, IQR (Interquartile range)= 8.96225) were significantly lower than those obtained from the reference method (median= 29.33, IQR= 8.1875, p value < .001).Figure 1 Spearman's rank correlation between ORF1ab Ct values from the STANDARDTM M10 SARS-CoV-2 assay and the reference method. The variables displayed a very strong positive correlation between the two variables (r= 0.954, p value < .001).
Figure 1:
As previously mentioned, the positive samples were subcategorized according to their ORF1ab Ct values. The Ct values from the two methods did not differ significantly (p value= .778), meaning there is no difference in Ct values due to the method in samples with high viral load (Figure 2 a). In samples with moderate viral load (Ct values ≥25 and ≤30), the Ct values from the STANDARDTM M10 SARS-CoV-2 assay (median= 26.89, IQR= 2.76) were found to be significantly smaller than the reference method (median= 27.89, IQR= 2.473, p value= .001408, Figure 2b).Figure 2 Ct values comparison between the STANDARDTM M10 SARS-CoV-2 assay and the reference method. (a) In samples with high viral load (Ct value <25), no differences between the two methods were detected. (b) In samples with moderate viral load (Ct value ≤25 and ≥30), the STANDARDTM M10 SARS-CoV-2 assay had a better performance than the reference method (p value= .001408). (c) In samples with low viral load (Ct value >30), the STANDARDTM M10 SARS-CoV-2 assay had also a better performance than the reference method (p value < .001).
Figure 2:
Regarding the samples with low viral load (Ct values >30), the Ct values from the STANDARDTM M10 SARS-CoV-2 assay (median= 32.41, IQR= 2.645) were also significantly smaller than those from the reference method (median= 33.29, IQR= 2.93625, p value < .001, Figure 2c).
4 DISCUSSION
From the beginning of the SARS-CoV-2 pandemic to date, real-time RT-PCR is considered the gold standard for diagnosing the COVID-19 [7,16]. This method is highly efficient and reliable, however heavy lab equipment and trained personnel are required to perform it. Furthermore, depending on the workload, results may take several hours to receive. An increasing number of rapid point-of-care (POC) platforms receive FDA (Food and Drug Administration) EUA (Emergency Use Authorization), which allow time-efficient diagnosing. The majority of these POC platforms are basically antigen tests [16], however many other POC platforms that base upon nucleic acid amplification techniques, such as real-time RT-PCR and isothermal nucleic acid amplification (RT-LAMP), are also being used. Such platforms are the Cue COVID-19 test, Abbott ID NOW, Cepheid Xpert Xpress SARS-CoV-2 test, Roche Cobas SARS-CoV-2 & Influenza A/B on the Cobas Liat System, Mesa BioTech Accula SARS-CoV-2, and BioFire Respiratory Panel 2.1-EZ [17].
In the current study, we assessed the performance of the STANDARDTM M10 SARS-CoV-2 assay in comparison to the TaqPath™ COVID-19 CE-IVD RT-PCR kit (Applied Biosystems™) as the reference method. The test showed high overall agreement with the reference method, with 97.75% accuracy (95% CI 95.77% to 98.97%). The accuracy is similar to estimated accuracies of other corresponding POC PCR-based assays that have received FDA EUA. Specifically, the overall agreement for the Roche Cobas SARS-CoV-2 & Influenza A/B on the Cobas Liat System has been estimated at 98.6% [18], while for the Cepheid Xpert Xpress SARS-CoV-2 test an accuracy of 99% has been reported [19]. Finally, the STANDARDTM M10 SARS-CoV-2 assay displayed lower Ct values compared to the reference method for samples with a Ct value above 25, since it was able to detect the ORF1ab target one cycle earlier, on average. This difference confirms the lower reported LoD of the index method compared to the reference method.
Two other studies have also evaluated the STANDARDTM M10 SARS-CoV-2 assay for its use at POC sites. The first evaluation study estimated the sensitivity and specificity of the assay for the ORF1ab target at 95.5% (95% CI 91.7% to 97.6%) and 100% (95% CI 98.7% to 100%), respectively [20]. Furthermore, they also confirmed the lower LoD of the STANDARDTM M10 SARS-CoV-2 assay, compared to the reference methods they used. The second evaluation study followed a more qualitative approach to evaluate the assay and estimated both sensitivity and specificity of 100% [6]. Our estimate of sensitivity (98%) is close to what is reported to the previous two evaluations, however the specificity we report here is lower (97.5%). The reason for this may be the more conservative way we handled the presumptive positive results, since we handled them as false positive results.
Regarding the discordant results between the reference test and the index test, we did not need to repeat the reference test. This decision was taken because all discordant samples came from people that were hospitalized. Therefore, we know that all positive samples that were discordant with the reference test came from diagnosed with COVID-19 people, within the last 15 days. Respectively, the negative samples came from people that were hospitalized for irrelevant reasons and had been tested at least once more within the last week. Thus, we used the result from the reference test as the basis for comparisons, and this is also the reason why we chose to treat the presumptive positive results from the index test as false negative or false positive, depending on the case.
At the time period we conducted the study, between January 2022 and March 2022, three SARS-CoV-2 variants were predominant across Crete, Delta variant and two Omicron variants (BA.1 και BA.2). Furthermore, the Omicron BA.1 variant was present throughout the whole time period of the study, while the Delta variant was present until middle of February. The Omicron BA.2 variant emerged at the end of February. The TaqPath™ COVID-19 CE-IVD RT-PCR kit (Applied Biosystems™) used as the reference PCR, could indicate prevalence of the variants through S gene drop out, that was characteristic of the Omicron BA.1 variant, therefore depending on the time period we could assume the possible variant present by the S gene drop out. The STANDARDTM M10 SARS-CoV-2 assay successfully detected the SARS-CoV-2 RNA, regardless the variants’ prevalence. Therefore, the efficacy of the assay is not mutation-dependent.
In conclusion, the evaluation of the STANDARDTM M10 SARS-CoV-2 assay demonstrated similar performance to a high-throughput laboratory real-time RT-PCR reference method and it is capable of accurate and rapid diagnosis of COVID-19 at the point of care. In particular, it has a run-time less than 60 minutes, depending on the viral load of the sample, with hands on time 2 to 3 minutes, with no need for external viral RNA purification process, while minimum lab equipment is required. Thus, we conclude that this assay can be a valuable tool in cases where immediate decision making is required for treatment or infection control policies.
FUNDING
The reagents for the STANDARDTM M10 SARS-CoV-2 assay were provided by SD BIOSENSOR (Republic of Korea). SD BIOSENSOR did not interfere with the evaluation of the test, the interpretation of the results or the preparation of the manuscript.
Uncited References
[14, 15]
CRediT authorship contribution statement
Maria-Eleni Parakatselaki: Investigation, Formal analysis, Writing – original draft. Georgia Alexi: Investigation, Writing – review & editing. Alexandros Zafiropoulos: Writing – review & editing, Supervision. George Sourvinos: Writing – review & editing, Supervision, Conceptualization.
CONFLICTS OF INTEREST
The authors declare no conflict of interest.
Appendix Supplementary materials
Image, application 1
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jcvp.2022.100129.
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| 0 | PMC9744673 | NO-CC CODE | 2022-12-15 00:04:04 | no | J Clin Virol Plus. 2022 Dec 13;:100129 | utf-8 | J Clin Virol Plus | 2,022 | 10.1016/j.jcvp.2022.100129 | oa_other |
==== Front
Comput Commun
Comput Commun
Computer Communications
0140-3664
1873-703X
Elsevier B.V.
S0140-3664(22)00461-3
10.1016/j.comcom.2022.12.011
Article
3D face recognition algorithm based on deep Laplacian pyramid under the normalization of epidemic control
Kong Weiyi a
You Zhisheng ab
Lv Xuebin b⁎
a National Key Laboratory of Fundamental Science on Synthetic Vision, Sichuan University, Chengdu, 610065, PR China
b School of Computer Science, Sichuan University, Chengdu, 610064, PR China
⁎ Corresponding author.
13 12 2022
13 12 2022
22 6 2022
2 12 2022
6 12 2022
© 2022 Elsevier B.V. All rights reserved.
2022
Elsevier B.V.
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Under the normalization of epidemic control in COVID-19, it is essential to realize fast and high-precision face recognition without feeling for epidemic prevention and control. This paper proposes an innovative Laplacian pyra- mid algorithm for deep 3D face recognition, which can be used in public. Through multi-mode fusion, dense 3D alignment and multi-scale residual fu- sion are ensured. Firstly, the 2D to 3D structure representation method is used to fully correlate the information of crucial points, and dense align- ment modeling is carried out. Then, based on the 3D critical point model, a five-layer Laplacian depth network is constructed. High-precision recognition can be achieved by multi-scale and multi-modal mapping and reconstruction of 3D face depth images. Finally, in the training process, the multi-scale residual weight is embedded into the loss function to improve the network’s performance. In addition, to achieve high real-time performance, our net- work is designed in an end-to-end cascade. While ensuring the accuracy of identification, it guarantees personnel screening under the normalization of epidemic control. This ensures fast and high-precision face recognition and establishes a 3D face database. This method is adaptable and robust in harsh, low light, and noise environments. Moreover, it can complete face reconstruction and recognize various skin colors and postures.
Keywords
3D face recognition
Multimodal fusion
Face reconstruction
Deep learning
Epidemic control
==== Body
pmc1 Introduction
Under the background of normalization of epidemic prevention and control, it is the focus of epidemic prevention work to do a good job of monitoring personnel flow. Some countries have introduced the policy of removing masks. Therefore, it is particularly critical to realize the non-contact, efficient and safe management of people or people in public places. Among them, there are two most serious problems. First, how to use the method of quickly recognizing faces in public places, you can confirm your identity, and get information about your health and itinerary. Second, how to use scientific and technological means to obtain information about people closely linked in time and space, and timely screen to avoid a large-scale outbreak of the epidemic [1]. To solve the above problems, face recognition and reconstruction algorithms are listed as important research directions by researchers. Because three-dimensional face recognition and three-dimensional reconstruction have many advantages, such as non-contact, non-sensory recognition, good range, and safety. Therefore, it can provide an effective method for the normalization of epidemic prevention and control, and effectively avoid the risk of cross-infection of bacteria and viruses caused by physical contact [2]. Concerning user privacy, first of all, all data sets used in this algorithm research are public data sets for research. Secondly, when the algorithm is applied to the 3D vision face recognition module, the collected face images only record the face feature values. Face image data will not be saved, so users don’t have to worry about privacy leakage at all. Therefore, under the background of the normalization of epidemic prevention and control, it is essential to realize face recognition of different skin colors and angles quickly, efficiently, and accurately in the face of many scenes without masks. This paper proposes an innovative three-dimensional face recognition algorithm based on the deep Laplacian pyramid. It can be used for rapid face recognition, and reconstruction in the normalization of epidemic prevention and control and is helpful to obtain their identity and health information efficiently. Because this paper focuses on the high-precision recognition and reconstruction of three-dimensional faces, the research in the field of face recognition is mainly analyzed below.
Face recognition is a biometric identification technology based on facial feature information for identity authentication. The development of this technology mainly relies on deep learning, 3D face recognition, and ultra-low resolution face [1], [2], [3]. Generally, face recognition is divided into two- dimensional face recognition and three-dimensional face recognition two categories. 3D face recognition is relative to 2D face recognition. The data used in two-dimensional face recognition is a two-dimensional image, which is essentially a projection of a three-dimensional object in a two-dimensional plane. Because the face itself has three-dimensional attributes, so the use of three-dimensional face data for face recognition has more advantages [4], [5], [6]. 3D face data can be estimated from 2D color images or obtained directly by 3D imaging equipment. That is to say, face recognition based on 3D is the mainstream research direction [7], [8]. The main research of this paper is also based on 3D face recognition.
However, previous studies on 3D face recognition and 2D face recognition are often independent. Traditional two-dimensional face recognition mainly uses mathematical methods to extract corresponding features from the image matrix, which generally scales invariant features. The commonly used algorithms include SURF, SIFT, HARRIS, GFTT, and so on. 3D face recognition processing is 3D data, such as point clouds, voxels, etc. These data are complete, three-dimensional, and can express the facial features of objects from various angles. The processing methods and processes are similar in two and three dimensions. The difference is that the data to be processed is different. Considering the limitations of two-dimensional face recognition and the difficulty of three-dimensional face recognition. In this paper, the data fusion strategy is innovatively adopted to combine two-dimensional data processing and three-dimensional data analysis. Using the idea of residual iteration, 2D and 3D features of the human face are fused without loss of network speed. The feature information of different levels of the image is highly correlated. In the network model design, the Laplace function is skillfully used to construct a pyramid structure, which is densely connected by residual modules. Each level is no longer a single independent distribution. It is a compact architecture. Based on this, our algorithm has higher recognition results. The generalization works better. Moreover, it can tolerate more postures, expressions, and skin tone changes.
Facial recognition outcomes are often analyzed at the data level. But this approach is not suitable for subjective visualization. Some researchers [6], [9] have proposed that facial recognition and reconstruction should not be completely independent of one another. Both perform matching calculations on features such as pixel and texture, so the recognition and reconstruction fields are also similar in principle. Inspired by the above, we use facial recognition and recon visualization for multimodal fusion. It aims at improving recon performance and reconstruction visualization. Furthermore, the traditional research of three-dimensional face recognition and face reconstruction is often independent of each other. Resulting in poor face pose diversity recognition. Face reconstruction research has its limitations. In addition, light noise and different facial skin colors and expressions have significant interference with 3D recognition, resulting in poor accuracy.
Under the background of normalization of epidemic prevention and control, in order to monitor the flow of people in real time. As well as the timely tracking of people infected in time and space in case of an outbreak. This paper proposes a five-layer Laplacian pyramid network structure to solve the above problems. This method is a 3D face reconstruction method based on depth residual matching, and has high accuracy in 3D face recognition. The problem of effective reconstruction of 3D face data under occlusion and high reflection conditions is solved. It solves the problem of multi-angle and multi-pose face reconstruction. Multi-mode end-to-end reconstruction strategy based on disparity matching. Through multi-dimensional matching and feature fusion, the problem of 3D face reconstruction without image feature information is effectively solved, and it has high robustness to the environment. Thanks to the real-time performance of non-inductive recognition and reconstruction of 3D algorithm. To a large extent, we guarantee the freedom of personnel, and the algorithms and research can be used to monitor the epidemic prevention and control, so as to better maintain social stability.
Under the background that COVID-19 needs to wear a mask, the existing face recognition algorithms need to locate the features of different local information of the face, or need to learn the global face as a whole, so they generally can’t recognize the face accurately. Based on this problem, our proposed algorithm not only pays attention to global face recognition, but also introduces learning factors with different resolutions. More attention is paid to the local feature recognition of the face, and the complete face reconstruction can be carried out, which makes a new direction for the high-precision face recognition and reconstruction work under the condition of wearing a mask.
The main contributions of the algorithm in this paper include:
1. Innovatively proposed multi-pose stereo face detection and dense alignment. The three-dimensional graph structure models of the front and side key points are established to provide a high-precision model for the following 3D face reconstruction algorithm.
2. Innovative proposed a lightweight end-to-end Laplacian 3D face recognition reconstruction network. It integrates 3D face recognition and reconstruction visualization into the entire network architecture. The loss function of residual design is introduced based on Laplace network architecture. The joint dense fusion strategy is used to reconstruct the disparity map of face structure image and face texture image, which improves the accuracy and speed of the algorithm to a certain extent.
3. This paper combines the relationship between face recognition and expression reconstruction to form a complete algorithm. It has universal applicability. It can be applied to face reconstruction and scene recognition in low light and low texture. It has stable and efficient performance for three-dimensional face reconstruction and recognition with different skin colors, expressions, and postures. It can be applied to practical projects.
2 Related work
As mentioned above, the main problems that our method can solve are 3D face recognition and visualization representation. We discuss the work closely related to these tasks in the following sections.
2.1 Traditional 3D face recognition
According to the source of 3D face data, the 3D face recognition method is divided into the 3D face recognition method based on a color image, the face recognition method based on high-quality 3D scan data, face recognition method based on a low-quality RGB-D image [10], [11]. Among them, the 3D face recognition method is based on color images and included in the use of 3D face model parameters for face recognition, using a 3D face model to synthesize a new human face image recognition [9]. Blanz [12] uses the model’s 3D geometric distortion for facial recognition. This method from a single image estimates the geometry and 3D texture parameters. Second, the Euclid distance of these parameters is used to determine if they belong to the same person. This method uses the benefits of the 3D facial model and gets a better recognition effect under specific conditions. However, the drawback is that it is highly affected by lighting and the calculation is very large [13].
A multi-pose 3D facial recognition method based on the combination of 3D geometry and local analysis is proposed [10], [11], [14]. To improve the recognition accuracy, this method could be divided into the different local 3D faces. Reconstruction by the method of 3D geometric face locally, different parts of the geometric parameters, and texture combination as recognition characteristics. According to the identification of each component to determine its weight in the overall classification, achieve the result that improves recognition constructed a statistical model for 3D face modeling and recognition [15]. By matching BFM with color images, the corresponding attitude and illumination settings can be obtained. At the level of recognition, the facial identity coefficients of the different models can be directly compared. However, BFM’s limitation is that it can only model neutral faces [16], [17], therefore it is not suitable for facial images with expressions. For the face recognition method based on high-quality 3D scanning data, which respectively includes the global feature method and local feature method in the global method, the face recognition method based on 3DMM and the face recognition method based on the curve are very classic. Papath [18] represented the face as a four-dimensional point set, and the elements in the set were composed of the three-dimensional coordinates of a point, and the gray level of the corresponding points in the two-dimensional image. ICP was suitable for matching between rigid surfaces, but the face was not a rigid surface, so some methods only used the areas less affected by expressions for recognition. Chang et al. [19] selected the nose region for ICP registration and recognition. Faltemier et al. [20] divided the face into 28 overlapping regions. Mohammadzade et al. [21] first found the nose tip of a three-dimensional face and intercepted a certain range of face regions according to the nose tip. Then, according to a reference face model, the iterative nearest neighbor normal point method is used to find the nearest neighbor point set corresponding to the reference model for each 3D face data. Finally, the normal vector of these points is used as the feature for face recognition ICP face registration, and the average distance of matching points is generally used as the similarity measure of two faces. Since the average distance is greatly affected by noise points, Hausdorff distance is used as the similarity measure of the two-point sets [22]. To reduce the influence of noise points and 3D point cloud sampling differences on ICP registration, also some researchers [23], [24] used sparse ICP combined with a resampling method for registration and achieved a good recognition effect.
Curvilinear method Drira et al. [25] used the radial curve based on the nose tip to represent the whole face surface. In this method, the nose tip is first located, and then the face surface is segmented by a plane passing through the nose tip at every certain Angle. The plane and face surface intersection line is a radial curve. Some radial curves are discontinuous or too short due to occlusion or missing surface data, and these radial curves are discarded. The rest of the curve is used for face recognition. The distance between curves was obtained by elastic shape analysis. Lei et al. [26] also defined a curve at every certain Angle with the tip of the nose as the starting point. According to the curve, the face depth map is sampled, and the depth value of the sampling point is composed of a vector. To reduce the influence of expression, only the features of the upper half of the face were extracted. Then the kernel principal component analysis was used to map the ARS to the high dimensional feature space. Finally, a support vector machine is used for face recognition.
To sum up, the above research on 3D face recognition is often one-sided. For a single face feature image processing. This does ensure the efficiency of the network model, but it loses a lot of other features. More facial features cannot be learned, which affects the accuracy of 3D recognition. For different skin colors, and different gender, multi-pose, and big expression recognition effect is not ideal.
2.2 3D face representation
3D face reconstruction methods have been rapidly developed into practical applications. Prime examples include VR/AR, 3D avatar creation, video editing, image synthesis face recognition, virtual makeup or voice-driven facial animation Refs. [27], [28], [29]. To produce the problem manageable, most existing methods combine prior knowledge of geometry or appearance by using pre-computed 3D face models. These models [30], [31], [32] reference rough human face shapes but fail to capture geometric details. Like emotion-dependent wrinkles, which are crucial for the authenticity and support analysis of human emotions. There in common are several effective ways to instantly recover detailed facial geometry, however, they typically require high quality training scans or lack robustness to occlusion. None of these academic studies looked at how wrinkles change with creative expression.
Before typically learning, it traditionally relies on the expression method of texture features, and high-precision 3D scanning is generally used as training data. So you can’t maintain an unconstrained image. To solve the above problems, deep learning research rises in the whole scientific field. Two-dimensional identification and reconstruction can not meet the practical application of engineering. Therefore, 3D face recognition and reconstruction are critically important [33]. However, the apparent lack of 3D face data and the considerable difficulty of modeling pose challenges to the reconstruction task. Scientifically based on this, 3D face reconstruction methods have been developed rapidly. To simplify the processing process, most of the existing methods rely on a 3D face model based on prior calculations. These models combine prior knowledge of geometry and appearance and can reconstruct rough face shapes, but cannot capture geometric details of the face, so it is difficult to reconstruct a multi-pose face state. There are moreover possible ways to miraculously restore smooth facial shapes. However, they typically require multiple high-quality scanning devices for multi-angle scanning and typically lack the robustness of occlusion reflection scenes.
According to the above research results, some key problems of face recognition can be summarized. Face recognition and reconstruction are frequently studied independently. 3D recognition and 2D recognition are not combined effectively. But essentially, the 3D data of the image is directly correlated with the 2D data. Therefore, multimodal fusion of 2D and 3D data is carried out in this paper. The two are no longer single and independent. This prevalent method typically has better face recognition effect. Better data generalization performance is guaranteed. And can tolerate more facial expressions and creative expressions, as private well as skin color. The research of face recognition and reconstruction method develops no integral problem. This paper typically presents an innovative design of Laplacian pyramid network structure. It typically aims to carefully construct end-to-end dense connection through iteration of residuals on different feature layers. There are five layers of loss functions for different data feature dimensions. Such network design effectively and cleverly integrates two-dimensional information and three-dimensional features of the face. The research of the two-dimensional face and three-dimensional recognition is no longer distributed independently. And the geometry structure of the face is learned by the clever 3D face point detection assisted network. It can improve the prediction accuracy of the algorithm and ensure the speed. Moreover, our algorithm has excellent recognition and reconstruction results for face images of different skin color, different posture and diverse race. Specific network design and loss functions are described in Chapters 3.
3 Proposed method
First of all, the rapid detection and positioning of faces in an extensive background is the key to determining whether the key point model can be effectively established. After that, the data pre-processing of two-dimensional face image needs to extract face key points under multiple positions, three-dimensional face reconstruction and recognition, and multi-angle facial three-dimensional key points on the front and side. The rapid cascade of human face detection and the capture of three-dimensional key points guarantee the complete reconstruction and recognition of multiple postures and human faces. So we study a deep 3D face recognition algorithm for Laplace pyramid matching. Our algorithm is proved in the face orientation Angle (−100 to ＋100), and densely connected structure of face features matching and computational reconstruction. It is worth mentioning that our network using Laplace pyramid architecture for depth estimation can ensure that the global features simultaneously, through the Laplace operator to capture and store local information, aims to reconstruct high precision face depth map for 3D recognition.
3.1 Acquisition of facial stereoscopic key points
First, a model is established, a deformable shape instance S is defined S=[x1,y1,…,xL,yL]T, and N images are trained, including L feature points. Where, the coordinates are expressed as (xi, yi), ∀i=1,…,L. Then, generalized Purkuk analysis and principal component analysis were used to extract the alignment and orthogonal basis, and the shape examples represented by mean and feature vectors were obtained by changing the plane rotation and shift parameters of proportional parameters to enhance the training data. (1) Sp=S¯+UP
Where U represents the orthogonal basis of n eigenvectors, S¯ represents the mean value of shape vectors, and p=[p1,p2,…,pn]T represents the shape parameter vectors.
The following definition of facial expression (texture) model for deformation function W(P), in the actual data for the general texture deformation through the definition of face texture, face appearance model set feature equation function F, used to extract human to image features, after the feature deformation for reference model and vectrization. (2) A=F(Ii)(W(Pi)),∀i=1,2,…,N
and then conduct principal component analysis on A to establish the example of gauss appearance: (3) A=A¯+UC
where A is the appearance parameter vector. Formula (1) and formula (3) describe the change of shape and appearance.
When given a training set with N images and L feature points in each image, S can align the feature points in the image (move the feature points to the position of the reference model through affine transformation), and adjust the position of each feature point (xi, yi), vi=1 …N, And the average value was taken to obtain the results in x=[xi1,…,xiL]T, y=[yi1,…,yiL]T where U can be obtained by taking the average value of the training shape s1. sl and s the difference between the average shape PCA after operation, and take the corresponding eigen value’s largest first n characteristic vectors are usually the eigenvalues of the eigenvectors corresponding to the total energy accounted for more than 90% of the total energy of adjusting the shape parameter vector p, equivalent to adjust the shape of the different characteristic vector expression of the weight, can make the shape of the different instances, as shown in Fig. 1.
The average shape is at the far left of the shape model instance. It also includes the side and depression results of 3D face modeling obtained by randomly generating the weights of the first five feature vectors within the range of [−3, 3], as shown in Fig. 2. The establishment of three-dimensional point model is required to fit the image feature residuals generated by the minimum. So we can represent as below. And the 3D point model we show as in Fig. 1. The three-dimensional modeling formula based on three-dimensional key points is shown as follows. (4) argminp,c‖t(w(p))−a¯−UaC‖2
3.2 Establish a dense multi-dimensional face alignment
In the field of vision research of face reconstruction, face alignment is the key to the quality of reconstruction and recognition [34], [35], [36]. Among the early methods, there are many alignment methods based on two-dimensional facial markers [37], [38], such as local model, two-dimensional calibration alignment based on neural network and so on [18], [21], [22]. However, the limitation of the traditional method is that it can only return to the visible area of the face, which leads to the inability to effectively express faces in different poses and environments.
In order to solve these problems, this paper proposes a multi-pose alignment model framework for 3D faces. A basic model is established from a two-dimensional facial texture image by stereo point fitting. Then, the spatial coordinates are reconstructed in the three-dimensional geometric legend by the method based on three-dimensional reconstruction. The dense alignment of three-dimensional faces can be efficiently realized. Firstly, to ensure the semantics of the position stereo feature points, we establish a three-dimensional coordinate system based on the facial stereo key points and the facial texture map. After that, we establish densely connected face alignment. Specifically, the two-dimensional texture map structure and key stereo points are used as constraints for network training. Construct the geometric structure of two-dimensional to three-dimensional faces. This effective scheme can obtain three-dimensional feature estimation parameters for stereo alignment in high-dimensional space. Therefore, our method does not need complex parameters such as distortion parameters and refractive index, which significantly speeds up the network’s overall training architecture and recognition rate. Based on the above research, we built a 3D geometric model of face texture image through intensive alignment of key points, which was used for supervision constraints of the Laplacian pyramid network. The auxiliary network learned faster and more feature visualization results were shown in Fig. 2.
Fig. 1 Facial key points of front and side faces.
Fig. 2 A 3D face alignment model with different angles of dense alignment.
3.3 Laplace Laplace pyramid network
We show the main algorithm structure in Fig. 3, the two-dimensional rectangle represents the two-dimensional convolution. Among them, the yellow two-dimensional convolution is mainly used to build the key feature point model of human face. Three-dimensional cube represents the cost volume of three-dimensional convolution. Where the green three-dimensional cube represents the cost volume of low and middle dimensions. The red cube represents the high-dimensional cost volume. The specific algorithm derivation and calculation process are as follows.
First, according to the given two-dimensional image as the input, after the establishment of the three-dimensional point model, the rough reconstruction is carried out to encode the image into a cost body, and then the residual is calculated through the Laplace pyramid network architecture to form a low-frequency and middle-frequency matching face depth image, and finally, through multi-mode fusion into a high-frequency complete depth map, The encoder we trained includes a ResNet network as a generator of low-frequency disparity and a three-dimensional pyramid network architecture. The specific calculation process is as follows: For the Laplace residual of the input face image, it is expressed as Lf. (5) Lf=If−UP(If+1),f=1,2,3
Where f represents the horizontal exponent of the Laplacian pyramid. If represents the UP obtained by downsampling the original input 12f−1 below let Rf be the residual depth of the pyramid network The depth residual contains the rough geometric features and facial expression features, as well as the information of the three-dimensional key points of the face. Through the series of multiple modules, the pixel-level stack is carried out to accurately restore the local details of each scale in the decoding process. Finally, the depth image is output through the highest sub-link of the Laplace pyramid: (6) Df=Rf+UP(Df+1),f=1,2,3
It can be seen that, through the residual updating iteration of the tower structure, the network can well predict the depth image of the 3D face. To make the decoding process of depth images more efficient, we add the operation of weight standardization in the activation of the convolution cost body. It is worth mentioning that to robustly estimate the depth of information. We design the decoder can completely in the course of backpropagation gradient normalization, thus improving the gradient flow. Among them, the backpropagation is calculated in each layer of the Laplace pyramid. This can ensure that the residual error information of the color depth of translation is the stability and ideal. We plotted Table 1, Table 2. The input and output of low frequency and high frequency are given, respectively. And the specific parameters of low frequency and high-frequency disparity volume.
Fig. 3 Laplacian pyramid net structure.(For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
3.4 Loss
We use face images with texture information to train our model with supervised learning. It contains 5 terms of Laplacian pyramid loss functions. The first term aims at training the coarse reconstruction low-resolution disparity. Same as, we use the smooth L1 loss between the texture images Dn and the predicted low-resolution disparity D˜n for each key point pixel n, which is widely used because of its low sensitivity to outliers and defined as (7) L1=1N∑n=1NsmoothL1(Dn−D˜n)
in which, (8) smoothL1=12θ2,if|θ|<1|θ|−12,otherwise
where N is the number of the key point pixels. The second term is used to supervise the key facial 3D point edge refinement in face, which is defined as (9) L2=1N∑n=1NsmoothL2(Dn,D˜nr)
where D˜n is the disparity depth value of pixel n in the refined low-resolution disparity depth map.
The third term focuses on training the high-resolution disparity facial depth generator. In other words, the training set for the high-resolution is dynamically generated. We use k to denote the set including the pixels where the absolute errors between the ground truth disparities and the lowresolution disparities are larger than 1. Then we use the pixels in k to train the high-resolution disparity facial depth generator and the loss is defined as (10) L3=1|K|∑n∈ksmoothL1(Dng−Dˆn)
Table 1 Low and high resolution disparity regression.
Critical Hierarchy Input parameter Output Tensor
Low-resolution Conv 3D, 3 × 3 × 3, f = 64 18D×18H×18W×64
Conv 3D, 3 × 3 × 3, f = 64, s = 2 116D×116H×116W×64
Conv 3D, 3 × 3 × 3, f = 64(double) 116D×116H×116W×64
Residual connection ×2 18D×18H×18W×32
Transposed 3D conv, 3 × 3 × 3, f = 32, s = 2 14D×14H×14W×1
Soft argmin 14H×14W
Upsampled low-disparity H×W
Key-point refined low disparity H×W
High-resolution Conv 3D, 3 × 3 × 3, f = F, s = 2 14D×14H×14W×F
Conv 3D, 3 × 3 × 3, f = 2F 14D×14H×14W×2F
Residual connection ×2 14D×14H×14W×2F
Transposed 3D conv, 3 × 3 × 3, f = F, s = 2 12D×12H×12W×F
Residual connection 12D×12H×12W×F
3 × 3 × 3, f = 1, s = 2 D×H×W×1
Soft argmin H×W
Table 2 Summary of our low and high cost volume architecture.
Layer Description Output Tensor
Input facial image H×W×3
High-resolution features
Conv 5 × 5, features = 32, s = 2 12H×12W×32
Conv 3 × 3 × 2, features = 32 12H×12W×32
Conv 3 × 3, features = 32 12H×12W×32
Residual connection 12H×12W×32
Conv 3 × 3, features = 8 12H×12W×8
High-resolution cost volume 12D×12H×12W×16
Low-resolution features
Conv 3 × 3 × 3, features = 64, s = 2 14H×14W×64
Residual connection 14H×14W×64
Conv 3 × 3, features = 32 14H×14W×32
Repeat features 18H×18W×32
Low-resolution cost volume 18D×18H×18W×64
where |K| denotes the number of elements in the set k and Dˆn is the predicted high-resolution facial disparity for pixel n.
We adopt the fourth term to supervise the final disparity facial depth map. The loss is defined as (11) L4=1N∑n=1nsmoothL1(Dng−Dn)
where Dn is the final disparity depth value of the pixel n.
The last term addresses on the problem of how to automatically select the disparities between the low-resolution and high-resolution disparities. For each pixel, low resolution disparity is selected if the high resolution disparity is greater than the absolute error between ground and low resolution dis-parity. During the training, we dynamically mark the pixels of each face image. For each pixel n, if ‖Dng−D˜n‖1≤‖Dnt−D˜n‖1 , we label the pixel n as pn=0. Otherwise, we label it as pn=1. Let yn0 and yn1 are the values of the pixel n in the two feature maps, respectively. Then we use a softmax loss to train. Then the loss is defined as (12) L5=−1N∑n=1N(1−pn)logyn0+pnlogyn1
The total loss function is represented as below. (13) LALL=L1+L2+L3+L4+L5
4 Experiments
The algorithm model is trained by dual-card NVIDIA 1080 TI GPU of Ubuntu 16.04 system, Pycharm and Matlab were used as visual platforms for training and modeling, respectively, which can be tested on GPU platforms.
In this paper, the Laplacian pyramid network is selected as the transfer learning model of the feature extraction subnet. The attenuation parameter is set to 5×10−4, and the learning rate and momentum parameters are set to 1e − 4 and 0.9 respectively. In addition, the random gradient descent method is used as a learning optimizer. By freezing the weight of the first K layer in the pre-training model, fine-tuning the network, and then training the remaining N–K layers to learn the weight and deviation of the unfrozen layer. Then, the optimal matching between frozen layers is found through continuous iteration, and the fine-tuning of network parameters is retrained according to the results. In order to intuitively show the 3D recognition capability of the proposed Laplacian pyramid network, the low-frequency features extracted from the first convolution block of the network are visualized. There are two convolution layers in the first convolution block, and each convolution layer has 64 filters. Therefore, we can generate 64 low-frequency feature maps for facial attribute mapping of each data type. In the second convolution block, there are two two-dimensional convolution layers. Through this operation, a 3D cost voxel is generated through this operation, which contains medium and high-frequency information, and then fused into the decoder through Laplace’s decoding network. Multi-modal fusion of facial feature information in two-dimensional and three-dimensional levels is obtained by five-layer regression iteration and fusion of various facial shapes and features related to expressions. This convolution layer can extract facial features with higher dimensions and finally output 512 feature maps. The depth of redundant representations will be combined into a single compact facial feature. Through the above operations, we make the network model robust and efficient, and we propose Laplace 3D face recognition network. It can form a high-level and high-frequency face recognition representation and more effectively recognize and reconstruct three-dimensional faces.
4.1 Data set
The BU-3DFE (Binghamton University 3D Facial Expressions) [39] database is widely used for static/dynamic 3D facial expression recognition. This database is the benchmark database for 3D facial expression recognition research. It contains 100 subjects (56% female and 44% male) aged 18 to 70 years. In addition to neutral expressions, there were six basic expressions (happiness, disgust, fear, anger, surprise, and sadness), each of which contained four intensity levels. Each subject had 25 3D facial expression models, and there were 2500 3D facial expression point cloud models and 2D facial texture images in the database.
Aflw2000-3D dataset [40] for evaluating challenging unconstrained 3D face alignment. The database contains the first 2000 images from the AFLW and is annotated with extended 3DMM parameters and 68 3D annotations. In the experiment, we add and use this database to evaluate performance on facial reconstruction and face alignment tasks.
Aflw-lfpa [41] is another extended dataset of AFLW. Images were extracted from AFLW according to attitude, and a test image dataset containing 1299 evenly distributed yaw angles was constructed. In addition, each image is tagged with 13 other landmarks, which are used to expand the only 21 visible landmarks in the AFLW. The database is evaluating tasks for 3D face alignment. We measured the accuracy of our results using 34 visible landmarks as ground truth values.
4.2 Evaluation index
There have been two types of face recognition tests: 1:1 face verification and 1: N face recognition. The 1:1 face verification test method used in this paper utilizes TAR as the ordinate and FAR as the abscissa. TAR@FAR = 1% has been used to evaluate the model’s performance. The test dataset would include positively and negatively sample pairs. Positive sample pairs contain two images of the same individual, while antagonistic sample pairs are two images of two different people. The accurate acceptance rate is called TAR. The positive sample of the comparison score in the face verification process is greater than the set threshold value in the positive sample of the total.
FAR is the false acceptance rate, indicating the Proportion of the comparison score of antagonistic sample pairs in the total number of opposing sample pairs when the comparison score of opposing sample pairs is greater than the set threshold in the face verification process. TAR@FAR = 1% represent N antagonistic sample pairs, which are input into the network model for feature comparison. N comparison scores are obtained, and the value with the highest score is taken as the threshold. Then all positive sample pairs are compared in the input network model. The Proportion of the number of positive sample pairs with the comparison score more significant than the threshold in the total positive sample pairs is TAR@FAR = 1%.
We adopted the preferred recognition rate (Top1) for the Test method of 1:n face recognition to evaluate the model’s performance. The depth Test data set in the table was taken as an example. The number of registered samples was 10000, the number of test samples was 2500, each test sample is compared with all samples in the registration set, and then the comparison score is sorted in descending order. If the tag with the highest score is the same as that of the test sample, it is the same person. Then the final Top1 is Rank1 by counting the number of Rank1 hits plus one Proportion of the hit number in the total test sample number.
When calculating the similarity score of two face features, Euclidean distance and cosine distance is usually used in face recognition. Euclidean distance directly calculates the distance between two points, and the calculation formula is shown below. Take the output features in this paper as an example. Since the output is a 512-dimensional feature vector, we use N to represent it. Thus get the distance of two face feature vectors. The smaller the distance, the closer the face. (14) d(x,y)=∑i=1n(xi−yi)2
Where, d represents Euclidean distance. x represents the point in n-dimensional space. y represents the point in n-dimensional space.
The cosine distance is the two face features as two vectors, calculate the cosine value of the Angle, as shown in the formula below. When the Angle between the two vectors is closer to 0, the difference is smaller, the face is closer to the face similarity score in this paper is calculated by the cosine distance. (15) d(x,y)=cosx→⋅y→‖x‖⋅‖y‖
Fig. 4 The first and fourth columns represent the original input image. The second and fifth columns represent the output texture image. The third and sixth columns are the final high-frequency depth images that our network outputs. Through this group of images, it is confirmed that our proposed network framework can truly recognize 3D faces and reconstruct depth disparity.
4.3 Qualitative evaluation
The Laplacian pyramid network of a single input image can be an excellent method to use 3D point geometry information and low frequency, medium frequency, and high-frequency information in the image to achieve realistic 3D face reconstruction. Our network architecture is shown in Fig. 3. The output of the comparison results can be seen in Fig. 4. More and more precise 3D face depth maps and texture map results are shown in Fig. 5. The visualization results of the reconstruction of different skin colors and races are displayed. Proved that our network architecture is an accurate 3D reconstruction. Moreover, it can complete 3D face recognition. Because compared with other methods, our network through continuous intensive iterative learning of The Laplacian pyramid and the supervision mechanism of three-dimensional key points. The smooth reconstruction of multi-pose and multi-view is realized. At present, the research results include PRNet [42] and 3DDFA-V2 [43], but the reconstruction results obtained by these methods are reconstructed after cutting surfaces. This creates artificial interference, and experimental results and effects are inconsistent. Our approach is to cascade output using an end-to-end network architecture. The experimental results are robust and reliable. The test of many data also confirms that our network is not sensitive to dark environments and low texture areas and has stable output performance.
It is worth mentioning that the general 3D face recognition task is heavy. The generic mapping is usually used for two-dimensional plane expansion. This operation for the two-dimensional face recognition effect is better and can better point matching estimation. Nevertheless, in the three-dimensional face task heavy, the effect is not ideal. For incomplete symmetry of the face, the three-dimensional structure will appear distorted.Fig. 5 This set of graphs shows the results we predicted for faces with different skin tones and different expressions. It contains output texture images of different tables and corresponding clear and smooth depth images.
Fig. 6 Multi-view multi-angle reconstruction of the display map.
We were inspired by the merits of generic mapping after the low-frequency output of the Laplace pyramid network. We adopt the strategy of depth mapping and integrate the geometric modeling of 3D key points. Multi-pose, multi-angle 3D face recognition, and reconstruction are realized. In Fig. 6, the multi-pose and multi-angle image reconstruction effects of different input images. In Fig. 6, the first column represents the depth image of the depth map. It can be seen that the deep face in the figure is spread out as a generic mapping structure. The second column shows the depth display result of the profile face. The third column represents the lateral upper body depth image display results. The fourth column represents the frontal upper body depth image results. The fifth column represents the reconstruction result of the full-face depth image of the front. This is output by the high superimposed frequency.
4.4 Quantitative evaluation
We compare the Laplace Pyramid network with other open methods, including 3DDFAV2 [43], RingNet [44], PRNet [42], 3DMM-CNN [45], DECA [46] and Extreme3D [47]. Note that the Plath Pyramid network intensively implemented 3D reconstruction and validated the SOTA performance. NoW benchmark included 2054 face images of 100 subjects without human interference. Then the 3D data matching training was conducted, and the test group and the verification group were divided by 8 : 2. Each subject had a reference 3D face scan. The images included images of neutral expressions indoors and outdoors and images of expressions from different angles from front to side. Assessment of this data set provides a standard definition, after strict alignment scan and reconstruction, the measurement of all reference scan vertices to the triangle mesh surface recent distance. For gender bias of the test results, we report (W) women and men (M), respectively. NoW error of the test object found that to restore women more accurate shape. Reconstruction error is expressed as follows: median: 1.18/1.19 (W/M), average: 1.32/1.45 (W/M), and standard: 1.21/1.21 (W/M). The Laplacian pyramid network presents the most advanced NoW results, containing the lowest mean median and standard deviation reconstruction errors. In this way, it is proved that detailed high-frequency shapes can improve visual quality more than rough shapes. At the same time, to verify the performance of our network more comprehensively.
We find that the predicted artificial preprocessing of the clipped surface mesh is smaller than the present reference plane, which will lead to a high reconstruction error of the missing area. For a fair comparison, we use the Basel standard output of the Basel Face Model (BFM) parameters for a complete reconstruction. Furthermore, get these complete mesh evaluations now. As shown in Table 3, the most advanced current results are given. Reconstruction errors with the lowest mean, median, and standard deviation are provided.Table 3 Reconstruction error on the NoW benchmark.system of units:mm.
Method Median Mean Std
3DMM-CNN [45] 1.84 2.34 2.07
PRNET [42] 1.51 1.98 1.89
SENet [48] 1.24 1.56 1.30
RING-NET [44] 1.20 1.54 1.32
3DDFAV2 [43] 1.24 1.58 1.39
MGC-NET [49] 1.32 1.89 2.70
DECA [46] 1.18 1.39 1.24
Ours 1.15 1.38 1.21
Fig. 7 This table show the different network and error map.
Fig. 8 This table show about different people facial and including different error map.
Table 4 Performance on the Feng benchmark. system of units: mm.
Method Median LQ Median HQ Mean LQ Mean HQ Std LQ Std HQ
3DMM-CNN [45] 1.89 1.86 2.34 2.30 1.90 1.88
PRNET [42] 1.80 1.58 2.40 2.06 2.19 1.79
SENet [48] 2.40 2.38 3.44 3.5 6.10 6.76
RING-NET [44] 1.66 1.59 2.02 2.03 1.78 1.67
3DDFAV2 [43] 1.64 1.48 2.09 1.90 1.87 1.63
DECA [46] 1.58 1.49 1.90 1.87 1.67 1.69
Ours 1.38 1.45 1.89 1.85 1.51 1.65
The benchmark of Feng et al. [50], which consisted of 2000 face images of 135 subjects and a reference 3D face scan image of each subject, was selected for testing. The benchmark consisted of 1344 low-quality (LQ) images extracted from videos and 656 high-quality (HQ) images taken in control scenes. The Laplacian pyramid network provides state-of-the-art performance by measuring the distance from all reference scan vertices to the nearest point on the reconstructed mesh surface, as shown in Table 4. In order to verify the performance of the error indicators in this paper more intuitively. A schematic diagram of the error area with color is presented. Among them, different colors show the error of different indicators. The smaller the area of error color map is, the better the network performance is. In Fig. 7, Fig. 8, we show the median, mean, and standard error for different networks. Median, mean, standard error for men and women.
In addition, we show TOP1 accuracy and TAR@FAR = 1% accuracy of different networks through intuitive bar charts. Including Attention-Net [51], ECANet-K9 [52], ECANet-K3 [53], SENet [48], Resnet-34 [54] and our network. As shown in Fig. 9, in two accuracy assessments. Our algorithm is more accurate than other algorithms. It is verified that our algorithm has superior performance in 3D face recognition. We compared data and feature performance from different models. The evaluation indicators include TAR@FAR = 1% and Top1. Our network uses 3D face data for training. Feature analysis uses multi-level depth features. As shown in Fig. 9, the 3D recognition accuracy of our model fusion is higher than that of other networks. In Fig. 10, we visualized the recognition result of the 3D face. It can be seen that the output results of our algorithm can completely reconstruct the front and side images of the face. This is all done by entering a two-dimensional image of a plane. The validity of the Laplacian face recognition algorithm is verified. For different races, different skin colors, different postures, and different facial expressions, the visual reconstruction effect has good robustness. (See Table 5)
Table 5 Comparsion results of the models.
Modal Dataset Feature TAR@FAR=1% Top1
Tang et al. [55] 3D sopes 92.16% 87.10%
Song et al. [56] 3D distance 93.08% 87.80%
Li et al. [57] 3D normals 91.2% 82.01%
Wang et al. [58] 3D crvatures 88.60% 83.60%
Zeng et al. [59] 3D curvature 79.63% 70.93%
Berretti et al. [60] 3D depth/SIFT 85.56% 77.54%
Yang et al. [61] 3D shape index 86.60% 82.30%
Li et al. [62] 2D＋3D meshHOG/SIFT 90.16% 86.32%
Ours 3D multi-scale deep feature 99.84% 93.64%
4.5 Ablation experiments
In order to verify the effectiveness of our network more specifically. Ablation experiments were introduced to verify the validity of each layer of the Laplacian pyramid network. In Fig. 10, the analysis can be obtained. In the ROC curve, the Laplace fusion module, that is, the high-frequency fusion module has the highest 3D face recognition accuracy. Its ROC curve is smoother, and its area is more extensive than other curves. It has been proved that the performance of the Laplace fusion module is the best. Secondly, the performance of depth maps is better. The reliability of selecting a depth map for fusion is verified. The third performance is the key fusion module. For this reason, we use this method to supervise the whole network and assist the overall network model in learning more facial features faster. Then we tested the 3D face recognition performance of different network architectures. You can refer to the performance analysis in Fig. 11. To verify the effectiveness of each layer in the network. We have done ablation experiments on each layer of the network. The green line represents the final performance of the Laplacian fusion layer. It can be seen that its roc curve is very stable, and tends to be high and stable after FAR is higher than Where the pink line represents the intermediate frequency level of the Laplacian network. The blue line represents the lowest frequency level of the Laplacian network. The red line represents the performance of the 2D texture layer, and it can be seen that its performance is the lowest. The yellow line represents the performance of the key point model. In a comprehensive analysis, with the hierarchical superposition of low frequency, intermediate frequency, and high frequency of the Laplacian network, the final fused network performance is far superior to other output layers. The effectiveness and high performance of the overall design of the network model are verified. In Fig. 12, we show the comparison results between the Laplace network and other mainstream networks. Includes ECANet-K3 [53], ResNet,62, SENet [48], PRNet [42] comparison. It can be seen that the performance of Laplace’s intermediate frequency layer and high-frequency output layer is much higher than that of other networks. The TAR value of the Laplacian high-frequency output layer represented by the green line is the highest when FAR is equal to 0.010. The pink line represents the lowest TAR value of ResNet. The comparative experiment proves that the final performance of our network is higher than other mainstream algorithms. We can see that the red Laplacian intermediate frequency model has the best effect in the initial ascent. After FAR is 0.002, it tends to be stable. The accuracy of the intermediate frequency model is above 0.9895. Green represents the Laplacian network model of high frequency fusion. Network performance did not improve quickly in the early days. This is because network models need to integrate multi-level learning. It can be seen that when FAR is 0.006, the performance of the high-frequency fusion model is significantly improved. The final 3D recognition rate is more than 0.9959. It is worth mentioning that our network performance is also the best in the comparison model. The ablation experiments above confirmed the effectiveness of our network. And it has higher efficiency of 3D recognition. It is necessary to observe the TAR value when FAR = 0.010. The larger the final value of TAR, the better the performance of the network. The green part is the highest frequency output of our network. The TAR value is the largest, and the performance of the network is the best. Moreover, while considering the network performance, we need to take into account the efficiency of the network. Therefore, the robustness of the model is also very stable.
Fig. 9 This figure shows the comparison of two kinds of accuracy evaluation indexes under different network architectures. The first line is the accuracy index of The Laplace network, which is higher than the results of other methods.
Fig. 10 This set of images shows the comparison results of our 3D visualization. The first and fifth columns represent the original input image. The second and sixth represent the output texture image. The third and seventh columns represent the output 3D frontal face image. The fourth and eighth columns represent the output side 3D face image.
Fig. 11 ROC curves of different layers and multimodal fusion of the Laplace pyramid network.(For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 12 ROC curves of different network structure and the Laplace pyramid network.(For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
5 Conclusion
This paper introduces the design of the Laplace end-to-end pyramid network. A convergence strategy for dense connection is adopted. The problems of 3D face registration, reconstruction, and 3D recognition are solved. By learning the 3D critical points of the human face, we can directly use regression to extract the complete 3D structure and semantic information from 2D images and then carry out 3D reconstruction and recognition. For other advanced algorithms, our work integrates reconstruction and 3D facial recognition. To ensure the quality of reconstruction and obtain the recognition effect. The quantitative and qualitative results show that this method is robust to pose, illumination and occlusion. Experiments on test data sets show that this method is superior to other methods. In addition, the recognition robustness of different facial poses, skin colors, and expressions is better. The experimental results show that this method is faster than other methods, has a higher 3D recognition rate, and is suitable for real-time applications. It can be used in COVID-19 epidemic normalization personnel management and has a good prospect for the establishment and engineering application of the 3D face database.
In future research, we will focus on using active, structured light to recognize and reconstruct 3D faces. The goal is to combine the functional, structured light theory with the current passive algorithm. A more universal and practical algorithm is studied. It will be used in facial recognition products to help prevent and control epidemics. Because face information involves privacy issues. We will consider introducing the federal learning technology in future work while training data and transmitting privacy with the control network model. Federal learning such as DEEP-FEL combined with the network model is adopted for training. Better control the privacy of user data.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data availability
No data was used for the research described in the article.
Acknowledgments
This work is supported by the funding from National Natural Science Foundation of China (Grant No. U21B2035).
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| 0 | PMC9744674 | NO-CC CODE | 2022-12-15 00:01:52 | no | Comput Commun. 2022 Dec 13; doi: 10.1016/j.comcom.2022.12.011 | utf-8 | Comput Commun | 2,022 | 10.1016/j.comcom.2022.12.011 | oa_other |
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World Allergy Organ J
World Allergy Organ J
The World Allergy Organization Journal
1939-4551
Published by Elsevier Inc. on behalf of World Allergy Organization.
S1939-4551(22)00110-7
10.1016/j.waojou.2022.100734
100734
Article
Covid-19 Vaccine Provocation Test Outcome In High-Risk Allergic Patients: A Retrospective Study From A Tertiary Hospital In Indonesia
KOESNOE Sukamto M.D., Ph.D. a∗
MARIA Suzy M.D. a
WIDHANI Alvina M.D., Ph.D a
HASIBUAN Anshari S. M.D. a
KARJADI Teguh H. M.D. a
KHOIRUNNISA Dhiya M.D. a
YUSUF Muhammad B.Med a
SUMARIYONO Sumariyono M.D. b
LIASTUTI Lies D. M.D. b
DJAUZI Samsuridjal M.D., Ph.D. Prof. a
RENGGANIS Iris M.D., Ph.D Prof a
YUNIHASTUTI Evy M.D., Ph.D. a
a Division of Allergy and Clinical Immunology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia
b dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia
∗ Corresponding author:Division of Allergy and Clinical Immunology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia -- dr. Cipto Mangunkusumo Hospital, Jl. Diponegoro No. 71, Jakarta 10430, Indonesia.
13 12 2022
13 12 2022
1007349 8 2022
30 10 2022
30 11 2022
© 2022 Published by Elsevier Inc. on behalf of World Allergy Organization.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Background
High COVID-19 vaccine coverage is essential. Patients who are considered high risk for hypersensitivity reactions and have had an allergic reaction to the COVID-19 vaccine are usually referred to an allergist for assessment of vaccination. Administration of a vaccine graded challenge (also known as a provocation test) is an option that can be considered in this population. This primary objective of this study is to describe the outcome of the COVID-19 vaccine provocation test and to understand the predicting factors associated with hypersensitivity reaction after the provocation test as the secondary objective.
Methods
Adult patients with a history of hypersensitivity reaction to the first COVID-19 vaccine and high-allergic patients underwent COVID-19 vaccine provocation test up until May 2022 were included. A protocol using skin prick test (SPT), intradermal test (IDT), followed by graded challenge was developed for the determined vaccine used.
Results
A total of 232 patients were included in the analysis. Twenty-eight had hypersensitivity to their first COVID-19 vaccine dose and 204 were high risk for allergic reaction. Hypersensitivity reactions occurred in 20 patients (8.6%, 95% CI: 5–12.2%), consisting of 4 reactions after SPT, 9 after IDT, 7 during or after titrated challenge. Half of the reactions were mild; however, three patients developed severe reactions. Patients with history of anaphylaxis were more likely to experience hypersensitivity reaction after provocation test (aRR = 2.79, 95% CI: 1.05-7.42).
Conclusion
Provocation test in COVID-19 vaccination has a high success rate in patients with a history of hypersensitivity to the first COVID-19 vaccine and in high allergic patients. History of anaphylaxis is associated with hypersensitivity reaction after a COVID-19 vaccine provocation test.
Keywords
Allergy
Anaphylaxis
COVID-19
Provocation test
Vaccination
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pmc
| 0 | PMC9744675 | NO-CC CODE | 2022-12-15 00:01:52 | no | World Allergy Organ J. 2022 Dec 13;:100734 | utf-8 | World Allergy Organ J | 2,022 | 10.1016/j.waojou.2022.100734 | oa_other |
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Sci Total Environ
Sci Total Environ
The Science of the Total Environment
0048-9697
1879-1026
The Authors. Published by Elsevier B.V.
S0048-9697(22)08017-2
10.1016/j.scitotenv.2022.160914
160914
Article
Evaluation of two different concentration methods for surveillance of human viruses in sewage and their effects on SARS-CoV-2 sequencing
Girón-Guzmán Inés a1
Díaz-Reolid Azahara a1
Cuevas-Ferrando Enric a
Falcó Irene a
Cano-Jiménez Pablo bc
Comas Iñaki bc
Pérez-Cataluña Alba a⁎
Sánchez Gloria a
a Department of Preservation and Food Safety Technologies, Institute of Agrochemistry and Food Technology, IATA-CSIC, Av. Agustín Escardino 7, Paterna 46980, Valencia, Spain
b Instituto de Biomedicina de Valencia (IBV-CSIC), C/ Jaume Roig, 11, Valencia 46010, Spain
c CIBER in Epidemiology and Public Health (CIBERESP), Valencia, Spain
⁎ Corresponding author.
1 Contributed equally to this work.
13 12 2022
1 3 2023
13 12 2022
862 160914160914
10 6 2022
9 12 2022
9 12 2022
© 2022 The Authors. Published by Elsevier B.V.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
During the current COVID-19 pandemic, wastewater-based epidemiology (WBE) emerged as a reliable strategy both as a surveillance method and a way to provide an overview of the SARS-CoV-2 variants circulating among the population. Our objective was to compare two different concentration methods, a well-established aluminum-based procedure (AP) and the commercially available Maxwell® RSC Enviro Wastewater TNA Kit (TNA) for human enteric virus, viral indicators and SARS-CoV-2 surveillance. Additionally, both concentration methods were analyzed for their impact on viral infectivity, and nucleic acids obtained from each method were also evaluated by massive sequencing for SARS-CoV-2. The percentage of SARS-CoV-2 positive samples using the AP method accounted to 100 %, 83.3 %, and 33.3 % depending on the target region while 100 % positivity for these same three target regions was reported using the TNA procedure.
The concentrations of norovirus GI, norovirus GII and HEV using the TNA method were significantly greater than for the AP method while no differences were reported for rotavirus, astrovirus, crAssphage and PMMoV. Furthermore, TNA kit in combination with the Artic v4 primer scheme yields the best SARS-CoV-2 sequencing results. Regarding impact on infectivity, the concentration method used by the TNA kit showed near-complete lysis of viruses. Our results suggest that although the performance of the TNA kit was higher than that of the aluminum procedure, both methods are suitable for the analysis of enveloped and non-enveloped viruses in wastewater by molecular methods.
Graphical abstract
Unlabelled Image
Keywords
Wastewater-based epidemiology
Enteric viruses
Sequencing
SARS-CoV-2
Editor: Paola Verlicchi
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pmc1 Introduction
Over the last two years, molecular analysis of SARS-CoV-2 in wastewater samples, has become very popular due to the potential for epidemiological surveillance using wastewater collected from wastewater treatment plants (WWTP), sewers or even aircrafts (Ahmed et al., 2022; Davó et al., 2021; Polo et al., 2020). However, the analysis of wastewater for virus surveillance is not new and had been used long before for epidemiological tracking of human enteric viruses such as poliovirus, norovirus, enterovirus, rotavirus, adenovirus and hepatitis A and E viruses (Asghar et al., 2014; Cuevas-Ferrando et al., 2020; Hellmér et al., 2014; Miura et al., 2016; Prevost et al., 2015; Santiso-Bellón et al., 2020).
Human enteric viruses pose one of the highest microbiological risks of water-borne infections (Wyn-Jones and Sellwood, 2001). Due to their excretion in feces, these viruses reach wastewater treatment systems and can contaminate other water sources into which they are discharged. The application of RT-qPCR is currently used as a gold standard method to provide information about levels of these pathogens in wastewater as well as in effluents (Haramoto et al., 2020). However, the low presence of viruses in wastewater in relation to other organisms and the complexity and variability of wastewater samples make viral concentration and nucleic acid extraction methods critical for these types of analyses (Haramoto et al., 2020).
During the current COVID-19 pandemic, several studies have compared different procedures for SARS-CoV-2 detection by RT-qPCR or digital PCR (Rusiñol et al., 2020b; Torii et al., 2022). Moreover, high-throughput sequencing techniques have been used for the analysis of SARS-CoV-2 genomes in wastewaters, evidencing their usefulness in detecting the linage introduction in a population, as well as in profiling new outbreaks, and tracking viral strains (Crits-Christoph et al., 2021; Izquierdo-Lara et al., 2021; Nemudryi et al., 2020; Pérez-Cataluña et al., 2022). Nevertheless, considering the potential of WBE for current and future treats, a broader comparison is needed, not only to establish methods for viral detection and quantification but also to characterize these using high-throughput sequencing techniques.
Therefore, the aim of this study was to evaluate the performance of two concentration methods for the detection of enteric viruses, viral fecal indicators, and SARS-CoV-2. Additionally, nucleic acids obtained from each concentration method were evaluated by targeted sequencing in terms of coverage across the SARS-CoV-2 genome.
2 Materials and methods
2.1 Viral concentration methods
Grab wastewater samples, collected from 6 different WWTPs on August 2021, were inoculated with 100 μL of porcine epidemic diarrhea virus (PEDV) strain CV777 as a coronavirus model and mengovirus (MgV) vMC0 (CECT 100000) as a non-enveloped counterpart. Two hundred milliliters of wastewater samples (n = 6) were concentrated through a previously validated aluminum-based adsorption-precipitation method (hereafter referred to as AP) (Pérez-Cataluña et al., 2021; Randazzo et al., 2019). In parallel, 40 mL of wastewater samples (n = 6) were processed with the vacuum concentration system using by Enviro Wastewater TNA Kit (Promega Corp., Spain) following the manufacturer's protocol (hereafter referred to as TNA). In brief, 0.5 mL of protease solution was added to 40 mL of wastewater, and samples were incubated statically for 30 min at room temperature (RT) and centrifuged at 3000 ×g for 10 min. Then, in duplicate, 20 mL of the supernatant was transferred to a clean tube and 5.5 mL of Binding Buffer 1, 0.5 mL of Binding Buffer 2, and 24 mL of isopropanol were added. The mixture was passed through a PureYield™ Midi Binding Column (Promega) using a VacMan® Vacuum Manifold (Promega). Five milliliters of Inhibitor Removal Wash (complemented with 40 % isopropanol as specified by the manufacturer's protocol) followed by 20 mL of RNA Wash Solution (complemented with 63 % ethanol 95 % as specified by the manufacturer's protocol) were passed through the column. Finally, the concentrated sample was eluted in 500 μL of nuclease-free water for nucleic acid extraction.
2.2 RNA extraction and virus quantification
Viral extraction from wastewater concentrates, obtained by the AP and the concentration procedure of the TNA kit, was carried out using the Maxwell® RSC Instrument (Promega) with the Maxwell RSC Pure Food GMO and authentication kit (Promega) and the “Maxwell RSC Viral total Nucleic Acid” running program.
Samples concentrated using the AP method were processed as described previously by Pérez-Cataluña et al. (2021). Samples concentrated by the TNA method were subjected to nucleic acid extraction using 500 μL of the eluate. This eluate was mixed with 150 μL of Binding Buffer 1 and 50 μL of Binding Buffer 2, both provided with the TNA kit, vortexed, and incorporated into a Maxwell RSC Cartridge (Promega).
Viral detection of SARS-CoV-2, PEDV, and MgV was performed by RT-qPCR using the One Step PrimeScript™ RT-PCR Kit (Perfect Real Time) (Takara Bio Inc., USA). SARS-CoV-2 detection was achieved by targeting the N1 region of the nucleocapsid gene and the IP4 region of the RNA-dependent RNA polymerase gene (Institut Pasteur, 2020). For N1, two RT-qPCR assays were tested; the One Step PrimeScript™ RT-PCR Kit (Perfect Real Time) was used with N1 primers and conditions described by (CDC, 2020) (hereafter referred to as N1-CDC); and the duplex RT-qPCR kit detection Wastewater SARS-CoV-2 RT-qPCR System (Promega) for SARS-CoV-2 and pepper mild mottle virus (PMMoV) (hereafter referred to as N1-Dup). Membrane gene (M) specific primers were used for PEDV detection as described by Puente et al. (2020). For MgV, detection was carried out using primers and probe described in (ISO 15216-1:2017). Reaction mixes, thermal cycling conditions, and sequences for primers and probes are listed in Pérez-Cataluña et al. (2021).
Levels of norovirus GI and GII, human astrovirus (HAstV), rotavirus (RV), hepatitis A virus (HAV) and hepatitis E viruses (HEV) were determined using the RNA UltraSense One-Step kit (Invitrogen, USA) as previously described (Randazzo et al., 2019).
Occurrence of crAssphage was established using the qPCR Premix Ex Taq™ kit (Takara Bio Inc.) using primers and conditions described by (Stachler et al., 2017).
Different controls were used in all assays: negative process control consisting of PBS; whole process control to monitor the process efficiency of each sample (spiked MgV and PEDV); and positive (reference material) and negative (RNase-free water) RT-qPCR controls. Moreover, undiluted and ten-fold diluted nucleic acid were tested in duplicate to check for inhibitors for all the targeted viruses.
Standard curves were determined according to the Public Health England (PHE) Reference Materials for Microbiology for norovirus GI (batch number 0122-17), norovirus GII (batch number 0247-17) and HAV (batch number 0261-2017) and reported as genomic copies (gc), while standard curves for RV, MgV, and HAstV were generated by amplifying ten-fold serial dilutions of viral suspensions in quintuplicates and calculating the number of PCR units (PCRU). Standard DNA material for crAssphage standard curve generation relied on a customized gBlock gene fragment (Integrated DNA Technologies, Coralville, IA) containing target sequence for CPQ_064 crAssphage primers set (Stachler et al., 2017).
Commercially available Twist Synthetic SARS-CoV-2 RNA Control (Control 2, MN908947.3) was used to prepare standard curves for SARS-CoV-2 quantification.
2.3 Effect of concentration procedure on viral infectivity
To accomplish this, 500 mL of a grab wastewater sample was inoculated with Murine norovirus (MNV-1, kindly provided by Prof. H. W. Virgin, Washington University School of Medicine, USA) and HAV strain HM-175/18f (ATCC VR-1402). In parallel, 500 mL of PBS was also artificially inoculated with both viruses. Two hundred milliliters of wastewater samples (n = 2) or PBS (n = 2) were concentrated through the AP procedure while 40 mL of wastewater samples (n = 2) or PBS (n = 2) were processed with the TNA Kit as described above. Then, concentrated samples were ten-fold diluted, and infectious viruses quantified using the Spearman-Karber method on confluent RAW 264.7 (ATCC TIB-71) and FRhK-4 (ATCC CRL_1688) monolayers for MNV and HAV, respectively (Falcó et al., 2018).
2.4 SARS-CoV-2 sequencing
Genomic sequencing of SARS-CoV-2 present in wastewater samples was carried out following ARTIC protocol versions 3 and 4, as version 4 was released during the study in response to the realization that some V3 primers were located in regions with key mutations. Sequencing libraries were generated using the Nextera Flex kit (Illumina, CA, USA) and sequenced on Illumina MiSeq platform by paired-end reads (2 × 200) (Pérez-Cataluña et al., 2022). Adaptors and nucleotides below Q30 Phred score were cleaned by using cutadapt software (Martin, 2011) and reformat.sh from bbmap (sourceforge.net/projects/bbmap/), respectively. Obtained clean reads were aligned to the genome of SARS-CoV-2 isolate Wuhan-Hu-1 (MN908947.3) using the Burrows-Wheeler Aligner v0.7.17-r1188 with default parameters (Li and Durbin, 2009) and indexed by samtools (Li et al., 2009). Genomic coverage for each sample was calculated using nucleotide positions with at least 20× depth.
2.5 Statistical analyses
Normal distribution was evaluated with Shapiro-Wilk tests. Significance of the differences in viral detection by RT-qPCR was evaluated using Student's t-test for normally distributed data (i.e. norovirus GI and GII, rotavirus, PMMoV, crAssphage, and MgV) and Mann-Whitney-Wilcoxon or Dunn's tests with adjusted p-values with the Holm method for not normally distributed data (i.e. PEDV, HAstrV, HEV, SARS-CoV-2).
The statistical analysis of differences in logarithmic reductions after cell culture assays was carried out by the post-hoc Tukey's method (p-value < 0.05) to compare and determine the difference among different concentration procedures.
The statistically significant differences in the results obtained after the genomic analysis (i.e. percentage of reads identified as SARS-CoV-2, percentage of SARS-CoV-2 genome coverage, and mean values of genomic depth) were calculated by pairwise comparisons using Student's t-test for the percentage values of SARS-CoV-2 reads and genomic coverage, and with the Mann-Whitney-Wilcoxon test for mean depth values. Differences were considered significant when the p-value was <0.05. All the statistical analyses were made with R Statistical Software (version 3.6.3).
3 Results
3.1 Comparison of the aluminum-based adsorption precipitation method (AP) and the direct capture method (TNA) for viral detection and recovery
Wastewater samples were processed using both the AP method (initial sample volume 200 mL) and the TNA Kit (initial sample volume 40 mL) for their ability to concentrate SARS-CoV-2, human enteric viruses, and viral fecal indicators from wastewater samples.
Wastewater samples were analyzed by targeting two different SARS-CoV-2 genomic fragments (N1 and IP4) to evaluate the sensitivity of each concentration method. The percentage of positive samples using the AP method was 100 %, 83.3 %, and 33.3 %, for N1-Dup, N1-CDC and IP4, respectively, while 100 % positivity for the three targets was reported using the TNA procedure (Fig. 1, Sup. Table S1). Significative differences (p-value = 0.02) were found between SARS-CoV-2 levels targeting IP4 in samples concentrated using the AP method and targeting N1-Dup concentrated by the TNA method (Fig. 1) while no differences were retrieved targeting N1-CDC.
The AP and TNA methods were also evaluated for their relative consistency in quantifying human enteric viruses (Fig. 2) and viral indicators (Fig. 3). HAV was not detected in any sample regardless of the method used (Sup. Table S1). The concentrations of norovirus GI (6.16 ± 0.73 log10 gc/L), norovirus GII (6.88 ± 0.43 log10 gc/L), and HEV (3.87 ± 0.49 log10 gc/L) using the TNA method were significantly greater (p-values of 0.042, 0.007, and 0.036, respectively) than using the AP method (Fig. 2).
No significant differences were found for RV and HAstrV levels. Furthermore, using the AP method, the percentage of positive samples were 50 % and 33.3 %, for HAstrV and HEV respectively, compared to 66.6 % and 100 % of positivity using the TNA method (Fig. 2, Sup. Table S1). Viral indicators showed mean values of 7.82 ± 0.36 log10 gc/L and 9.55 ± 0.25 with the AP method, and 8.32 ± 0.22 log10 gc/L and 9.45 ± 0.21 log10 gc/L with the TNA method, for PMMoV and crAssphage, respectively (Fig. 3). Neither of the two viruses showed significant differences in terms of their detection using the two methods.
Regarding the process controls recoveries, mean values for PEDV were 141.20 % ± 36.03 % and 38.57 ± 5.22 % for the AP and TNA methods, respectively. For MgV, these values were 6.82 ± 4.80 % in the AP method and 33.68 ± 11.62 % in the TNA method. Statistically significant differences were found for MgV (p-value = 0.001) and PEDV (p-value = 0.0008) recoveries, showing higher recoveries with the AP method for PEDV and with the TNA method for MgV (Fig. 3).Fig. 1 Levels (log10 gc/L) for three genetic SARS-CoV-2 targets in analyzed wastewaters (n = 6) using the aluminum-based adsorption-precipitation (AP, blue boxes) and the Enviro Wastewater TNA Kit (TNA, red boxes). Different letters denote significant differences (p-value < 0.05) with non-parametric Dunn's test.
Fig. 1
Fig. 2 Levels (log10 gc/L for Norovirus GI and GII, and HEV; log PCRU/L for HAstrV and RV) of human enteric viruses in wastewaters (n = 6) using the aluminum-based adsorption-precipitation (AP, blue boxes) and the Enviro Wastewater TNA Kit (TNA, red boxes). Different letters denote significant differences (p-value < 0.05) for each virus levels between each concentration method with Student's t-test (norovirus GI and norovirus GII) and Wilcoxon test (HEV). Crosses at the bottom represent negative samples.
Fig. 2
Fig. 3 A) Percentages of PEDV and MgV recoveries, and B) Levels (log10 gc/L) of viral indicators PMMoV and crAssphage, in wastewaters (n = 6) using the aluminum-based adsorption-precipitation (AP, blue boxes) and the Enviro Wastewater TNA Kit (TNA, red boxes). Different letters denote significant differences (p-value < 0.05) for each virus levels between each concentration method with t-test (MgV and PMMoV) and Wilcoxon test (PEDV).
Fig. 3
3.2 Comparison of the aluminum-based adsorption precipitation method and direct capture method for virus viability
Table 1 shows the infectious viruses recovered after concentration of PBS and sewage samples using both approaches. In samples concentrated using the AP procedure, levels of infectious MNV and HAV were not reduced (p > 0.05). The TNA procedure did not retrieve infectious MNV in PBS and wastewater samples while HAV concentration was statistically (p < 0.05) reduced by 2.5 and 2.1 log in PBS and wastewater samples respectively.Table 1 Mean values of murine norovirus (MNV) and hepatitis A virus (HAV) titers (log TCID50/mL) and logarithmic reductions obtained for PBS and wastewater samples concentrated using the aluminum-based adsorption-precipitation (AP) and the Enviro Wastewater TNA Kit (TNA). Different letters denote significant differences between treatments.
Table 1Concentration method Sample MNV HAV
Titer (log TCID50/mL) Log reduction Titer (log TCID50/mL) Log reduction
PBS 6.76 ± 0.07 a – 6.04 ± 0.21 a –
AP PBS 6.64 ± 0.24 a 0.13 5.95 ± 0.27 a 0.09
Wastewater 7.14 ± 0.07 b −0.38 5.45 ± 0.10 b 0.59
TNA PBS <1.15 c >5.61 3.57 ± 0.00 d 2.47
Wastewater <1.15 c >5.61 3.95 ± 0.00 c 2.09
3.3 SARS-CoV-2 sequencing
Six grab wastewater samples were concentrated with both concentration methods and nucleic acids were extracted as described above. Additionally, two primer schemes (i.e. Artic V3 and V4, https://github.com/artic-network/artic-ncov2019/tree/master/primer_schemes/nCoV-2019) were used. Fig. 4 shows the results obtained after bioinformatics analyses regarding percentage of viral reads classified as SARS-CoV-2, the percentage of genome of SARS-CoV-2 covered, and the mean values of coverage depth. The mean percentage of reads identified as SARS-CoV-2 ranged from 20.5 ± 15.0 % in AP-V4 to 55.1 ± 26.7 % in TNA-V4. Statistical analyses showed significative differences in the percentages of SARS-CoV-2 reads between the AP method amplified with the primer scheme V4 and the TNA method (p-values of 0.03 for TNA-V3 and 0.008 for TNA-V4), with the reads being lower when the AP-V4 method was used. Regarding the percentage of genome coverage, samples processed with the TNA method and amplified with the V4 primer scheme showed higher genome coverages (83.7 ± 15.5 %) and significant differences (p-value = 0.02) compared with the other methods, with the exception of the TNA method with V3 primer scheme (61.4 ± 26.8 %) which did not show significant differences with respect to the results obtained with TNA-V4 (Fig. 4, Fig. 5 ). Mean depth values were higher with method TNA-V4 (mean values 727.2 ± 367.8) which showed slight significative differences (p-value = 0.04) with method AP-V3 (318.2 ± 70.7). However, variability was higher in TNA-V4 than in the other analyzed methods.Fig. 4 Values obtained between the different concentrations methods tested in the study of the percentage of SARS-CoV-2 reads (A), SARS-CoV-2 genome coverage (B), and mean genome depth above 20× (C) after amplicon-based sequencing of SARS-CoV-2 with Artic primer scheme version 3 (V3) and 4 (V4). For each analysis (n = 6), boxes with the same letter show differences not statistically significant (p-value < 0.05).
Fig. 4
Fig. 5 X-axis: genome coverage of the SARS-CoV-2 reference genome MN908947.3 (only nucleotides with depth higher to 20×) in logarithmic scale (max 4 log) for each sample. Y-axis: logarithm of the depth (>20×) for each nucleotide position of the SARS-CoV-2 genome. NC, not covered. Blue, aluminum-based adsorption-precipitation; Red, Enviro Wastewater TNA Kit.
Fig. 5
4 Discussion
Wastewater-based epidemiology has proven to be an effective and useful tool for virus surveillance and outbreak detection, both for enteric viruses and for viruses that can be excreted in feces and urine (Asghar et al., 2014; Cuevas-Ferrando et al., 2020; Hellmér et al., 2014; Miura et al., 2016; Polo et al., 2020; Prevost et al., 2015; Santiso-Bellón et al., 2020). However, the detection of viruses in wastewater entails a previous step of sample concentration due to the low proportion of viruses compared to other microorganisms in these types of samples. Different concentration procedures have already been described and compared; however so far there is no standardized protocol for human enteric virus and SARS-CoV-2 detection (Rusiñol et al., 2020a; Torii et al., 2022). In this study, two different methods for wastewater concentration were evaluated for the detection of human enteric viruses, and viral indicators. Moreover, the performance of these procedures for SARS-CoV-2 detection and characterization by sequencing was evaluated using two different primer schemes.
The aluminum-based adsorption precipitation method (AP) has been used for the detection of enteric viruses in wastewater so far (Cashdollar and Wymer, 2013; Ikner et al., 2012). Furthermore, this method has also been validated for SARS-CoV-2 detection (Pérez-Cataluña et al., 2021) and it is currently used as a reference method in the Spanish COVID-19 wastewater surveillance project for the detection of SARS-CoV-2 and its variants (VATar COVID-19) (Carcereny et al., 2021). On the other hand, the TNA method has been recently validated for SARS-CoV-2 and viral fecal indicators, but no data about its feasibility for enteric virus detection has been published (Jiang et al., 2022; Mondal et al., 2021).
Even though the number of samples analyzed was limited, our results showed differences in viral recoveries of process control viruses (i.e. PEDV and MgV). In the case of PEDV, used as a model of enveloped viruses, the AP method showed higher recovery rates than the TNA method. However, the percentage of SARS-CoV-2 positive samples using the TNA method performed better (Fig. 1, Sup. Table S1). Regarding recovery rates of MgV, used as a model on non-enveloped viruses, higher recoveries were obtained when the TNA method was used. These recovery rates (mean 33.7 %) were similar to the ones obtained by Borgmästars et al. (2021) for MgV and human enteric viruses (Norovirus GI and GII, and HAV) with skimmed milk flocculation (SMF). However, with the SMF technique, 10 L were used for sample concentration, while with the TNA method only 40 mL were processed, simplifying the whole procedure. Moreover, enteric viruses (with the exception of RV and HAstrV) and PMMoV were detected more frequently when the TNA method was used, reinforcing the suitability of the TNA method in the detection of non-enveloped viruses.
Cell culture assays were carried out to evaluate the potential viability/infectivity of the viral particles present in the sewage after both concentration methods were applied. Our results showed that the AP concentration method is more successful for this purpose than TNA, which reported no infectious titers for MNV or infectivity loss of >2 log for HAV after being concentrated. This result could be due to the presence of alcohols (isopropanol and ethanol) in the TNA kit composition affecting viral infectivity. As expected, HAV was more resistant to the alcohols present in the TNA kits. Therefore, with regards to viral infectivity in sewage samples (Cuevas-Ferrando et al., 2021), the present results showed that the concentration methods applied need to be carefully validated.
Due to the limitations that classical techniques used in virus detection sometimes present, such as PCR or cell culture techniques, the use of massive sequencing technologies for the study of viruses in the environment is currently on the rise. For this reason, the European Union urges researchers to analyze SARS-CoV-2 in wastewater using these techniques. However, few studies have analyzed the concentration effects in genome sequencing. Thus, the effect of the two concentration methods as well as the primer scheme effect in SARS-CoV-2 genome sequencing was also evaluated. Regarding the percentage of genome coverage, samples processed with the TNA method showed higher genome coverages than with the other studied method. Similar results were obtained for genome coverage in the study performed by Kevill et al. (2022), although the authors did not find significative differences between the methods tested in their study. Values obtained with TNA-V4 regarding genome coverage were higher than the ones reported by Izquierdo-Lara et al. (2021) who showed average values of the percentage of SARS-CoV-2 genome of 51.3 ± 14.7 %. However, these authors performed an ultracentrifugation method for sample concentration that can produce lower virus recoveries, which would also affect sequencing (Hmaïed et al., 2016; Izquierdo-Lara et al., 2021; Prado et al., 2021; Ye et al., 2012). These results suggested that the use of the TNA method combined with the amplification of SARS-CoV-2 genomes using the Artic primer scheme V4 would give better results than with the other methods; although a high intravariability between samples can be produced.
5 Conclusions
WBE has proven to be an effective tool in epidemiological surveillance. However, the different methods used for the analysis of wastewater samples may produce differences in the results obtained. In this work, two sample concentration methods for virus analysis using molecular and cell culture techniques were compared alongside the two most commonly used primer schemes for SARS-CoV-2 genomic sequencing. Our results showed concentration methods are critical for the surveillance of human enteric viruses and SARS-CoV-2. In this sense, the use of the concentration system through the TNA system produces better results in terms of sensitivity and SARS-CoV-2 coverage sequencing. However, this technique completely reduces virus viability, indicating that methods such as aluminum precipitation would be recommended if these samples are to be tested on cell culture. Furthermore, concentration by the TNA method in combination with the Artic v4 primer scheme yields better sequencing results on sewage samples. Our results provide new information on the effects of the methods used for WBE studies, allowing us to improve this tool for use in epidemiology.
The following is the supplementary data related to this article.Sup. Table S1
Levels (log10 gc/L) in SARS-CoV-2 (A), human enteric viruses (B and C) and viral indicators (D), crAssphage and PMMoV, in wastewaters (n = 6) using the aluminum-based adsorption-precipitation (Al) and the Enviro Wastewater TNA Kit (TNA). Nd, not detected; HAV, Hepatitis A virus; HEV, Hepatitis E virus.
Sup. Table S1
CRediT authorship contribution statement
Inés Girón-Guzmán: Investigation, formal analysis, writing, and reviewing. Azahara Díaz-Reholid: Investigation, formal analysis, writing, and reviewing. Enric Cuevas-Ferrando: Investigation, formal analysis, visualization, writing, and reviewing. Irene Falcó: Investigation, formal analysis, writing, and reviewing. Pablo Cano-Jiménez: Investigations and formal analysis. Iñaki Comas: Supervision, funding acquisition, writing, and reviewing. Alba Pérez-Cataluña: Investigation, formal analysis, visualization, writing, and reviewing. Gloria Sánchez: Conceptualization, supervision, funding acquisition, writing, and reviewing.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data availability
Data will be made available on request.
Acknowledgements
This research was supported by project MCEC-WATER (PID2020–116789RB-C42/AEI/FEDER, UE) funded by Spanish 10.13039/100014440 Ministry of Science, Innovation and Universities ; the 10.13039/501100000780 European Commission NextGenerationEU fund, through CSIC's 10.13039/100006090 Global Health Platform (PTI Salud Global) to GS and IC, the COVID-19 wastewater surveillance project (VATar COVID19) and the Lagoon project (PROMETEO/2021/044). IGG is recipient of a predoctoral contract from the 10.13039/501100003359 Generalitat Valenciana (ACIF/2021/181), EC-F is recipient of a predoctoral contract from the MICINN Call 2018 (PRE2018-083753) and AP-C was supported by a postdoctoral fellowship from the Generalitat Valenciana (APOSTD/2021/292). We acknowledge MITECO for authorizing the sampling. The authors thank Agustin Garrido Fernández, and Andrea Lopez de Mota for their technical support.
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| 0 | PMC9744676 | NO-CC CODE | 2022-12-15 23:15:24 | no | Sci Total Environ. 2023 Mar 1; 862:160914 | utf-8 | Sci Total Environ | 2,022 | 10.1016/j.scitotenv.2022.160914 | oa_other |
==== Front
J Vasc Surg
J Vasc Surg
Journal of Vascular Surgery
0741-5214
1097-6809
Published by Elsevier Inc. on behalf of the Society for Vascular Surgery.
S0741-5214(22)02605-2
10.1016/j.jvs.2022.12.002
Article
COVID-Associated Acute Limb Ischemia During the Delta Surge And The Effect Of Vaccines
Xie Bowen MD 1∗
Semaan Dana B. MD 1
Binko Mary A. BS MS 2
Agrawal Nishant BS 2
Kulkarni Rohan N. MD 1
Andraska Elizabeth A. MD MS 1
Sachdev Ulka MD 1
Chaer Rabih A. MD MS 1
Eslami Mohammad H. MD MPH 1
Makaroun Michel S. MD 1
Sridharan Natalie MD MS 1
1 Division of Vascular Surgery, UPMC, Pittsburgh, PA
2 University of Pittsburgh School of Medicine, Pittsburgh, PA
∗ Corresponding author Bowen Xie, MD Division of Vascular Surgery, UPMC Heart and Vascular Institute, South Tower 200 Lothorp Street Pittsburgh, PA 15213 (650) 906-5434;
13 12 2022
13 12 2022
16 8 2022
29 11 2022
2 12 2022
© 2022 Published by Elsevier Inc. on behalf of the Society for Vascular Surgery.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Objective
Hypercoagulability is common in SARS-CoV-2 and has been associated with arterial thrombosis leading to acute limb ischemia (ALI). Our objective was to determine the outcomes of concurrent COVID-19 infection and ALI, particularly during the Delta variant surge and the impact of vaccination status.
Methods
A retrospective review was performed of patients treated at a single healthcare system between March 2020 and December 2021 for ALI and recent (<14 days) COVID-19 infection or who developed ALI during hospitalization for the same disease. Patients were grouped by year as well as by pre and post Delta variant emergence in 2021 based on WHO timeline (January-May vs. June-December). Baseline demographics, imaging, interventions, and outcomes were evaluated. A control cohort of all ALI patients requiring surgical intervention for a two-year period prior to the pandemic was used for comparison. Primary outcomes were in-hospital mortality and amputation-free survival. Kaplan-Meier survival and Cox proportional hazards analysis were performed.
Results
40 acutely ischemic limbs were identified in 36 patients with COVID-19, the majority during the Delta surge (52.8%) and after the wide availability of vaccines. The rate of COVID-19 associated ALI, though low overall, nearly doubled during the Delta surge (0.37% vs. 0.20%, p-value=.09). Baseline demographics and comorbidities are summarized in Table 1. Intervention (open or endovascular revascularization vs. primary amputation) was performed on 31 limbs in 28 individuals with the remaining 8 treated with systemic anti-coagulation. Post-operative mortality was 48% and overall mortality was 50%. Major amputation following revascularization was significantly higher with COVID ALI (25% vs. 3%, p=0.006) compared to the pre-pandemic group. 30-day amputation-free survival was significantly lower (log-rank p<0.001). COVID infection (aHR=6.2, p<0.001) and age (HR=1.1, p=0.006) were associated with 30-day amputation in multivariate analysis. Severity of COVID infection, defined as vasopressor usage, was not associated with post-revascularization amputation. There was a higher incidence of re-thrombosis in the latter half of 2021 with the Delta surge as reintervention for recurrent ischemia of the same limb was more common than our previous experience (21% vs. 0%, p=0.55). COVID-19 associated limb ischemia occurred almost exclusively in non-vaccinated patients (92%).
Conclusion
ALI observed with Delta appears more resistant to standard therapy. Unvaccinated status correlated highly with ALI occurrence in the setting of COVID-19 infection. Information of limb loss as a COVID complication among non-vaccinated may help to increase compliance.
Keywords
Acute limb ischemia (ALI)
COVID-19
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pmcIntroduction
Since the beginning of 2020, the SARS-CoV-2 (COVID-19) pandemic has had a devastating impact on the United States with over 82 million cases and over 1 million deaths.1 , 2 Though the primary manifestation of COVID-19 infection involves the pulmonary system, there has been documented involvement of various other organ systems including cardiovascular, neurologic, renal, and hematologic.3
Hypercoagulable states have been shown to be associated with COVID-19 infection primarily in the venous system with several studies documenting the presence of venous thromboembolisms and pulmonary embolisms in COVID-19 patients.4 , 5 It has been postulated that the prothrombotic state arises from underlying endothelial dysfunction and endotheliitis due to direct infection of the vascular endothelium by the COVID-19 virus leading to thrombus formation.6, 7, 8, 9 Several case reports and small multi-center studies have shown an elevated incidence of arterial thrombosis leading to acute limb ischemia in COVID-19 infections with increased mortality, amputation rates and intervention failure.10, 11, 12, 13, 14, 15 However, most of these series were prior to the advent of vaccines.
The COVID-19 vaccines were approved by the FDA for emergency use in December of 2020.16 Shortly after the wide-availability of vaccines, in May of 2021, the World Health Organization (WHO) identified the emergence of the Delta COVID-19 variant, putting an even larger strain on the healthcare system with high numbers of breakthrough infection, increased virulence, and transmissibility.17 Currently there is no study evaluating the association of the Delta variant COVID-19 infection with the incidence of acute limb ischemia (ALI).
This study serves to determine the outcomes of concurrent COVID-19 infection and ALI, particularly during the Delta variant surge and the impact of vaccination status. We hypothesize that the hypercoagulable state induced by active COVID-19 infection leads to worsened outcome in instances of acute limb ischemia, particularly in unvaccinated patients.
Methods
This was a retrospective study evaluating the incidence of COVID-19-associated ALI across at a single healthcare, multi-hospital network between January of 2020 and March of 2022. The University of Pittsburgh Institutional Review Board approved this study (STUDY21100134). Informed consent was obtained for all patients undergoing intervention.
Data Source and Patient Cohort
The electronic medical record (EMR) was queried for patients aged >18 years with ALI and a recent (<14 days) COVID-19 positive test or for those who developed limb ischemia during hospitalization for COVID-19.18 COVID-19 infection was confirmed by polymerase chain reaction testing or positive testing documentation from outside facilities. Patients presenting with ALI and negative COVID-19 testing or no COVID-19 testing were excluded. A control cohort of unmatched patients with ALI requiring surgical intervention for a two-year period prior to the COVID-19 pandemic (2018-2019) was used for comparison of outcomes.
Baseline demographic information, imaging, interventions, and outcomes were obtained from the EMR. Clinical indicators of ALI were evaluated using the Rutherford scale of acute limb ischemia based on the presence limb pain, motor, or sensory deficit and pulse/doppler exam. Pre-operative laboratory results and imaging were collected with the location of the occlusion documented. Vasculature patency was assessed using duplex ultrasound, computed tomography angiography (CTA), or digital subtraction angiography. Interventions were defined as either open surgical, endovascular, hybrid, primary amputation or non-operative based on operative reports and documentation. Post-operative outcomes and follow-up information were documented. Major adverse limb events (MALE) include the need for subsequent major amputation and open or endovascular reintervention due to vessel re-thrombosis. Additional complications included initiation of vasopressor support or renal replacement therapy, cardiac failure defined by myocardial infarction or pulmonary failure as represented by mechanical ventilation and mortality either during the index hospitalization or on subsequent readmission/follow-up. The initiation of post-operative vasopressor support was used as a surrogate for severity of COVID-19 infection in our study.
Outcomes
Primary outcomes were all-cause in-hospital mortality and 30-day amputation-free survival. The EMR, which is linked to the Social Security death index, was used to identify the death date as well as the amputation date. The cause of death was determined by documented death summaries and classified as COVID-19 related (respiratory failure, multisystem organ failure, or septic shock secondary to initial COVID-19 infection), non-COVID-19 related (any other cause of death), or unknown. 30-day amputation-free survival was defined as not having a major amputation or death within 30-days of the index admission date. Major amputation was defined as either above ankle amputation, or upper limb above wrist amputation.
Secondary outcomes included hospital length of stay and MALE (rate of reintervention, and 30-day major amputation post-revascularization). Reintervention was defined as a return to the operating room due to recurrent ischemia or loss of patency after the primary intervention and was categorized as open surgical, endovascular, hybrid, or amputation.
Statistical Analysis
Baseline characteristics for pre-COVID and COVID-19 cohorts were compared using Pearson χ2 and Fisher exact tests for categorical variables and presented as number (frequency %). For continuous variables, Mann-Whitney and the Student t-test were used and presented as mean (± standard deviation). Amputation-free survival at 30-days between the two groups was compared by Kaplan-Meyer survival analysis with associated log-rank testing. Cox proportional hazard analysis was also utilized to assess for factors associated with amputation-free survival. The models generated adjusted hazard ratios (aHR) with 95% confidence intervals (95% CI). A p-value ≤ .05 was determined to be statistically significant. All analyses were performed with Stata 17 (StataCorp, College Station, TX). Informed consent was obtained with consent to be treated and all patients were de-identified.
Subgroup analysis
To assess the effect of the emergence of the Delta variant and vaccination status on COVID-19 associated ALI, patients were grouped as pre-Delta (all cases from 2020 until May 2021) and post-Delta (June 2021 until December 2021) based on WHO timeline. For this subgroup analysis, we compared baseline characteristics using the same statistical methods described above. We also described characteristics and outcomes of individuals who presented with COVID-19 associated ALI after the emergence of the Omicron variant in 2022.
Results
A total of 40 COVID-19 associated ischemic limbs in 36 patients were identified throughout the study period in comparison to 74 ischemic limbs in 68 patients in the pre-COVID cohort. 18 out of 40 (45%) limbs were initially admitted for COVID infection while the remaining 22 (55%) were admitted for ALI and found to be COVID positive after testing or tested positive at home but did not meet hospitalization criteria based on their COVID symptoms. The majority of subjects presented during the Delta surge (52.8%) and after the wide availability of vaccines. COVID-19 variant information, however, was not available at the time of the study. A total of 13522 cases of COVID-19 hospitalization were identified in the healthcare network between 2020 to 2021. The rate of COVID-19 associated ALI, though low overall, nearly doubled during the Delta surge (0.37% vs. 0.20%, p-value=.09). A total of 212 cases of ALI were identified in the healthcare network between 2020 to 2021. The incidence of COVID-associated ALI during this study period was 17%. The average age of the COVID-19 associated ALI cohort was significantly older than the pre-COVID group (69.1 ± 11.4 vs. 63.3 ± 14.4, p-value=.03). In both groups, the majority were male and Non-Hispanic Whites, matching the demography of the Western Pennsylvania patients (Table 1 ). Within the COVID-19 associated ALI group, there was a 32.5% incidence of PAD, though the symptoms were not obtainable, as well as a significantly larger proportion who have had no prior history of vascular interventions (72% vs. 59%, p-value<.001) as compared to the control. There was a higher proportion of patients with a history of stroke or transient ischemic attack (TIA) within the COVID-19 associated ALI group (30% vs. 12%, p-value=.02). There were no significant differences in the proportion of patients with a history of venous thromboembolism (VTE) or hypercoagulable disorders between the two groups. The COVID-19 associated ALI group more often presented with Rutherford Class I ischemia on initial evaluation when compared to the unmatched control group (28% vs. 8%, p-value=.03).Table 1 Baseline demographics of the pre-COVID ALI cohort vs. COVID-19 associated ALI cohort
Pre-COVID ALI
74 (64.9%) COVID ALI
40 (35.1%) p-value
Age, mean (SD) 63.3 (14.4) 69.1 (11.4) .029
Gender
Male 45 (61%) 29 (72%) .23
Female 29 (39%) 11 (28%)
Ethnicity
White 65 (88%) 36 (90%) .032
Black 7 (9%) 0 (0%)
Hispanic 0 (0%) 1 (2%)
Other/Unknown 2 (3%) 3 (8%)
Smoking
Non-Smoker 26 (35%) 18 (46%) .38
Current Smoker 19 (26%) 6 (15%)
Previous Smoker 29 (39%) 15 (38%)
IV Drug Use 4 (5%) 0 (0%) .30
History of VTE 6 (8%) 3 (8%) 1.00
Hypertension 48 (65%) 32 (80%) .13
CAD 28 (38%) 13 (32%) .68
CHF 4 (5%) 5 (12%) .27
Diabetes 25 (34%) 16 (40%) .54
CKD 8 (11%) 6 (15%) .56
ESRD 3 (4%) 2 (5%) 1.00
History of Stroke/TIA 9 (12%) 12 (30%) .024
HLD 29 (39%) 14 (35%) .69
History of Hypercoagulable Disease 6 (8%) 3 (8%) 1.00
Malignancy 10 (14%) 7 (18%) .59
COPD 15 (20%) 11 (28%) .48
History of Vascular Intervention
None 44 (59%) 29 (72%) <.001
Endo 30 (41%) 6 (15%)
Open 0 (0%) 5 (12%)
History of Amputation
None 65 (88%) 35 (88%) .67
Minor Amp 6 (8%) 2 (5%)
Major Amp 3 (4%) 3 (8%)
Anticoagulation 17 (23%) 8 (20%) .81
Aspirin 34 (46%) 17 (42%) .84
Antiplatelets 26 (35%) 8 (20%) .13
Rutherford Classification
Class I 6 (8%) 11 (28%) .025
Class IIa 30 (42%) 13 (32%)
Class IIb 34 (47%) 13 (32%)
Class III 2 (3%) 3 (8%)
In the COVID-19 associated ALI group, intervention (open or endovascular revascularization vs. primary amputation) was performed on 32 limbs in 28 individuals with the remaining 8 patients treated with systemic anti-coagulation. Of the 32 limbs undergoing interventions, 12 required adjunctive treatment during the index operation that was presumed to address underlying disease that was present within the native vasculature (stenting, balloon angioplasty or endarterectomy with and without patch angioplasty). 11 of the 40 ischemic limbs were on pressors prior to any intervention or at the time of vascular intervention with 45% that were treated with medical management. Only one patient was on veno-veno extracorporeal membrane oxygenation (ECMO) and was managed with anticoagulation alone. In the 10 ischemic limbs treated solely with endovascular intervention, all underwent catheter-directed intervention with the use of thrombolytic agents and 6 interventions employed the use of catheter-directed aspiration as an adjunct. Of the combined hybrid and open interventions listed in Table 2 , there were 4 bypasses with the remainder of interventions being thromboendarterectomies. All but one of the hybrid interventions involved concomitant stenting proximal to site of thrombectomy/bypass with the remaining concluding with only a diagnostic angiogram. There was a significantly higher proportion of subjects who received either non-surgical management or primary amputation (30% vs. 0%, p-value<.001) in the COVID-19 associated ALI group as compared to the control with the majority of the non-operative and primary amputation patients intubated at the time of ALI diagnosis (70%). There were 37 ischemic lower extremities and 3 ischemic upper extremities in our cohort. The majority of the thrombus located proximally (17/40) (i.e. iliac/femoral or subclavian/axillary/brachial) as opposed to distally (12/40) (i.e. popliteal/tibial or radial/ulnar) and the remaining being multi-level in nature (9/40), occurring mainly during the Delta surge (6/9). There were, however, no differences in the management or outcomes when stratifying by occlusion location (Supplemental Table 1). There was also a significantly longer length of stay (19.3 ± 14.1 vs. 10.4 ± 9.3, p-value<.001) as well as a higher rate of 30-day major amputation (25% vs. 3%, p-value<.001) within the COVID-19 associated ALI group as compared to the control (Table 2).Table 2 Treatment and post-intervention outcomes of pre-COVID ALI vs. COVID-19 associated ALI
Pre-COVID ALI
74 (64.9%) COVID ALI
40 (35.1%) p-value
Treatment Type
Open 21 (28%) 11 (28%) <.001
Endovascular 19 (26%) 10 (25%)
Hybrid 34 (46%) 7 (17.5%)
Medical Only 0 (0%) 9 (22%)
Amputation 0 (0%) 3 (7.5%)
Reintervention 7 (16%) 7 (17.5%) .88
Total Length of Stay, mean (SD) 10.4 (9.3) 19.3 (14.1) <.001
In-hospital Mortality 6 (8%) 19 (48%) <.001
Post-Intervention Amputation 11 (14.9%) 7 (17.5%) .54
30-day Amputation 2 (3%) 11 (28%) .001
30-day Mortality 8 (11%) 17 (42%) <.001
Post-operative in-hospital mortality was 48% and overall mortality was 50% in the COVID-19 associated ALI cohort. Almost all deaths in the COVID-19 associated ALI cohort were COVID-19 related, with only one patient having a non-COVID-19 related mortality. This individual survived their index COVID-19 hospitalization with the cause of death being hemorrhagic shock secondary to gastrointestinal bleeding. Patients who were treated non-operatively had a higher mortality rate when compared to others who received some form of intervention (63%). Amongst the 8 non-surgically managed patients, 5 were deceased secondary to COVID pneumonia and the remaining did not require any major amputations. The 30-day amputation free survival in the COVID-19 associated ALI group was 45%, which was significantly lower than the pre-COVID cohort (89%) by Kaplan-Meier analysis (Figure 1 ). On multivariate analysis, COVID infection was associated with increased 30-day amputation (aHR 6.2 [95% CI, 2.3 – 16.8], p-value<.001) and in-hospital mortality (aHR 10.1 [95% CI, 2.7 – 37.4] , p-value=.001). Increased age was also a determinant of 30-day amputation and in-hospital mortality (Supplemental Table 2 and Supplemental Table 3). Severity of COVID infection, defined by vasopressor usage in our cohort, was not associated with post-revascularization amputation (p-value=.68) or non-operative management (p-value=.5).Figure 1 30-day Kaplan-Meier Amputation Free Survival Curve
Subgroup analysis
Since the beginning of 2021 with implementation of COVID vaccines, there have been 26 ischemic limbs with 19 (73%) presenting during the Delta surge. There was a significantly lower proportion of subjects who exclusively underwent endovascular revascularization as compared to the months prior to the surge (0% vs. 41% p-value<.001). The instances of COVID-19 associated ALI occurred almost exclusively in non-vaccinated patients with only two vaccinated individuals presenting during the Delta surge with concurrent infection and limb ischemia, both of whom received two doses of the Pfizer vaccine without any clinical evidence of vaccine-induced thrombotic thrombocytopenia (Table 3 ). Furthermore, there was also a higher incidence of re-thrombosis during the Delta surge as reintervention for recurrent ischemia of the same limb was more common when compared to the first half of 2021 (Table 4 ), though not statistically significant (21% vs. 0%, p-value=.55).Table 3 Baseline demographics of pre-Delta ALI vs. Delta ALI cohorts
Pre-Delta COVID ALI
17 (47.2%) Delta COVID ALI
19 (52.8%) p-value
Age, mean (SD) 71.6 (12.1) 66.4 (11.2) .19
Gender
Male 14 (82%) 12 (63%) .27
Female 3 (18%) 7 (37%)
Ethnicity
White 15 (88%) 17 (89%) .79
Hispanic 1 (6%) 0 (0%)
Other/Unknown 1 (6%) 2 (11%)
Vaccination Status 0 (0%) 2 (11%) .49
Smoking
Non-Smoker 8 (47%) 9 (50%) 1.00
Current Smoker 2 (12%) 3 (17%)
Previous Smoker 7 (41%) 6 (33%)
History of PAD 6 (35%) 6 (32%) 1.00
History of VTE 3 (18%) 0 (0%) .09
Hypertension 15 (88%) 14 (74%) .41
CAD 7 (41%) 5 (26%) .48
CHF 4 (24%) 1 (5%) .17
Diabetes 8 (47%) 6 (32%) .50
CKD 6 (35%) 0 (0%) .006
ESRD 1 (6%) 1 (5%) 1.00
History of Stroke/TIA 6 (35%) 6 (32%) 1.00
HLD 9 (53%) 3 (16%) .03
History of Hypercoagulable Disease 2 (12%) 1 (5%) .59
Malignancy 4 (24%) 2 (11%) .39
COPD 5 (29%) 5 (26%) 1.00
History of Vascular Intervention
None 12 (71%) 14 (74%) .88
Endo 2 (12%) 3 (16%)
Open 3 (18%) 2 (11%)
History of Amputation
None 14 (82%) 17 (89%) .79
Minor Amp 1 (6%) 1 (5%)
Major Amp 2 (12%) 1 (5%)
Anticoagulation 4 (24%) 4 (21%) 1.00
Aspirin 9 (53%) 7 (37%) .50
Antiplatelets 6 (35%) 1 (5%) .03
Multiple Limbs Affected 1 (6%) 7 (37%) .04
Rutherford Classification
Class I 5 (29%) 6 (32%) .59
Class IIa 6 (35%) 4 (21%)
Class IIb 4 (24%) 8 (42%)
Class III 2 (12%) 1 (5%)
Table 4 Treatment and post-intervention outcomes of pre-Delta ALI vs. Delta ALI cohorts
Pre-Delta COVID ALI
17 (47.2%) Delta COVID ALI
19 (52.8%) p-value
Treatment Type
Open 4 (24%) 6 (32%) .01
Endovascular 7 (41%) 0 (0%)
Hybrid 1 (6%) 6 (32%)
Medical Only 4 (24%) 5 (26%)
Amputation 1 (6%) 2 (11%)
Reintervention 3 (17.6%) 4 (21%) .79
Reintervention Type
Open 3 (100%) 1 (25%) .05
Hybrid 0 (0%) 3 (75%)
Post-Intervention Amputation 2 (12%) 4 (22%) .66
Total Length of Stay, mean (SD) 19.6(13.9) 18.6 (12.4) .82
In-hospital Mortality 6 (35%) 12 (63%) .18
30-day Amputation 3 (18%) 8 (42%) .13
30-day Mortality 7 (41%) 9 (47%) .75
A total of 4 ALIs in 4 individuals were identified during the Omicron surge (January 2022-March 2022) which was a drastic, though non-significant, drop-off compared to the Delta surge (0.19% vs. 0.37%, p-value=1.00). Only one subject had been vaccinated with two doses of the Pfizer vaccine. One patient underwent open revascularization and three patients underwent endovascular revascularization. There were no major amputations or mortalities at 30-days within this subgroup.
Discussion
The results of this study demonstrated that limb ischemia in the setting of acute COVID-19 infection is associated with significant mortality as well as an increased risk of limb loss despite revascularization. Thirty-six ischemic limbs were identified between 2020 and 2021 during the COVID-19 pandemic with a near two-fold increase in incidence during the more virulent and severe Delta variant surge compared to previous variants (0.37% vs 0.21%). The overall incidence of ALI in the setting of COVID-19 infection for our study was similar at 0.27% compared that seen at various New York City hospital systems early in the pandemic at approximately 0.4%.19 , 20 Our study demonstrated a drastic change in the outcomes of revascularization in ALI when associated with concurrent COVID-19 infection. The majority of ischemic events in the COVID-19 associated ALI cohort were de novo, in patients without a history of vascular disease or prior vascular interventions when compared to the control ALI cohort (72% vs. 59%), highlighting the viremia-induced hypercoagulability that has been documented in literature.21, 22, 23 While there have been multiple studies reporting the instances and outcomes of COVID-19 associated thrombotic events, most of these studies were published at the beginning of the pandemic and in small patient cohorts.15 , 19 , 23, 24, 25 To the authors’ knowledge, this is a unique institutional series valuating the outcomes of COVID-associated limb ischemia with a particular focus on the Delta variant surge.
It is important to highlight the potential preventive effects of appropriate vaccination in our patient cohort as COVID-associated ALI occurred almost exclusively amongst the unvaccinated subjects. The overall effects of the Delta wave during the COVID-19 pandemic has been highlighted by Manzur-Pineda et al. with an increase in the overall rate of thrombotic events, the majority of which were venous in nature.26 Furthermore, similar to the vaccination status of our cohort (92% unvaccinated), COVID-related thrombotic complications occurred almost exclusively within the unvaccinated population (94%) in their study. This could potentially serve as an important basis for the promotion of public health initiatives and improvement in vaccination rates in local communities.
The results of our study fall in line with the previously documented findings with a 30-day major amputation rate of 28% as well as a 30-day mortality rate of 42%, both of which were significantly higher than the control ALI group from 2 years prior. Etkins et al.20 reported an overall in-hospital mortality of 46% and Faries et al.19 noted an in-hospital mortality of 33%. This was further reflected in the significant decrease in 30-day amputation-free survival when compared to the control ALI group (45% vs 89%). The results are even more striking when separated based on the emergence of the Delta variant with no incidents of post-revascularization reintervention or amputation in the post-vaccination era (January-May 2021) prior to the emergence of the Delta variant (0% vs. 21%). This may highlight the increased virulence and lethality of the Delta variant that has been demonstrated in the mortality data by the Centers for Disease Control and Prevention (CDC).17 Amongst our cohort of COVID-19 associated ALI, there were 6 limbs (15%) where acute ischemia was the sole initial manifestation of their underlying COVID infection as has been previously reported.14 , 27 It was interesting to note that the 30-day major amputation rates for our study population varied dramatically when comparing between COVID and non-COVID ALI patients at 28% vs 3% (p=0.001). While Kahlberg et al. reported a secondary major limb amputation rate of 5.4% in their cohort out of Milan during their 2-month study period 28, Faries et al. noted a more comparable major amputation rate of 28% at 6 months in their COVID-19 associated ALI patients.19 Furthermore, Goldman et al. also noted a similar amputation rate of 25% amongst their cohort of patients with COVID-19 in their 3-month study period.25 This could potentially be caused by the change in the virus itself as a large portion of major 30-day amputations originated since the emergence of the Delta variant (73%).
The results of our multivariate Cox regression models showed that the only significant predictors for in-hospital mortality and 30-day amputation when controlling for other variables (i.e. age and gender) were COVID infection and age. There was also a notable change in the treatment algorithm for ALI that has emerged since the pandemic with a significant increase in nonoperative management and primary amputation within our COVID cohort (30% vs. 0%), and a shift away from endovascular revascularization during the Delta surge (0% vs 41%) (Table 2). This highlights the tenuous presentation status of COVID patients and a shift towards a more palliative/conservative treatment model in severe cases of this particular variant. Furthermore, the elevated mortality rate seen with COVID-associated ALI occurred almost exclusively due to complications from their index COVID-19 infection (i.e. multi-system organ failure or respiratory decompensation) and could also be largely preventable with appropriate vaccination. As new variants emerge, their impact on the incidence and outcomes of COVID-associated ALI remains to be seen. Preliminary data from our institution during the Omicron emergence demonstrates a decrease rate of reintervention after index revascularization as well as a decreased rate of major amputation and mortality when compared to the delta variant.
There are several limitations to our study. First, given the retrospective nature the total number of COVID-associated ischemic limbs were likely larger than those reported in our study. This could in part be due to the substantial rate of false negatives amongst polymerase reaction tests leading to exclusion of ischemic limbs with negative COVID tests during our study period.29 While it had become standard protocol amongst the vascular division to test all patients presenting with ALI for COVID-19 during the peak of the pandemic as well as the Delta surge, additional patients could still have been missed because of subclinical undiagnosed COVID infection with concurrent ALI, and also based on the search criteria in our electronic medical records as those whom both COVID and limb ischemia were not documented were excluded. Particularly at the beginning of the pandemic, critically-ill patients with acute arterial thrombosis may have had their ischemic events attributed to increasing vasopressor support or systemic illness without exploration or documentation defined limb ischemia. While hypercoagulable testing was not routinely performed on the COVID-associated ALI cohort as active COVID-19 infection, once discovered, was suspected to be the most likely cause of their underlying limb ischemia, there were no difference in the history of previously documented hypercoagulability disorder between our cohorts. Given the unequal distribution of COVID-19 cases within the United States, our small cohort size may be a result of stricter public health restrictions and lower population density of western Pennsylvania. The rarity of the events also prevents adequate matching from our control group, though despite the lower rate of vascular disease comorbidities there was still a significantly lower rate of amputation-free survival within our COVID-associate ALI group. Finally, given our temporal restriction of 14 days between ALI and COVID symptoms/testing, there may be a significant number of delayed ALI after COVID infection that may have been excluded and will need to be further investigated in the future.
Conclusion
In our evaluation of COVID-associated ALI in the UPMC health system, ALI observed with the Delta variant appeared more frequently and more resistant to standard therapy, as demonstrated by the higher rate of reintervention. The overall post-revascularization mortality and major amputation rates were significantly increased in the setting of concurrent COVID infection. In our clinical experience, unvaccinated status correlated highly with ALI, suggesting a potential protective effect of vaccination against thrombotic limb threatening ischemia. Whether the protection is due to the vaccination status or other correlative factors needs to be clarified. Increased awareness of limb loss as a COVID complication among non-vaccinated individuals may help to increase compliance and vaccination rates in the community.
Supplemental Table
Supplemental Table 1 Management and outcomes of COVID-19 associated ALI by thrombus location
Proximal
17 (44.7%) Distal
12 (31.6%) Multi-level
9 (23.7%) p-value
Limb
Lower Extremity 15 (88%) 11 (92%) 9 (100%) 0.78
Upper Extremity 2 (12%) 1 (8%) 0 (0%)
Treatment Type
Open 7 (41%) 1 (8%) 3 (33%) 0.09
Endovascular 1 (6%) 4 (33%) 5 (56%)
Hybrid 3 (18%) 3 (25%) 1 (11%)
Medical Only 5 (28%) 3 (25%) 0 (0%)
Amputation 2 (12%) 1 (8%) 0 (0%)
Reintervention 3 (18%) 2 (17%) 2 (22%) 1.00
30-day Amputation 4 (24%) 4 (33%) 3 (33%) 0.81
Supplemental Table 2 Multivariate Cox proportional hazard model for 30-day amputation
Hazard Ratio [95%CI] p-value
COVID-19 Infection 6.2 2.3 – 16.8 < 0.001
Age 1.1 1.0 – 1.1 0.006
Gender a 0.6 0.2 – 1.5 0.268
History of Vascular Intervention b
Endo 0.4 0.11 – 1.5 0.168
Open 1.4 0.4 – 5.4 0.63
Rutherford Classification c
Class IIa 2.7 0.7 – 10.8 0.156
Class IIb 2.8 0.7 – 11.7 0.158
Class III 3.6 0.5 – 23.9 0.186
Treatment Type d
Endovascular 0.3 0.1 – 1.7 0.179
Hybrid 1.3 0.4 – 4.1 0.591
Medical Only 0.9 0.2 – 4.1 0.984
Amputation 4.5 0.5 – 42.9 0.196
a: male gender is the reference group
b: no history of vascular interventions is the reference group
c: Rutherford Class I is the reference group
d: Open surgical treatment is the reference group
Supplemental Table 3 Multivariate Cox proportional hazard model for in-hospital mortality
Hazard Ratio [95%CI] p-value
COVID-19 Infection 10.1 2.7 – 37.4 0.001
Age 1.1 1.0 – 1.1 0.047
Gender a 0.7 0.2 – 2.4 0.581
History of Vascular Intervention b
Endo 0.1 0.1 – 0.6 0.019
Open 0.7 0.1 – 3.7 0.684
Rutherford Classification c
Class IIa 3.2 0.7 – 14.1 0.126
Class IIb 7.5 1.4 – 40.3 0.019
Class III 7.9 1.1 – 60.1 0.047
Treatment Type d
Endovascular 2.2 0.3 – 14.7 0.415
Hybrid 3.6 0.9 – 14.9 0.074
Medical Only 3.2 0.6 – 16.1 0.16
Amputation 0.6 0.1 – 6.6 0.662
a: male gender is the reference group
b: no history of vascular interventions is the reference group
c: Rutherford Class I is the reference group
d: Open surgical treatment is the reference group
Presentation: A subset of our work was presented as plenary session on June 16, 2022 at The Society of Vascular Surgery 2022 Vascular Annual Meeting, Boston, MA, United States
Declarations of interest: none
Funding: Research reported in this publication was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number T32HL098036. (Andraska, Xie)
The University of Pittsburgh holds a Physician-Scientist Institutional Award from the Burroughs Wellcome Fund (Andraska)
Table of Contents Summary
Post-revascularization mortality and amputation in acute limb ischemia (ALI) were significantly higher in the setting of concurrent COVID infection in this retrospective, single institute cohort study. Unvaccinated status also correlated with the occurrence of ALI in the setting of COVID-19 infection.
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Research and Practice in Thrombosis and Haemostasis
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The Author(s). Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis.
S2475-0379(22)02195-1
10.1016/j.rpth.2022.100010
100010
Original Article
Effects of Convalescent Plasma Infusion on the ADAMTS13-VWF Axis and Endothelial Integrity in Patients with Severe and Critical COVID-19
Zhang Quang M.D. 1∗
Ye Zhan M.D., Ph.D. 1∗
McGowan Paul M.D. 1
Jurief Christopher M.D. 1
Ly Andrew M.D. 1
Bignotti Antonia B.A. 1
Yada Noritaka M.D., Ph.D. 1
Zheng X. Long M.D., Ph.D. 12†
1 Departments of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA
2 Institute of Reproductive and Developmental Sciences, The University of Kansas Medical Center, Kansas City, KS 66160, USA
† Correspondence should be sent to: X. Long Zheng, M.D., Ph.D. Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, 3901 Rainbow Blvd, 5016 Delp, Kansas City, KS 66160.
∗ Contribute equally to this project.
13 12 2022
13 12 2022
1000104 7 2022
28 10 2022
30 10 2022
© 2022 The Author(s)
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Background
Convalescent plasma infusion (CPI) was given to COVID-19 patients during the early pandemic with a mixed therapeutic efficacy. However, the impacts of CPI on the ADAMTS13-VWF axis and vascular endothelial functions are not known.
Methods
Sixty hospitalized COVID-19 patients were enrolled into the study; 46 received CPI and 14 received no-CPI. Plasma ADAMTS13 activity, VWF antigen, endothelial syndecan-1, and soluble thrombomodulin (sTM) were assessed before and 24h after treatment.
Results
Patients with severe and critical COVID-19 exhibited significantly lower plasma ADAMTS13 activity than the healthy controls. Conversely, these patients showed a significantly increased VWF antigen. This resulted in markedly reduced ratios of ADAMTS13 to VWF in these patients. The levels of plasma ADAMTS13 activity in each individual patient remained relatively constant throughout hospitalization. Twenty-four hours following CPI, plasma ADAMTS13 activity increased by ∼12% from the baseline in all patients and ∼21% in those who survived. In contrast, plasma levels of VWF antigen varied significantly over time. Patients who died exhibited a significant reduction of plasma VWF antigen from the baseline 24 hours following CPI, whereas those who survived did not. Furthermore, patients with severe and critical COVID-19 showed significantly elevated plasma levels of syndecan-1 and sTM, similar to those found in patients with immune thrombotic thrombocytopenic purpura. Both syndecan-1 and sTM levels were significantly reduced 24 hours following CPI.
Conclusions
Our results demonstrate the relative deficiency of plasma ADAMTS13 activity and endothelial damage in patients with severe and critical COVID-19, which could be modestly improved following CPI therapy.
Keywords
COVID-19
endothelial injury
convalescent plasma
ADAMTS13
VWF
Sydencan-1
and thrombomodulin
==== Body
pmcEssentials
•Severe COVID-19 patients show reduced plasma ADAMTS13 and increased von Willebrand factor (VWF)
•Plasma ADAMTS13 levels do not fluctuate greatly in COVID-19 patients during hospitalization
•Convalescent plasma infusion improves ADAMTS13/VWF axis and endotheliopathy in severe COVID-19
•Our findings support the use of convalescent plasma in a subset of COVID-19 patients
| 0 | PMC9744678 | NO-CC CODE | 2022-12-15 00:01:52 | no | Res Pract Thromb Haemost. 2022 Dec 13;:100010 | utf-8 | Res Pract Thromb Haemost | 2,022 | 10.1016/j.rpth.2022.100010 | oa_other |
==== Front
J Formos Med Assoc
J Formos Med Assoc
Journal of the Formosan Medical Association
0929-6646
0929-6646
Formosan Medical Association, Elsevier
S0929-6646(22)00443-0
10.1016/j.jfma.2022.12.004
Original Article
Management of cardiovascular symptoms after Pfizer-BioNTech COVID-19 vaccine in teenagers in the emergency department
Liao Ying-Feng MD a
Tseng Wei-Chieh MD ab
Wang Jou-Kou MD, PhD a
Chen Yih-Sharng MD, PhD c
Chen Chun-An MD, PhD a
Lin Ming-Tai MD, PhD a
Lu Chun-Wei MD a
Wu Mei-Hwan MD, PhD a
Chiu Shuenn-Nan MD, PhD a∗
a Department of Pediatrics, National Taiwan University Hospital and Medical College, National Taiwan University
b Department of Emergency Medicine, National Taiwan University Hospital and Medical College, National Taiwan University
c Department of Surgery, National Taiwan University Hospital and Medical College, National Taiwan University
∗ Corresponding author. Department of Pediatrics, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan 100, [] Fax: +886 2 23147450.
13 12 2022
13 12 2022
27 5 2022
29 11 2022
7 12 2022
.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Background
Cardiovascular complications after Pfizer–BioNTech COVID-19 (BNT) vaccination are a concern, especially in adolescents. We analyzed the risk factors for myocarditis after BNT vaccination.
Methods
We used a special evaluation protocol for all patients aged 12 to 18 years who presented to our emergency department with cardiovascular symptoms after BNT vaccination.
Results
A total of 195 patients (109 boys and 86 girls) were enrolled. Eleven (5.6%) patients presented with arrhythmia (arrhythmia group), 14 (7.2%) had a diagnosis of pericarditis/myocarditis (the peri/myocarditis group), and the remaining 170 were controls (no cardiac involvement). Chest pain (77.6%) was the most common symptom. The median time from vaccination to symptom onset was 3 days. In the peri/myocarditis group (13 myocarditis and 1 pericarditis), the median time to the peak troponin T level was 5 days after vaccination. Abnormal electrocardiographic changes, including ST-T changes and conduction blocks, were more commonly detected in the peri/myocarditis group (85.7% vs. 12.4% in the control group, p < 0.01). Echocardiography revealed normal ventricular function in all patients. Symptoms were resolved before discharge in all, with the median duration of hospital stay being 4 days. The electrocardiography was the most appropriate screening tool for myocarditis, with a sensitivity and specificity of 85.7% and 87.6%, respectively.
Conclusion
Pericarditis or myocarditis was diagnosed in 7.2% of adolescents presenting to the emergency department with cardiovascular symptoms after BNT vaccination. In addition to the troponin T level, ECG change listed above can be used as a screening tool for vaccine-induced cardiac complications.
Keywords
COVID-19
BNT vaccine
chest pain
myocarditis
electrocardiogram
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pmc
| 0 | PMC9744679 | NO-CC CODE | 2022-12-15 00:01:52 | no | J Formos Med Assoc. 2022 Dec 13; doi: 10.1016/j.jfma.2022.12.004 | utf-8 | J Formos Med Assoc | 2,022 | 10.1016/j.jfma.2022.12.004 | oa_other |
==== Front
Cytokine
Cytokine
Cytokine
1043-4666
1096-0023
Elsevier Ltd.
S1043-4666(22)00318-0
10.1016/j.cyto.2022.156109
156109
Article
Frequency of IRF5+ dendritic cells is associated with the TLR7-induced inflammatory cytokine response in SARS-CoV-2 infection
Cords Leon a
Woost Robin a
Kummer Silke a
Brehm Thomas T. ab
Kluge Stefan c
Schmiedel Stefan a
Jordan Sabine a
Lohse Ansgar W. a
Altfeld Marcus bd
Addo Marylyn M. abe
Schulze zur Wiesch Julian ab
Beisel Claudia abf⁎
a Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
b German Center for Infection Research (DZIF), Partner Site Hamburg - Lübeck - Borstel - Riems, Hamburg, Germany
c Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
d Research Department Virus Immunology, Leibniz Institute for Virology (LIV), Hamburg, Germany
e Institute for Infection Research and Vaccine Development, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
f Department of Internal Medicine IV, Gastroenterology and Infectious Diseases, University Hospital Heidelberg, Germany
⁎ Corresponding author at: Department of Internal Medicine IV, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
13 12 2022
13 12 2022
15610918 4 2022
20 10 2022
7 12 2022
© 2022 Elsevier Ltd. All rights reserved.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
The SARS-CoV-2 infection leads to enhanced inflammation driven by innate immune responses. Upon TLR7 stimulation, dendritic cells (DC) mediate the production of inflammatory cytokines, and in particular of type I interferons (IFN). Especially in DCs, IRF5 is a key transcription factor that regulates pathogen-induced immune responses via activation of the MyD88-dependent TLR signaling pathway. In the current study, the frequencies of IRF5+ DCs and the association with innate cytokine responses in SARS-CoV-2 infected individuals with different disease courses were investigated. In addition to a decreased number of mDC and pDC subsets, we could show reduced relative IRF5+ frequencies in mDCs of SARS-CoV-2 infected individuals compared with healthy donors. Functionally, mDCs of COVID-19 patients produced lower levels of IL-6 in response to in vitro TLR7 stimulation. IRF5+ mDCs more frequently produced IL-6 and TNF-α compared to their IRF5− counterparts upon TLR7 ligation. The correlation of IRF5+ mDCs with the frequencies of IL6- and TNF-α producing mDCs were indicators for a role of IRF5 in the regulation of cytokine responses in mDCs. In conclusion, our data provide further insights into the underlying mechanisms of TLR7-dependent immune dysfunction and identify IRF5 as a potential immunomodulatory target in SARS-CoV-2 infection.
Keywords
SARS-CoV-2
Dendritic cells
Interferon regulatory factor 5
Toll-like receptor 7
Interferon-α
Tumor necrosis factor-α
Interleukin-6
Abbreviations
CRP, C-reactive protein
ECMO, Extracorporal membrane oxygenation
B1 HMGB1, High-Mobility-Group-Protein
ICU, Intensive care unit
IRF, Interferon regulatory factor 5
IFN-α, Interferon-α
IL-6, Interleukin-6
MFI, Mean fluorescence intensity
mDC, Myeloid Dendritic Cell
PBCM, Peripheral Blood Mononuclear Cell
pDC, Plasmacytoid Dendritic Cell
PCR, Polymerase chain reaction
SNPs, single-nucleotide polymorphisms
TLR, Toll-like receptor 7
TNF-α, Tumor necrosis factor alpha
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pmc1 Introduction
Coronavirus disease 2019 (COVID-19) caused by infection with the novel severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), presents with a wide range of clinical manifestations, with most patients experiencing a mild to moderate course, while others progress to severe or critical disease [1]. The underlying causes of these different clinical phenotypes are not yet fully understood. A potential pathophysiological mechanism may be a dysregulation of inflammatory responses, leading to a so-called “cytokine storm” [2], [3], [4], [5], [6], [7].
Dendritic cells (DCs) play a crucial role in the innate immune response against viral infections. RNA viruses, such as SARS-CoV-2, are sensed by DCs via Toll-like receptors (TLRs), including TLR7, resulting in the production of innate and inflammatory cytokines [8]. In humans, at least two distinct DC subsets, (HLA-DR+CD11c−CD123+) plasmacytoid DCs (pDCs) and (HLA-DR+CD11c+CD123−) myeloid DCs (mDCs), have been identified and are known to respond to different TLR ligands [9]. Some studies have shown a decreased number of plasmacytoid and myeloid DCs in response to acute SARS-CoV-2 infection in peripheral blood and described an association with disease severity [10], [11]. Increasing data suggest an important role of the TLR7 pathway and its resulting cytokine production in the outcome of COVID-19 [12], [13]. A better understanding of the pathways downstream of TLR7 signaling is an essential step in the design of new therapeutic targets to modulate harmful immune responses in COVID-19. One potential target of interest that is known to play a critical role in responses through the TLR - myeloid differentiation primary response 88 (MyD88) pathway is the Interferon regulatory factor (IRF) 5 [14]. After viral sensing, IRF5 is a key transcription factor for the activation of innate immune responses by induction of several inflammatory cytokines, including type I interferons (IFN), tumor necrosis factor-alpha (TNF-α), and Interleukin-6 (IL-6) [14], [15], [16], [17]. So far, data about the expression signature on DCs, especially after TLR7-dependent activation, and its functional consequences in SARS-CoV-2 infection have not been described.
In this study, the IRF5 expression pattern was analyzed on different peripheral blood dendritic cell populations in a cohort of COVID-19 patients, and the potential association of IRF5 with the impaired cytokine production pattern of patients with COVID-19 was tested. With this study, we provide further insights into underlying mechanisms of TLR7-dependent immune dysfunction and identify IRF5 as a potential immunomodulatory target in SARS-CoV-2 infection and other viral diseases.
2 Material and Methods
2.1 Study population
A total number of 46 study participants were enrolled in this study between March 2020 and April 2021 at the University Medical Center Hamburg-Eppendorf, Germany. Venous whole blood samples from SARS-CoV-2 infected patients (n=30) and uninfected healthy individuals (n=16) were collected in Vacutainer CPT tubes (BD). All COVID-19 patients were treated as inpatients and SARS-CoV-2 infection was confirmed by polymerase chain reaction (PCR) of nasopharyngeal or oropharyngeal swab specimen as previously described [18]. Disease severity was graded by clinical presentation according to the STAKOB [19] (Robert Koch Institute, Berlin, Germany; classification adapted from WHO Therapeutics and COVID19: living guideline, see also Supplementary Table S1). All participants gave written informed consent. The study was approved by the local ethics board of the Ärztekammer Hamburg (PV4780, PV7298).
2.2 Sample processing and stimulation
Peripheral blood mononuclear cells (PBMC) were isolated by density gradient centrifugation and cryopreserved in Roswell Park Memorial Institute medium (RPMI1640, Gibco) supplemented with 25% heat-inactivated fetal calf serum (FCS) and 10% dimethylsulfoxide. Cryopreserved PBMCs were thawed as needed and either directly stained for surface markers and intranuclear IRF5 or stimulated as previously described [20]. In short, samples were stimulated with 1µg/ml of CL097 (Sigma-Aldrich) for 20h at 37°C and 5% CO2 in RPMI1640 supplemented with 10% heat-inactivated FCS, 1% penicillin/streptomycin, and 1% HEPES (Gibco). To inhibit the cytokine secretion, Brefeldin A (Sigma-Aldrich) at a final concentration of 5µg/ml was added after one hour.
2.3 Intracellular staining of IRF5 protein and flow cytometric analysis
PBMCs were stained for surface markers and intranuclear IRF5. The cells were washed and stained with LIVE/DEAD fixable Near-IR dead cell stain (Invitrogen) and fluorochrome-conjugated surface antibodies (see Supplementary Table S2). Cells were fixed using 1% paraformaldehyde and subsequently permeabilized with 0.1% Triton X-100. Fixed cells were first incubated with an anti-IRF5 antibody (E7F9W, Cell Signaling Technology) for 20 minutes and then a secondary anti-rabbit-IgG AlexaFluor488 antibody (Cell Signaling Technology) for 15 minutes. Stimulated samples and unstimulated controls were stained for intracellular cytokines with fluorochrome-labeled antibodies. Samples were acquired within 12 hours on a BD LSRFortessa II (BD Biosciences). Cells were analyzed using FlowJo 10.7 software (BD Biosciences) with the exclusion of doublet cells. mDCs were identified as LD−, CD3−, CD14−, CD19−, CD20−, HLA-DR+, CD11c+, and CD123− cells. pDCs were identified as LD−, CD3−, CD14−, CD19−, CD20−, HLA-DR+, CD11c−, and CD123+ cells. Background staining was assessed for every sample by staining without the primary anti-IRF5 antibody (isotype control).
2.4 Assessment of antibody specificity
IRF5 expression is mainly restricted to DCs and B cells [17], [21], [22]. To confirm antibody specificity, the expression of IRF5 in CD3+ T cells was identified with the aid of isotype controls (see Supplementary Figure S1). In line with the literature [23], antibody specificity was considered to be reliable as CD3+ T cells did not express IRF5.
2.5 Statistical analyses
GraphPad Prism v7 (GraphPad Software) was used to analyze the data. Mann-Whitney U tests and Wilcoxon matched-rank tests were used to determine statistical significance between unpaired and paired data sets, respectively. Spearman’s rank correlation coefficient was calculated to determine the correlation between different data sets. A p-value < 0.05 was considered significant.
3 Results
3.1 Clinical characteristics of patients with SARS-CoV-2 infection
30 individuals hospitalized with acute SARS-CoV-2 infection were recruited at the University Medical Center Hamburg-Eppendorf between March 2020 and April 2021 (Table 1 ). 16 healthy, uninfected individuals served as a control group. Infected patients had different clinical manifestations showing a moderate (n=13), severe (n=11), or critical (n=6) course of COVID-19. The patients were enrolled within 20 days (mean 5.5 days) after they tested positive for SARS-CoV-2 by PCR from nasopharyngeal or oropharyngeal swab specimens.Table 1 Clinical characteristics of patients with acute SARS-CoV-2 infection and healthy donors. Values are given as absolute numbers with percentages or mean with range. Time since diagnosis refers to the time passed since the first positive PCR swab. Laboratory results are derived from the clinical database from the day of the sampling ±2 days. Abbreviations: n/a, not applicable; ECMO, extracorporeal membrane oxygenation; CRP, C-reactive protein; IL-6, Interleukin-6. Reference values of laboratory results: CRP <5mg/dl; IL-6 <7ng/l; Procalcitonin <0.5µg/l; Ferritin 10-291µg/l; D-dimer 0.21-0.52mg/l. † Procalcitonin results were only available for n=12 and n=10 individuals with moderate or severe COVID-19, respectively.
COVID-19 Healthy donors
moderaten=13 severen=11 criticaln=6 n=16
Age in years, mean (range) 54 (36-86) 64 (52-75) 64 (52-75) 37 (21-66)
Sex at birth, n (%)femalemale 7 (53.8%)6 (46.2%) 5 (45.5%)6 (54.5%) 3 (50%)3 (50%) 8 (50%)8 (50%)
Days since diagnosis, mean (range) 3.9 (1-10) 7.4 (2-20) 5.7 (1-15) n/a
Comorbidities, n (%)nonehypertensiondiabetesheart diseaseslung diseasescancerother 2 (15.4%)5 (38.5%)3 (23.1%)4 (30.8%)1 (7.7%)1 (7.7%)9 (69.2%) -4 (36.4%)4 (36.4%)2 (18.2%)4 (36.4%)-5 (45.5%) -3 (50%)4 (66.7%)2 (33.3%)1 (16.7%)2 (33.3%)5 (83.3%) 16 (100%)------
Intensive Care Unit, n (%)invasive ventilationECMO 2 (15.4%)-- 6 (54.5%)1 (9.1%)- 6 (100%)4 (66.7%)2 (33.3%) n/a
Oxygen supplementation, n (%) 4 (30.8%) 11 (100%) 6 (100%) n/a
Laboratory results, mean (range)CRP [mg/l]IL-6 [ng/l]Procalcitonin [µg/l] †Ferritin [µg/l]D-dimer [mg/l] 29 (<4-72)17.4 (<1.5-49.8)0.04 (<0.02-0.25)409.4 (6.8-1503.3)1.82 (<0.19-16.57) 73 (11-202)55.3 (<1,5-181.2)0.09 (0.02-0.18)568.1 (74.7-1249.2)3.68 (0.63-23.05) 140.7 (52-207)92.5 (14.6-230.5)0.37 (0.06-1.04)693.2 (111.6-1948.7)1.62 (0.37-3.66) n/a
Patients still alive, n (%) 13 (100%) 9 (81.8%) 4 (66.7%) n/a
Moderately ill patients had a mean age of 54 years (range: 36-86) and thus were slightly younger than the patients with severe (mean 64 years; range: 52-75) or patients with a critical course (mean 64 years; range: 52-75). Sex ratios were balanced in all groups. Chronic diseases were more common among severely and critically ill patients (n=17/17; 100%) than the moderately ill ones (n=11/13; 84.6%). The most common comorbidities were hypertension (n=12/30; 40.0%) and diabetes (n=11/30; 36.7%). All patients with a severe or critical course of disease (n=17/17; 100%) required oxygen supplementation, while only 30.8% (n=4/13) of patients with moderate disease had oxygen administered. In all groups, a certain proportion of patients were admitted to the intensive care unit (ICU). Of the individuals with moderate COVID-19, 15.4% (n=2/13) were admitted to the ICU, but no invasive ventilation or extracorporeal membrane oxygenation (ECMO) was necessary. However, 54.5% (n=6/11) of severely infected and 100% (n=6/6) of critically infected patients required a stay at the ICU with 9.1% (n=1/11) and 66.7% (n=4/6) requiring intubation, respectively. ECMO was established in two patients (33.3%) with critical COVID-19. Certain inflammation markers such as C-reactive protein (CRP), Interleukin-6 (IL-6), Procalcitonin, and Ferritin were extracted from the clinical database. Expectedly, mean values for all of these parameters were higher with increasing disease severity. Levels of IL-6 were highest in critically ill patients compared to those with a severe or a moderate course of diseases (mean IL-6: 92,5ng/l versus 55,35ng/l and 17,45ng/l, respectively). Elevated d-dimers, which are indicative of COVID-19 associated coagulopathy [24] and prognosis [25], did not follow this trend.
Three months after SARS-CoV-2 infection, all moderately infected individuals (n=13/13; 100%), 81.8% (n=9/11) of severely infected, and 66.7% (n=4/6) of critically infected patients were still alive.
3.2 Patients with SARS-CoV-2 infection show reduced relative frequencies of dendritic cell subsets
It has been described that the frequencies of all dendritic cell subtypes are reduced in the peripheral blood of COVID-19 patients [10], [11], [26]. Therefore, we first aimed to confirm this finding in our cohort. The frequency of Lin−HLA-DR+CD123−CD11c+ mDCs and Lin−HLA-DR+CD123+CD11c− pDCs (Figure 1 A) was determined of single lymphocytes in the PBMC of COVID-19 patients and compared to healthy donors. Indeed, the patients with acute SARS-CoV-2 infection exhibited significantly lower frequencies of both pDCs (mean 0.31% vs 0.54%, P = 0.0178) and mDCs (mean 0.62% vs 1.40%, P = 0.0438) compared with healthy individuals (Figure 1 B). These observations suggest a suppression of mDC and pDC populations in patients with acute SARS-CoV-2 infection.Figure 1 SARS-CoV-2 infection is associated with profound alterations of the dendritic cell compartment. (A) PBMC of COVID-19 patients and healthy donors (HD) were analyzed by flow cytometry to assess the blood dendritic cell compartment. Plasmacytoid dendritic cells (pDCs) were identified as single, viable, Lin−, HLA-DR+, CD11c−, CD123+ cells (pink), and myeloid dendritic cells (mDCs) as single, viable, Lin−, HLA-DR+, CD11c+, CD123− cells (orange). (B) The frequencies of both pDCs and mDCs of single lymphocytes were significantly reduced in patients with COVID-19 compared with healthy controls. (C) While the pDCs of SARS-CoV-2 infected patients showed comparable frequencies of IRF5+ cells and a similar IRF5 MFI compared with healthy donors, (D) IRF5+ mDCs were significantly reduced and the IRF5 MFI also tended to be lower in mDCs of COVID-19 patients. (E) IRF5 expression
In DCs, IRF5 is involved downstream of the TLR7 signaling pathway as a master transcription factor in the activation of genes for inflammatory cytokines [27]. Thus, potential alterations in the expression of IRF5 could contribute to the COVID-19 pathogenesis. As assessed by flow cytometry, there was no difference of IRF5+ pDCs (mean 54.38% vs 62.4%, P = 0.9094) or the IRF5 MFI in pDCs (P = 0.9801) between COVID-19 patients and healthy donors (Figure 1 C). The extremely broad range of the IRF5+ frequency could not be satisfactorily explained by any clinical parameters but could be the result of single nucleotide polymorphisms (SNPs) in the IRF5 gene influencing its expression [28]. However, the mDCs of COVID-19 patients less frequently expressed IRF5 (81.36% vs 97.46%, P < 0.0001), and the IRF5 MFI also tended to be lower (P = 0.0571) compared to healthy controls (Figure 1 D). Age, sex, and disease severity were not associated with a decrease in any of the DC populations or their IRF5 expression (Supplementary Figures S2-S4). Of note, the IRF5 MFI was significantly higher in mDCs than in pDCs in both the samples of COVID-19 patients and healthy donors (Figure 1 E). This suggests that IRF5 might be of greater importance in the regulation of mDCs than pDCs. Taken together, acute SARS-CoV-2 infection was associated with a profound alteration of the dendritic cell compartment, particularly the decrease of DC subsets and reduced IRF5 expression in mDCs.
3.3 Functions of dendritic cells of patients with acute SARS-CoV-2 infection following TLR7 stimulation ex vivo
TLR7 sensing and signaling are important for the recognition of SARS-CoV-2 and the initiation of innate immune responses [8], [13]. To assess the impact of TLR7 signaling on the IRF5 expression and cytokine production in the dendritic cell populations, PBMC of COVID-19 patients and healthy donors were stimulated with a synthetic TLR7 agonist (CL097) [20]. The cytokine production and IRF5 expression were measured by flow cytometry.
Upon stimulation, the frequency of IRF5+ pDCs was significantly increased in both patients with acute SARS-CoV-2 infection (P = 0.0078) and healthy individuals (P = 0.0078; Figure 2 A). While the frequency of IRF5+ pDCs following TLR7 stimulation was comparable between COVID-19 patients and healthy donors (mean 68.3% vs 58.8%, P = 0.3213), healthy individuals tended to more strongly upregulate IRF5 according to the MFI (Figure 2 A), although this did not reach statistical significance (P = 0.0592). However, the pDCs activation as measured by the upregulation of HLA-DR (Figure 2 B) was comparable between COVID-19 patients and healthy donors and the proportion of IL-6, TNF-α or IFN-α producing pDCs did not differ either (Figure 2 C). Of note, the production of TNF-α but not the other cytokines were negatively associated with patient age (Supplementary Figure S5). These results suggest preserved functionality in the remaining pDCs of COVID-19 patients regarding the investigated parameters despite the strong suppression of the pDC populations.Figure 2 pDCs upregulate IRF5 upon TLR7 ligation. (A) pDCs upregulate IRF5 similarly upon TLR7 engagement in both COVID-19 patients and healthy donors. (B) Comparable upregulation of HLA-DR on pDCs upon TLR7 ligation between COVID-19 patients and healthy controls. (C) No significant alterations between COVID-19 patients and healthy donors in the cytokine profile of pDCs upon TLR7 ligation. For comparison of IRF5+ frequency before and after TLR7 stimulation within the COVID-19 group and the healthy donors, statistical significance was determined with a Wilcoxon matched-rank test. For all other analyses, a Mann-Whitney U-test was performed. Red dots indicate individuals with acute SARS-CoV-2 infection and grey dots show healthy donors.
was significantly higher in mDCs compared to pDCs. For all analyses, a Mann-Whitney U-test was performed to assess the statistical significance. Red dots indicate individuals with acute SARS-CoV-2 infection and grey dots show healthy donors.
The mDCs responded somewhat differently to the CL097 stimulus. The proportion of IRF5+ mDCs did not increase significantly upon TLR7 ligation (Figure 3 A), neither for the COVID-19 patients (P = 0.8311) nor the healthy donors (P = 0.5469). However, consistent with the data in pDCs, the mDCs of patients with acute COVID-19 seemed to have a reduced capacity to upregulate IRF5 according to the MFI change although this was not statistically significant (P = 0.0908; Figure 3 A). Furthermore, the upregulation of HLA-DR as an indicator of DC activation was comparable between COVID-19 patients and healthy donors (Figure 3 B). To further analyze the functionality of the mDCs in SARS-CoV-2 infection, the percentage of IL-6 and TNF-α producing mDCs was determined by flow cytometry after TLR7 stimulation (Figure 3 C). Compared with healthy individuals, mDCs of COVID-19 patients had significantly lower levels of IL-6 producing mDCs (P = 0.0231). The numbers of TNF-α+ mDCs were comparable with healthy donors and there were no relevant numbers of IFN-α producing mDCs. There was no association between mDC responsiveness and age (Supplementary Figure S6). These results demonstrate an impaired cytokine response of mDCs in response to TLR-7 stimulation in SARS-CoV-2 infected individuals.Figure 3 Reduced frequencies of IL-6+ mDCs in patients with COVID-19. (A) There was no significant increase of IRF5+ mDCs upon TLR7 engagement in both COVID-19 patients and healthy donors, but a trend towards stronger upregulation of IRF5 MFI by healthy donors. (B) Comparable upregulation of HLA-DR on pDCs upon TLR7 ligation between COVID-19 patients and healthy controls. (C) No significant differences between COVID-19 patients and healthy donors with respect to TNF-α production but IL-6 production of pDCs upon TLR7 ligation. For comparison of IRF5+ frequency before and after TLR7 stimulation within the COVID-19 group and the healthy donors, statistical significance was determined with a Wilcoxon matched-rank test. For all other analyses, a Mann-Whitney U-test was performed. Red dots indicate individuals with acute SARS-CoV-2 infection and grey dots show healthy donors.
3.4 IRF5+ frequency correlates with IL-6 and TNF-α production on mDCs of COVID-19 patients
To understand the role of IRF5 in the regulation of dendritic cells, the association between IRF5 expression and cytokine production was assessed. For both pDCs and mDCs, we observed higher frequencies of IL-6 and TNF-α producing cells within the IRF5+ populations compared to their IRF5− counterparts (Figure 4 A-B and Supplementary Figure S7A-B). These differences could be observed in COVID-19 patients and healthy donors alike but was more pronounced in mDCs than pDCs. Regarding IFN-α production, there was no difference between IRF5+ and IRF5− pDCs (Supplementary Figure S7C). Just like the higher IRF5 MFI in mDCs (Figure 1 E), these results suggest that IRF5 might be more important for the regulation of effector functions of mDCs than pDCs. We detected a correlation of IRF5+ mDCs with the cytokine-producing mDCs of COVID-19 patients which was not present for pDCs and supported these findings (Figure 4 A-B and Supplementary Figure S7A-C). Additionally, the IRF5 MFI correlated with the IL-6 MFI in mDCs (Supplementary Figure S8A). However, the IRF5 MFI did not correlate with the IL-6 MFI in pDCs or with the MFI of the other cytokines (Supplementary Figure S8A-B). Interestingly, the IRF5+ populations of pDCs and mDCs also showed higher frequencies of cells expressing the inhibitory receptor CD85k (ILT-3) compared to the IFR5− populations (Figure 4 C and Supplementary Figure S7D). Again, on mDCs we could observe a strong correlation CD85k+ and IRF5+ cells for both COVID-19 patients and healthy donors. Taken together, these results are indicators for a potential role of IRF5 as a regulator of IL-6 and TNF-α production as well as CD85k expression in mDCs.Figure 4 Indicators for a role of IRF5 in the regulation of IL-6 and TNF-α production in mDCs. (A) IRF5+ mDCs more frequently produce IL-6, (B) TNF-α, and (C) express CD85k compared to their IRF5− counterparts upon TLR7 ligation and correlate with their frequencies. For comparison of IRF5+ and IRF5− cells within the COVID-19 group and the healthy donors, statistical significance was determined with a Wilcoxon matched-rank test. For all other analyses, a Mann-Whitney U-test was performed. Spearman’s rank correlation coefficient was calculated to determine correlations. Red dots indicate individuals with acute SARS-CoV-2 infection and grey dots show healthy donors.
4 Discussion
The dysregulation of innate immune responses is a feature of severe COVID-19 [26]. DC subsets play a critical role in the activation of innate immune responses: during acute viral infections, DCs sense pathogens via the nucleic acid sensor TLR7 and produce high levels of pro-inflammatory cytokines in response [29]. We aimed to investigate the association of IRF5 with the TLR7-dependent immune regulation in the DC compartment in COVID-19.
In accordance with previously published studies that characterized host immune responses in COVID-19 [10], [11], [26], [30], [31], [32], we observed a significant decrease of the myeloid and plasmacytoid DC frequencies in the peripheral blood of infected patients independently of the disease severity. These results suggest that DCs, the main producers of type I IFNs, are impaired in COVID-19, which is consistent with previously published studies [11], [31], [32] and with murine SARS-CoV infection [33]. A possible explanation could be DC migration from peripheral blood to local inflammatory site tissue. Accordingly, Sanchéz-Cerrillo et al. described that mDCs of patients with severe COVID-19 preferentially migrate to the lungs [34].
IRF5 acts downstream of TLR7 and subsequently induces cytokine production, particularly in DCs [14], [15], [16], [17]. IRF5 has been implicated in many inflammatory-driven diseases, such as systemic lupus erythematosus and inflammatory bowel disease [28]. So far only a few studies about the functional characteristics and role of IRF5 in COVID-19 induced immune responses have been published. In the current study, IRF5 expression levels in DCs of infected patients and healthy individuals were analyzed to gain a better understanding of its importance in COVID-19, where it may contribute to harmful innate immune responses. Here, we could show that IRF5+ mDCs were significantly reduced but the frequency of IRF5+ pDCs was maintained in SARS-CoV-2 infected individuals compared to healthy donors, as measured by flow cytometry. While TLR7 stimulation led to a significant upregulation of IRF5+ pDCs, IRF5+ mDCs did not significantly change in response to TLR7. However, compared to healthy individuals, infected individuals still tended to have impaired IRF5 MFI upregulation following TLR7 stimulation in both pDCs and mDCs. Altogether, these results suggest that IRF5 is partially regulated by TLR7 signaling and hence is critically involved in the pathogenesis of COVID-19.
A study by Yin et al. reported that IRF5 is required for the IFN response induced by SARS-CoV-2 in Vero E6 cells [35]. To determine whether the reduced IRF5+ DCs are associated with impaired cytokine production and altered IFN response, PBMCs were stimulated with the TLR7 agonist CL097 [20]. Contradicting our hypothesis, the dendritic cell cytokine profiles of COVID-19 patients were comparable to the ones in healthy donors following TLR7 stimulation. Solely, TLR7-stimulated mDCs of COVID-19 patients showed an impaired capacity to produce IL-6. These data suggest that while COVID-19 causes a depletion of blood DCs, the cytokine response is largely maintained. In contrast, a previous study by Pérez-Gémez et al. investigating immune dysregulation in COVID-19 observed a decrease in pDC levels and a considerable reduction of IFN-α production following TLR9 stimulation in acute SARS-CoV-2 infected patients [32]. Arunachalam et al. showed that the IFN-α production of pDCs was impaired in SARS-CoV-2 infected patients compared to healthy individuals [31].
While we could not confirm these alterations of the innate cytokine response in COVID-19 patients after TLR7 stimulation, our study provides strong indications for a potential role of IRF5 in the regulation of IL-6 and TNF-α production in mDCs and to a smaller degree as well in pDCs. In contrast, IFN-α production of pDCs seemed to be mostly independent of the IRF5 expression. This renders IRF5 a possible therapeutic target since an inhibition could potentially reduce IL-6 and TNF-α mediated hyperinflammatory states while maintaining antiviral type I IFN activity. Of note, the inhibitory receptor CD85k had also strong associations to the IRF5 expression in both pDCs and mDCs. Although this could be interpreted as a marker of DC activation or an intrinsic regulatory mechanism to limit excessive immune responses, future studies need to address the importance of this finding.
Limited sample numbers and thus underpowered analyses restrain our results to some extent. Therefore, there is the need to investigate the role of IRF5 in larger cohorts. Also, age differences between healthy controls and COVID-19 patients might affect the interpretation of our data due to altered cytokine secretion in aged immune systems [36]. However, we did not find the age to be a confounding factor for altered IRF5 expression or cytokine production. While in our results show coinciding cytokine and IRF5 expression, we cannot causally link IRF5 to DC functionality because we were not able to perform an IRF5 knockdown. Furthermore, multiple SNPs have been identified in the human IRF5 gene that alters the expression levels of IRF5 and hence influence the magnitude of host inflammatory responses and risk of severe COVID-19 [28], [37], which was not considered in this study. Future studies should further differentiate the different mDC subsets, in particular CD141+ mDCs and CD1c+ mDCs to examine potential differences in the IRF5 regulation [9].
Taken together, we observed a significant decrease in the percentage of DC subsets in the peripheral blood of SARS-CoV-2 infected patients. mDCs of SARS-CoV-2 infected patients exhibited lower levels of IRF5 at baseline and both mDCs and pDCs tended to upregulate IRF5 less upon stimulation with TLR7 agonists compared with healthy individuals. However, DCs of SARS-CoV-2 infected patients produced comparable levels of inflammatory cytokines, including IFN-α, TNF-α, and IL-6. Our data provide strong indications for a potential role of IRF5 as a regulator of inflammatory cytokine responses in mDCs. These results identify IRF5 as a potential immunomodulatory target in COVID-19 and other inflammatory diseases.
Data availability statement: Data storage is performed by the University Hospital Hamburg-Eppendorf. Data are available upon request from the corresponding author and can be shared after confirming that data will be used within the scope of the originally provided informed consent.
Funding statement: CB was funded by the DZIF Clinical Leave and Maternity Leave Program. CB received a grant from GILEAD Förderprogramm Infektiologie.
Conflict of interest disclosure: The corresponding author (CB) states on behalf of all authors that there is no conflict of interest.
Author contributions: L.C., R.W., S.Kum., and C.B. performed research, collected and analyzed data; L.C., J. SzW., and C.B. designed and directed the research project; L.C. and C.B. reviewed the literature, and drafted the paper. S.K., A.W.L., M.A., M.M.A., and J.SzW. gave important input to the manuscript; T.T.B., S.Klu., S.S., and S.J. recruited study samples. All authors read and approved the final manuscript.
CRediT authorship contribution statement
Leon Cords: Conceptualization, Methodology, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization. Robin Woost: Investigation. Silke Kummer: Investigation, Project administration. Thomas T. Brehm: Resources. Stefan Kluge: Resources. Stefan Schmiedel: Resources. Sabine Jordan: Resources. Ansgar W. Lohse: Resources. Marcus Altfeld: Validation, Writing – review & editing. Marylyn M. Addo: Resources, Writing – review & editing. Julian Schulze zur Wiesch: Conceptualization, Resources, Writing – review & editing, Supervision. Claudia Beisel: Conceptualization, Methodology, Formal analysis, Data curation, Writing – original draft, Writing – review & editing, Visualization, Supervision, Funding acquisition.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data availability
Data will be made available on request.
Acknowledgments
We cordially thank the volunteers participating in this study.
==== Refs
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| 0 | PMC9744680 | NO-CC CODE | 2022-12-16 23:20:04 | no | Cytokine. 2023 Feb 13; 162:156109 | utf-8 | Cytokine | 2,022 | 10.1016/j.cyto.2022.156109 | oa_other |
==== Front
Lancet Reg Health Southeast Asia
Lancet Reg Health Southeast Asia
The Lancet Regional Health. Southeast Asia
2772-3682
2772-3682
The Author(s). Published by Elsevier Ltd.
S2772-3682(22)00146-9
10.1016/j.lansea.2022.100129
100129
Articles
An Observational Multi-centric COVID-19 Sequelae Study among Health Care Workers
Shukla Ajay Kumar a∗
Atal Shubham a
Banerjee Aditya a
Jhaj Ratinder a
Balakrishnan Sadasivam a
Chugh Preeta Kaur b
Xavier Denis c
Faruqui Atiya c
Singh Aakanksha c
Raveendran Ramasamy d
Mathaiyan Jayanthi d
Gauthaman Jeevitha d
Parmar Urwashi I. e
Tripathi Raakhi K. e
Kamat Sandhya K. e
Trivedi Niyati f
Shah Prashant f
Chauhan Janki f
Dikshit Harihar g
Mishra Hitesh g
Kumar Rajiv g
Badyal Dinesh Kumar h
Sharma Monika i
Singla Mamta j
Medhi Bikash k
Prakash Ajay k
Joshi Rupa k
Chatterjee Nabendu S. l
Cherian Jerin Jose l
Kamboj Ved Prakash m
Kshirsagar Nilima n
a Department of Pharmacology, All India Institute of Medical Sciences, Saket Nagar, Bhopal, Madhya Pradesh 462020
b Department of Pharmacology, Vardhman Mahavir Medical College & Safdarjung Hospital, near AIIMS Hospital, Ansari Nagar West, New Delhi, Delhi 110029
c Department of Pharmacology, St John's Medical College Sarjapur - Marathahalli Rd, beside Bank Of Baroda, John Nagar, Koramangala, Bengaluru, Karnataka 560034
d Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education & Research, JIPMER Campus Rd, Gorimedu, Priyadarshini Nagar, Puducherry, 605006
e Department of Pharmacology & Therapeutics, Seth G. S. Medical College & K. E. M. Hospital, Acharya Donde Marg, Parel East, Parel, Mumbai, Maharashtra 400012
f Department of Pharmacology, Medical College, Baroda, Vinoba Bhave Rd, Anandpura, Vadodara, Gujarat 390001
g Department of Pharmacology, Indira Gandhi Institute of Medical Sciences, Allahabad bank, Bailey Rd, Sheikhpura, Patna, Bihar 800014
h Department of Pharmacology, Christian Medical College and Hospital, Brown Rd, CMC Campus, Ludhiana, Punjab 141008
i Department of Paediatrics, Christian Medical College and Hospital, Brown Rd, CMC Campus, Ludhiana, Punjab 141008
j Department of Psychiatry, Christian Medical College and Hospital, Brown Rd, CMC Campus, Ludhiana, Punjab 141008
k Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Madhya Marg, Sector 12, Chandigarh, 160012
l ICMR Secretariat, Dept. of Health Research, Ministry of Health and Family Welfare, V. Ramalingaswami Bhawan, P.O. Box No. 4911. Ansari Nagar, New Delhi - 110029
m ICMR-NvCCP TAG Chairperson, Dept. of Health Research, Ministry of Health and Family Welfare, V. Ramalingaswami Bhawan, P.O. Box No. 4911. Ansari Nagar, New Delhi - 110029
n Emeritus Scientist ICMR, TAG Member, Dept. of Health Research, Ministry of Health and Family Welfare, V. Ramalingaswami Bhawan, P.O. Box No. 4911. Ansari Nagar, New Delhi - 110029
∗ Corresponding author details: Dr Ajay Kumar Shukla Assistant Professor, Department of Pharmacology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh-462020, India Mob: +91 97555 26266
13 12 2022
13 12 2022
1001295 8 2022
18 11 2022
30 11 2022
© 2022 The Author(s)
2022
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Background
India have seen more than 43 million confirmed cases of COVID-19 as of April 2022, with a recovery rate of 98.8%, resulting in a large section of the population including the healthcare workers (HCWs), susceptible to develop post COVID sequelae. This study was carried out to assess the nature and prevalence of medical sequelae following COVID-19 infection, and risk factors, if any, associated with them. Methods: This was an observational, multicenter cross-sectional study conducted at eight tertiary care centers. The consenting participants were HCWs between 12-52 weeks post discharge after COVID-19 infection. Data on demographics, medical history, clinical features of COVID-19 and various symptoms of COVID sequelae was collected through specific questionnaire.
Finding: Mean age of the 679 eligible participants was 31.49 ± 9.54 years. The overall prevalence of COVID sequelae was 30.34%, with fatigue (11.5%) being the most common followed by insomnia (8.5%), difficulty in breathing during activity (6%) and pain in joints (5%). The odds of having any sequelae were most significantly higher among participants who had moderate to severe COVID-19 (OR 6.51; 95% CI 3.46 – 12.23) and lower among males (OR 0.55; 95% CI 0.39-0.76). Besides these, other predictors for having sequelae were age (≥ 45 years), presence of any comorbidity (especially hypertension and asthma), category of HCW (non-doctors vs doctors) and hospitalisation due to COVID-19.
Interpretation: Approximately one-third of the participants experienced COVID sequelae. Severity of COVID illness, female gender, advanced age, co-morbidity were significant risk factors for COVID sequelae. Funding: This work is a part of Indian Council for Medical Research (ICMR)- Rational Use of Drugs network. No additional financial support was received from ICMR to carry out the work, for study materials, medical writing, and APC.
FundingIndian Council of Medical Research (ICMR) through its Task Force Project on Rational Use of Medicines.
Keywords
long COVID
COVID sequelae
SARS-CoV-2
COVID-19
ICMR-RUMC
Abbreviations
ACE2, Angiotensin-converting enzyme 2
AE, Adverse events
BMI, Body mass index
CAD, Coronary artery disease
COVID-19, Corona virus disease 2019
CI, Confidence interval
CTRI, Clinical Trials Registry- India
DASS-21, Depression
Anxiety, and Stress Scale-21
ENT, Ear, nose, and throat
GERD, Gastroesophageal reflux disease
HCQ, Hydroxychloroquine
HCW, Health care worker
ICMR, Indian council of medical research
MOHFW, Ministry of Health and Family Welfare
Govt. of India, OR
Odds ratio, PCOS
Polycystic Ovarian Disease, PLOG
Polymerase gamma-related disorders, p-value: Probability value
NICE, National Institute for Health and Clinical Excellence
RHD, Rheumatic heart disease
RUMC, Rational use of medicine center
SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2
WHO, World Health Organization
==== Body
pmc Research in context
Evidence before this study
During the COVID-19 pandemic population of India was widely inflicted. These sections of population are susceptible to develop COVID-19 sequelae. Prior data on COVID sequelae in Indian population are limited. It has been observed that majority of the symptoms of the COVID sequelae are under-reported. High quality evidence for the duration of COVID sequelae are also lacking.
Added value of this study
The study highlights the prevalence of COVID sequelae in the specific subset of healthcare workers among the Indian population. The study describes sequelae among COVID survivors who have various categories of risk factors. The study highlights the pattern of symptoms most commonly seen as COVID sequelae including general symptoms and system wise presentations. It is also attempted to evaluate association of such symptoms with various demographic and medical characteristics of the participants.
Implications of all the available evidence
The study results will aid in conducting the screening programmes and specialized outpatient clinics for the assessment of COVID sequelae. These can be developed primarily to focus on the sub-section of the population having higher risk to have COVID sequelae. To combat under-reporting of the symptoms, these programmes and clinics can stress on eliciting the symptoms based on the common pattern of symptoms in COVID sequelae.
Introduction
On March 11, 2020, Coronavirus disease 19 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was declared a pandemic by World Health Organization (WHO).1 A number of those affected continue to suffer from long term effects of COVID which have been termed variously as COVID sequelae, post COVID symptoms, or post COVID condition.2, 3, 4 In India alone, 43,045,527 confirmed cases have been discharged as on April 19, 2022 with a recovery percentage of 98.8%,5 indicating that a large section of the population is susceptible to develop COVID sequelae.
The Government of India has issued guidelines for the management of post COVID complications affecting different systems of the body,6 and outpatient department services are being provided in various parts of India.7 , 8
A questionnaire-based study in China in 538 COVID-19 survivors reported general symptoms (49% of patients), symptoms related to the respiratory (39%), and cardiovascular system (13%), and psychosocial symptoms (22.7%) as the most frequent sequelae three months after discharge.2 Many other studies in different settings have found the prevalence of post-COVID sequelae from 49% to 76%.9, 10, 11, 12, 13 However, while health care workers (HCWs) are most liable to get exposed to this infection, to the best of our knowledge, no study has been reported from India to assess COVID-19 sequelae among HCWs. The post COVID sequelae by their very nature could effect on job performance which is especially important for HCWs. The Indian Council Medical Research (ICMR) recommended hydroxychloroquine (HCQ) for prophylaxis among asymptomatic (HCWs) involved in the care of COVID-19 cases.14 The effect of HCQ prophylaxis on the incidence of COVID sequelae also remains to be assessed.
This study was thus carried out to explore the COVID- 19 sequelae and associated risk factors among HCWs. We planned to assess the nature and prevalence of medical sequelae following COVID-19 infection, as well as the association of COVID-19 manifestations and other risk factors with the COVID sequelae.
Methods
This multi-centric cross-sectional study was conducted at eight tertiary care hospitals associated with Indian Council of Medical Research (ICMR) Rational Use of Medicine Centers (RUMCs) across India between July-October 2021 with the primary objective of assessing the nature and prevalence of post-COVID-19 sequelae along with the associated risk factors 12-52 weeks post-recovery following COVID-19 infection amongst health care workers (HCWs). All the sites obtained approval from their Institutional Ethics Committees to conduct the study. The study was registered at The Clinical Trials Registry- India (CTRI) with CTRI no. CTRI/2021/06/034255.
Any newly occurring or remaining symptoms or signs in COVID-19 patients after 3 months (12 weeks) of discharge from the hospital (or declared discharged in case of non-hospitalized patients) were defined as sequelae in our study as reported by Xiong Q et al from China.2 In the guidelines issued by National Institute for Health and Clinical Excellence (NICE), in collaboration with the Scottish Intercollegiate Guidelines Network and the Royal College of General Practitioners, the post COVID-19 syndrome has been defined as symptoms and signs that develop during or after an infection with COVID-19 and continue for more than 12 weeks and cannot be explained by any other diagnosis.3 World Health Organization (WHO) has defined post COVID-19 condition as symptoms that occur after 3 months of onset of COVID-19 which persist for at least 2 months and cannot be explained by an alternative diagnosis.4 As this study was planned before the above guidelines were issued, we have adopted the available definition of COVID sequelae for the study as mentioned above.2 By default any patient with COVID sequelae as defined in our study also fulfilled the post COVID-19 syndrome definition of NICE guidelines.
The consenting participants included doctors, nurses, paramedical and ancillary staff with COVID-19 (confirmed SARS-CoV-2 positivity on RT-PCR) along with asymptomatic cases, who recovered (were declared ‘discharged’) as per national guidelines between 12-52 weeks post COVID-19 infection.15 Eligible HCWs were identified from a previous study database of this research group for the assessment of HCQ prophylaxis among HCWs16, as well as any other available institutional database. HCWs with any serious co-morbid medical or mental health condition and pregnant women were excluded as many of the sequelae under assessment are commonly seen as presentations of these conditions.
Eligible HCWs were approached telephonically initially by trained research staff which included doctors and non-doctors. Upon receiving written consent, a structured interview was administered and responses collected. In the case record form, the demographic details, medical history, COVID-19 treatment details, details of investigations, and information regarding the general and system-wise sequelae symptoms were collected by the researcher while the participants were encouraged to self-administer the Depression, Anxiety, and Stress Scale-21, (DASS21) questionnaire and the modified sleep disorders questionnaire.17 In case participants found it difficult to self-administer any of the questionnaire, they were assisted by the investigators.
The sample size to find the prevalence of COVID-19 sequelae with a 95 percent confidence interval and a precision of 2.5 percent was calculated to be 292, assuming a prevalence of the least prevalent medical sequelae of COVID-19 of 5%. The sample size for identifying an independent variable as the risk factor, with an anticipated odds ratio of 1.3, a conventional two-tailed test, with power and alpha at 80% and 5%, respectively, were found to be 557 at a probability of occurrence rate of 0.3 for the outcome variable. Hence the sample size of 557 was considered for the study
Statistical Analysis
Clinical and demographic data were categorized and expressed as mean (+standard deviation) and percentage, respectively. Medical sequelae prevalence was reported in percentages and proportions. Odds ratios with a 95% confidence interval were calculated, along with p values using chi-square test in order to measure the association of medical sequelae with risk factors. Simple logistic regression was done using IBM SPSS version 28. A comparison was done between HCWs who received HCQ prophylaxis and those who did not receive HCQ prophylaxis, in terms of the occurrence of medical sequelae following COVID-19 infection. A subgroup analysis was carried out between HCWs who recovered within 12-24 weeks and HCWs who recovered between >24-52 weeks.
Role of the funding source
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Results
Site and participant characteristics:
Out of 1223 HCWs with confirmed COVID-19 who were contacted, 928 participated (75.88 %), with similar response rate between centres. The reasons for not participating could not be ascertained individually, but the common reasons as reported by the sites were hectic work schedule, unwilling to participate, change in place of posting or lengthy case report form. Out of the 928 participating HCWs, 249 were excluded for not fulfilling the inclusion criteria (as per the protocol, HCWs who recovered from COVID between 12-52 weeks were to be recruited for the sequelae study. 34 participants were recruited <12 weeks post recovery and 215 participants were recruited >52 weeks post recovery from COVID-19 respectively. Thus, a total of 679 eligible HCWs from eight sites were included in the final analysis. Of them, there were 270 doctors (39.76%), 181 nurses (26.66%) and the rest were other categories (hospital staff: 103, lab attendant/technician: 39, administrative staff: 30, research staff: 18, hospital attendant & security: 13 each, housekeeping: 12).
Table 1 summarizes the demographic and clinical status of the participants. The mean age of the participants was 31.49 ± 9.54 years and almost an equal proportion of male and female HCWs participated. At least one comorbidity was reported by 90 HCWs (13.25%), among which hypertension was the most common (5.74%) followed by diabetes and asthma.Table 1 Baseline characteristics and co-morbidity status of study participants
Characteristic Category Frequency (%)
(N= 679)
Age < 45 years 596 (87.78)
≥ 45 years 83 (12.22)
Gender Male 334 (49.19)
Female 345 (50.81)
Body mass index (BMI) Overweight / Obese (≥ 25 kg/m2) 235 (34.61)
Non-obese (< 25 kg/m2) 444 (65.39)
Designation Doctors (including interns) 270 (39.76)
Nursing staff 181 (26.66)
Other staff 228 (33.58)
Smoking Never smoked 615 (90.57)
Current smoker 39 (5.74)
Former smoker 25 (3.68)
Alcohol Lifetime abstainer 545 (80.27)
Current drinker 113 (16.64)
Former drinker 21 (3.09)
Co-morbidity Hypertension 39 (5.74)
Diabetes 25 (3.68)
Asthma 21 (3.09)
Heart Failure 1 (0.15)
Others* 53 (7.81)
Presence of co-morbidities Any 1 co-morbidity 90 (13.25)
Any 2 co-morbidities 13 (1.91)
Any ≥3 co-morbidities 7 (1.03)
*Others include Hypothyroidism: 16; thyroid: 8; cardiac diseases (CAD, bicuspid aortic valve, RHD): 5; migraine & tuberculosis: 3 each; ankylosing spondylitis, PCOS, hyperlipidaemia, migraine, sinusitis: 2 each; anemia, anxiety, arthritis, carcinoma colon, cholesterol, dermatitis, epilepsy, fatty liver, GERD, lichen plannus, pericarditis, pleural effusion, POLG (progressive external ophthalmoplegia- mutation in POLG gene), reactive arthritis, recurrent allergies, rheumatoid arthritis, right bundle branch block, sickle cell trait: 1 each
COVID-19 and related characteristics:
As shown in table 2 , ∼ 90% of the participants had received a dose of COVID-19 vaccine (74.82% received Covishield and 14.28% Covaxin), with more than 70% having taken two doses. Only a small proportion (11.2%) had taken chemoprophylaxis with HCQ. Majority of the participants reported suffering from mild COVID-19 (73.9%), whereas 18.4% had asymptomatic infection. A very small proportion (2.06%) reported to have had COVID-19 a second time.Table 2 Prophylaxis, vaccination, and COVID-19 status of study participants
Characteristic Category Frequency (%)
(N= 679)
HCQ prophylaxis taken Yes 76 (11.19)
No 603 (88.81)
Duration of HCQ prophylaxis <1-2 weeks 15 (2.21)
3-6 weeks 26 (3.83)
≥ 7 weeks 35 (5.15)
Vaccination (irrespective whether the participant had COVID-19 exposure or not) One dose taken 118 (17.38)
Both the dose taken 487 (71.72)
No vaccine dose taken 74 (10.90)
Name of vaccine taken Covishield 508 (74.82)
Covaxin 97 (14.28)
COVID-19 status Symptomatic 554 (81.59)
Asymptomatic 125 (19.41)
Severity of COVID-1918 Mild 502 (73.93)
Moderate 48 (7.07)
Severe 4 (0.59)
2nd episode of COVID-19 Yes 14 (2.06)
No 665 (97.94)
Hospitalisation due to COVID-19 Yes 310 (45.66)
No 369 (54.34)
Hospitalisation duration ≥ 10 days 139 (20.47)
< 10 days 171 (25.18)
Prevalence and pattern of COVID-19 sequelae:
Out of the 679 participants, 206 HCWs reported having suffered from at least one of the assessed medical sequelae giving an overall prevalence of 30.34%. Out of these, 7.51% participants had 2 sequelae and 9.72% had 3 or more sequelae. The detailed pattern of COVID-19 sequelae reported by participants, with their prevalence, is displayed in table 3 .Table 3 Prevalence of COVID-19 sequelae among study participants
Characteristic Symptom/ Sequelae Prevalence n (%)
HCWs with any sequelae (one or more) 206 (30.34)
HCWs with one sequelae 89 (13.11)
HCWs with two sequelae 51 (7.51)
HCWs with three or more sequelae 66 (9.72)
General Symptoms Has any of the symptoms 174 (25.63)
Fatigue 78 (11.49)
Pain in joints 34 (5.01)
Soreness in muscles 30 (4.42)
Fever 19 (2.80)
Cardiovascular-Respiratory Symptoms Has any of the symptoms 120 (17.67)
Difficulty in breathing while doing any physical activity 41 (6.04)
Cough 31 (4.57)
Tightness in chest 15 (2.21)
Throat Pain 14 (2.06)
Difficulty in breathing while at rest 11 (1.62)
Sensation of irregular or fast heartbeat 8 (1.18)
Gastrointestinal Symptoms Has any of the symptoms 26 (3.83)
Reduced Appetite 9 (1.33)
Nausea 7 (1.03)
Diarrhoea 6 (0.88)
Abdominal pain 4 (0.59)
ENT Symptoms Has any of the symptoms 18 (2.65)
Sore throat 13 (1.91)
Pain in the ear 3 (0.44)
Ringing sensation in ears 2 (0.29)
Neuro-psychiatric Symptoms Has any of the symptoms 228 (33.57)
Headache 31 (4.57)
Loss of smell 31 (4.57)
Loss of taste 27 (3.98)
Difficulty in concentrating 14 (2.06)
Difficulty to focus on the usual things 12 (1.77)
Forgetting things easily 11 (1.62)
Pins & needles sensation or numbness in hands or feet 7 (1.03)
Difficulty in thinking clearly or getting anything done 5 (0.74)
Sleep disorder (Insomnia) 58 (8.54)
Depression 9 (1.33)
Stress 7 (1.03)
Anxiety 1 (0.15)
Dermatological Symptoms Skin rash 7 (1.03)
Fatigue (11.5%) and sleep disorder (insomnia) (8.5%) were the most common sequelae suffered by the participants. Difficulty in breathing while doing any physical activity (6%) and pain in joints (5%) were the next most commonly reported sequelae. Other relatively common general sequelae were soreness in muscles (4.4%) and fever (2.8%). Among system-wise sequelae, the most common were cough, headache, loss of smell (4.6% each respectively), loss of taste (4%), sore throat (1.91%), reduced appetite (1.33%) and skin rash (1%) in the different systems. It was also seen that depression and stress were seen in 1.3% and 1% HCWs respectively.
Among participants with multiple sequelae, fatigue and difficulty in breathing while doing physical activity or insomnia (3.4% each) were the sequelae most commonly seen together followed by fatigue and pain in joints (3%), and insomnia and headache (2.4%). (Supplementary table 1)
Association of COVID-19 manifestations and other risk factors with sequelae:
Upon calculation of odds ratio to assess association of various demographic, clinical and COVID-19 parameters, deemed as possible risk factors, with the occurrence of medical sequelae among the participants, it was found that the odds of having sequelae were most significantly higher if the participant had moderate – severe COVID-19 (OR 6.51; 95% CI 3.46 – 12.23).
As depicted in table 4 (and supplementary table 2), in the univariate analysis, the odds of suffering from a post COVID sequelae were also significantly higher among HCWs ≥ 45 years of age (OR 2.03; 95% CI 1.27-3.25), those who had any comorbidity (OR 2.01); more specifically in those who had asthma (OR 2.61) and hypertension (OR 2.06). In contrast, the odds of having sequelae were found to be significantly lesser among males (OR 0.55) and among doctors as well as doctors and nursing staff as a combined group compared to other HCWs (OR 0.65 and 0.70 respectively).Table 4 Association of various risk factors with COVID-19 sequelae among study participants
Risk Factors HCWs having any sequelae HCWs not having any sequelae Category wise prevalence of sequelae (%) Odds ratio; (95% CI) p- value
Gender Male 80 254 23.95 0.55; (0.39-0.76) 0.00036
Female 126 219 36.52
Age (yrs) Age ≥45 37 46 44.58 2.03; (1.27-3.25) 0.0025
Age <45 169 427 28.36
Obesity Overweight / Obese (BMI ≥ 25 kg/m2) 78 157 33.19 1.23; (0.87-1.72) 0.239
Non-obese (BMI < 25 kg/m2) 128 316 28.83
Occupation Doctors 66 204 24.44 0.65; (0.44-0.88) 0.0069
Nurses & other HCWs 140 269 34.23
Doctors & Nurses 125 326 27.72 0.7; (0.49-0.98) 0.0037
Other HCWs 81 147 35.53
Co-morbidities Any co-morbidity present 48 62 43.64 2.01; (1.32-3.06) <0.0011
Any co-morbidity absent 158 411 27.77
Diabetes present 11 14 44.00 1.85; (0.82-4.15) 0.135
Diabetes absent 195 459 29.82
Asthma present 11 10 52.38 2.61; (1.09-6.25) 0.031
Asthma absent 195 463 29.64
Hypertension present 18 21 46.15 2.06; (1.07-3.96) 0.029
Hypertension absent 188 452 29.38
Prophylaxis and Vaccination HCQ prophylaxis taken 22 54 28.95 0.93; (0.55-1.57) 0.779
HCQ prophylaxis not taken 184 419 30.51
Vaccinated with at least 1 dose 181 424 29.92 0.84; (0.50-1.40) 0.495
Not vaccinated with any dose 25 49 33.78
COVID-19 severity Symptomatic COVID-19 175 379 31.59 1.4; (0.90-2.18) 0.137
Asymptomatic COVID-19 31 94 24.80
Moderate – severe COVID-19 37 15 71.15 6.51; (3.46-12.23) <0.0001
Mild COVID-19 138 364 27.49
There was no significant change in the odds of having post COVID-19 sequelae due to preventive chemoprophylaxis with HCQ or vaccination (one or two doses) or due to hospitalisation for COVID-19 or having symptomatic infection. Similarly, other factors such as obesity, smoking or alcohol intake, presence of diabetes, or blood group also did not significantly increase the odds of having sequelae.
Upon assessing association of the various factors with the commonly seen COVID sequelae individually (Supplementary table 3), it was found that moderate-severe COVID-19 remained a risk factor for most of the common sequelae other than loss of taste and smell, whereas presence of any comorbidity, hypertension and being doctors did not remain significant predictors for most of the sequelae. Age ≥45 years and female gender remained significant predictors for some sequelae but not for others like sleep disorder, soreness in muscles.
Similarly, assessment of association of COVID sequelae with multiple comorbidities and other risk factors showed that the odds of having sequelae were higher in participants who had multiple comorbidities together, significantly among those with both hypertension and diabetes. (Supplementary table 4) Number of participants with concurrent multiple comorbidities and risk factors such as drinking and smoking were however quite low, making the analysis non-conclusive.
Logistic regression analysis
Taking into account the odds ratios obtained for various factors, a multivariate logistic regression analysis was performed to assess the strength of association of significant risk factors with the occurrence of sequelae. A forward stepwise approach was used and a regression model was developed that showed overall significance (p < 0.001). Table 5 displays the variables in the final regression model with the adjusted odds ratio. Moderate – Severe COVID remained an independent predictor for risk of having COVID sequelae (adjusted OR 5.83; 95% CI 3.05 – 11.14) and male gender was a protective factor (adjusted OR 0.56; 95% CI 0.4 – 0.8).Table 5 Multivariate Logistic Regression Analysis for Associated Risk Factors
Variable Adjusted Odds ratio; p value 95% CI for adjusted Odds Ratio
Age 1.362; 0.278 0.780 – 2.377
Gender (Male vs Female) 0.560; 0.001 0.395 - 0.795
Doctors vs Other HCWs 0.745; 0.115 0.516 - 1.074
Presence any co-morbidity (Yes vs No) 1.447; 0.136 0.890 - 2.351
COVID Severity (Moderate-Severe vs Mild) 5.832; <0.001 3.054 - 11.139
Constant 0.000; <0.001 -
The regression equation obtained was:
Log (p/1-p) odds of COVID sequelae= -0.695 + 1.763*COVID severity – 0.580*Male gender
Subgroup analysis according to time of participation post COVID-19
A pre-specified subgroup analysis was conducted by categorising the participants according to the time of their participation in the study as 12 – 24 weeks and >24 – 52 weeks post recovery from COVID-19. (See supplementary tables)
There were no significant differences in the subgroups in demographic characteristics except for drinking status – lifetime abstainer / former drinker, but some differences were seen in the proportion of participants having taken HCQ prophylaxis or both doses of vaccine (higher in the >24 – 52 weeks’ subgroup), as well as type of vaccine taken - covishield or covaxin). (Supplementary tables 5 and 6)
In terms of the post COVID-19 sequelae suffered, there were some significant differences in the prevalence of symptoms such as soreness in muscles, fever, headache, loss of taste which were all seen to be more prevalent in the participants who participated between 12 – 24 weeks of COVID-19 recovery. Prevalence of other symptoms was not significantly different in the two subgroups. (Supplementary table 7)
Moderate-severe COVID-19 remained a significant risk factor for occurrence of sequelae in both subgroups. Results showed that odds of having a COVID-19 sequelae remained lower with male gender and higher with age ≥45 respectively in both the subgroups of participants but statistical significance was retained for the >24 – 52 weeks’ subgroup only whereas odds of sequelae were significantly reduced for doctors with/out nursing staff for the 12 – 24 weeks’ subgroup only. In case of comorbidities, the odds with presence of any comorbidity and asthma remained significantly elevated for the >24 – 52 weeks’ subgroup, but hypertension did not remain a significant predictor for occurrence of sequelae in either of the subgroups. Rest of the results remained in congruence with those obtained in the overall analysis. (Supplementary table 8)
Ancillary analysis:
The drugs most commonly used for management of COVID-19 among the participants were vitamin supplements (in all prescriptions), paracetamol (69.66 %), azithromycin (44.18 %), levocetirizine (14.14 %), ivermectin (11.93 %) and doxycycline (10.16 %). (Supplementary table 9) The symptoms most commonly reported by participants at the time of having COVID were cough (15.76 %), myalgia (13.99 %), headache (11.49 %), fatigue / weakness (9.87 %) and sore throat (8.1 %). (Supplementary table 10)
Among the 504 HCWs who received 1st dose of Covishield vaccine, the most common adverse events (AEs) seen were fever (53.97 %), body ache (43.06 %), injection site tenderness / pain / warmth (35.91 %), headache (23.02 %), and myalgia (18.65 %). Similar AEs were seen with the 2nd dose of the vaccine as well, but in much lesser proportions. (Supplementary table 11) Similarly, the common AEs reported by participants who received the 1st or 2nd doses of Covaxin were fever, injection site tenderness / pain / warmth, and general body ache; by proportionately fewer HCWs than those receiving Covishield.
Discussion
In this cross-sectional study in 679 confirmed COVID-19 (hospitalized and non-hospitalized) health care workers, the prevalence of COVID sequelae was found to be 30.34% after 12-52 weeks of their discharge. Other studies which included both hospitalized and non-hospitalized COVID-19 patients, reported prevalence rates of COVID sequelae between 30% to 64%9 , 13 , 19 , 20 while studies that included hospitalized patients only, reported comparatively higher prevalence rates ranging from 49% to 87.4%.2 , 21, 22, 23 Consistent with the findings of our study, the most common overall symptoms were general symptoms followed by neuropsychiatric and cardio-respiratory symptoms,2 , 19 , 21 , 23 , 24 while fatigue, sleep disorder, difficulty in breathing while doing any physical activity, pain in joints, and loss of smell, and headache were the most commonly reported individual symptoms.2 , 9 , 19 , 22, 23, 24 All these symptoms have been included in the various guidelines for managing the long-term effects of COVID-19.3 , 4 , 6 In a multinational online survey in 3762 participants, for more than 91% of the patients the recovery time was more than six months. The most common reported symptoms after six months were fatigue, post-exertional malaise, and cognitive dysfunction. There were 203 symptoms reported across ten organ systems. Patients had multisystem involvement for more than seven months.25 The difference in the study results of this study from our study can be attributed to the different study populations and study settings.
Guidelines issued by the MOHFW (Ministry of Health and Family Welfare, Government of India) also mentioned fatigue as the most common COVID sequel. Cardiovascular, neurological, and nephrological components have been implicated for causing fatigue. Among symptoms due to cardiovascular system involvement in long COVID, myocardial involvement has been implicated in 20-30% of hospitalized patients who have been affected by severe COVID. Cardiomyocyte damage, thrombosis, microvascular dysfunction, and cytokine storm have been implicated as the cause of myocardial injury. Shortness of breath, dry cough, and chest pain are the most common respiratory sequelae among COVID-19 patients. Fatigue, changes in concentration, impaired memory, myalgias, headaches, sleep disorders, dizziness, anosmia, and ageusia are the most commonly reported neurological sequelae. Reactivation of latent SARS CoV-2 in the central nervous system has been suggested to be responsible for these neurological sequelae.6
The odds of having COVID sequelae were found significantly higher in females as compared to males, both in ours and several other studies.2 , 24 , 26 , 27 A study in 180 COVID-19 patients found no association between COVID sequelae with gender or co-morbidity.9 This can be attributed to the smaller sample size of the study. In particular, fatigue, cough, loss of smell, loss of taste, and headache were found to be significantly more common in females than in males.2 , 23 , 28 The odds of having COVID sequelae were found to be significantly higher in participants 45 years or older as compared to their younger counterparts. This is consistent with the finding of a longitudinal study in COVID-19 (both non-hospitalized & hospitalized) survivors, wherein sequelae of COVID-19 were found to be more prevalent with advanced age.20 , 26 , 27
We also found an association between persistent COVID-19 symptoms with hospitalisation.
However, in adjusted models, this association was no longer statistically significant, implying that the association was related to a higher prevalence of co-morbidity, severe illness, and older age among hospitalized patient groups.
Similar to our study, previous studies have reported higher odds of having COVID sequelae in participants with comorbidity20 , 29 Similarly, the odds of having COVID sequelae were found to be significantly higher in participants who had severe or moderately severe COVID as compared to the participants who had mild COVID. In a prospective cohort study in adult COVID-19 patients, vaccination was not found to improve symptoms of post-acute sequelae of COVID-19.30 A retrospective cohort study in HCWs, high BMI and previous pulmonary disease was found to be a risk factor for 35-day long-COVID characteristics.31 A multicentric retrospective cohort study in HCWs found that higher antibody titres were associated with decreased risk of SARS-CoV-2 breakthrough infections.32
Interestingly, we found that doctors and nursing staff were at lower risk for COVID sequelae than ancillary staff, although the reasons for this difference are not clear. On the other hand, no significant difference was found in the odds of having COVID sequelae with respect to HCQ prophylaxis.
There have been multiple potential mechanisms proposed for the development of COVID sequelae. These include direct viral invasion via ACE2 receptors, hidden viral reservoirs, immune and inflammatory disturbances, altered microbiome, imbalance in the renin-angiotensin system, and abnormal metabolism and mitochondrial dysfunction.32 Which of these particular mechanisms is responsible for the development of the specific sequelae remains to be explored. Abnormal immunometabolism and mitochondrial dysfunction could be responsible for fatigue33 while residual reservoir of the virus may lead to loss of smell and taste.34
The role of health care workers during the period of COVID-19 pandemic cannot be undermined. COVID-19 pandemic has not only exposed HCWs to unprecedented levels of risk but also to the higher levels of stress due to the increased work pressure. The incidence of COVID sequelae among HCWs will affect their performance on the long term and consequently will have impact on health care settings.
Due to the insufficient understanding and data on COVID sequelae, there is a lack of research on management, including self-management practices among patients having COVID sequelae.35 The study results provide useful insight into the wide range of symptoms experienced by COVID-19 survivors. These symptoms will affect their quality of life as well as performance at workplace as compared to the pre-illness level. As millions of people have suffered from COVID-19, the prevalence of COVID-sequelae is going to be substantial. The planning for the management of the health care services can be devised based on the prevalence and risk factors of COVID sequelae.
This was an observational questionnaire-based study. No objective assessments like laboratory or radiographic investigations were carried out per se for the study. Being a cross-sectional study, there was no follow-up of the patients. The inclusion of health care workers only, limits the generalization of the results. As the participants were asked to report experienced symptoms within the designated periods, this could impact the reliability of symptom prevalence estimates leading to the possibility of both under-reporting and over-reporting of symptoms. The definition of WHO for post-COVID condition has recently introduced a newer criterion that symptoms should persist for at least two months to qualify for the post-COVID condition. In this cross-sectional study duration of presenting symptoms could not be accurately assessed. The subgroup analysis was relatively underpowered as one of the participant subgroups had comparatively lesser sample size.
Our findings highlight the prevalence and pattern of COVID sequelae along with the associated risk factors among a special subgroup of COVID-19 survivors – the health care workers. Approximately one-third of the participants experienced COVID sequelae. Female gender, advanced age, co-morbidity, and severity of COVID illness were risk factors for COVID sequelae. Considering the heterogeneity in symptoms of COVID sequelae, longitudinal studies with follow-up assessments and treatment interventions are further required. These studies will foster an understanding of the natural history of the disease and prediction of risk factors to devise evidence-based treatment guidelines for the management of long-term effects of COVID.
Contributors
NK and AS conceptualized the study while NK, AS, SA, RJ and BS were responsible for methodology. Data collection and curation was done by all authors. Data analysis was done by SA and AB. Validation of the study protocol was done by NK whilst final validation of the results was done by SA, AS, NK, and AB. Visualizations, project supervision, and resource management were led by NK, AS, SA and JC. Original draft was prepared by AS, SA RJ and AB, whilst revisions and final editing were done by all authors. All authors have read and approved the final manuscript for publication.
Data sharing statement
Data supporting this study’s findings are available from the corresponding author (AS: [email protected]) upon review of request by the Indian Council for Medical Research (ICMR)- Rational Use of Drugs network.
Declaration of interests
All other authors declare no competing interests.
Supplementary Material
mmc1
Acknowledgements
We gratefully acknowledge Technical Advisory Group members of Indian Council for Medical Research, Government of India their support and guidance. We also acknowledge Dr. Saurav Mishra and Dr. Ponmani Ponnambalam for assisting in preparing the protocol, Sateesh Meena for assisting in data entry, final data cleaning and compilation, Dr. Lydia Solomon, Lata Pancholi, Dr. Sukalyan Saha Roy, Dr. Dhara Naik, Dr. Yash Chauhan for collection and tabulation of the data for their respective centres.
Trial registration: CTRI/2021/06/034255
==== Refs
References
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25 Davis H.E. Assaf G.S. McCorkell L. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact EClinicalMedicine 38 2021 101019 34308300
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27 Taquet M. Dercon Q. Luciano S. Geddes J.R. Husain M. Harrison P.J. Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19 PLOS Med 18 2021 e1003773 34582441
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31 Vimercati L. De Maria L. Quarato M. Caputi A. Gesualdo L. Migliore G. Association between Long COVID and Overweight/Obesity J Clin Med 10 2021 4143 34575251
32 Porru S. Monaco M.G.L. Spiteri G. Carta A. Pezzani M.D. Lippi G. SARS-CoV-2 Breakthrough Infections: Incidence and Risk Factors in a Large European Multicentric Cohort of Health Workers Vaccines 10 2022 1193 36016081
33 Ramakrishnan R.K. Kashour T. Hamid Q. Halwani R. Tleyjeh I.M. Unraveling the Mystery Surrounding Post-Acute Sequelae of COVID-19 Front Immunol 12 2021 686029 34276671
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| 0 | PMC9744681 | NO-CC CODE | 2022-12-15 00:01:52 | no | Lancet Reg Health Southeast Asia. 2022 Dec 13;:100129 | utf-8 | Lancet Reg Health Southeast Asia | 2,022 | 10.1016/j.lansea.2022.100129 | oa_other |
==== Front
Gastroenterol Clin North Am
Gastroenterol Clin North Am
Gastroenterology Clinics of North America
0889-8553
1558-1942
Elsevier Inc.
S0889-8553(22)00092-9
10.1016/j.gtc.2022.12.002
Article
The Pancreas in COVID-19 Infection
Correia de Sá Tiago MD ∗
General Surgery Department, Centro Hospitalar do Tâmega e Sousa, Penafiel, Portugal
Rocha Mónica MD
Hepato-pancreato-biliary Unit, General Surgery Department, Centro Hospitalar do Tâmega e Sousa, Penafiel, Portugal
∗ Corresponding author: Tiago Correia de Sá
13 12 2022
13 12 2022
© 2022 Elsevier Inc. All rights reserved.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Synopsis
An association between acute pancreatitis (AP) and Coronavirus disease 2019 (COVID-19) has been proposed, but the mechanisms of pancreatic injury of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) and the implicative role on the development of AP are not yet fully understood. On the other hand, patients admitted with AP who are infected by SARS-CoV-2 should be carefully managed, as evidence indicates a more aggressive disease course. COVID-19 also imposed major challenges on pancreatic cancer management.
We conducted an analysis on the mechanisms of pancreatic injury by SARS-CoV2 and reviewed published case reports of AP attributed to COVID-19. We also examined the pandemic effect on pancreatic cancer diagnosis and management, including pancreatic surgery.
Key words
Acute pancreatitis
COVID-19
SARS-CoV-2
pancreatic cancer
chronic pancreatitis
==== Body
pmcDisclosure statement: The Authors have nothing to disclose.
| 0 | PMC9744682 | NO-CC CODE | 2022-12-15 00:04:04 | no | Gastroenterol Clin North Am. 2022 Dec 13; doi: 10.1016/j.gtc.2022.12.002 | utf-8 | Gastroenterol Clin North Am | 2,022 | 10.1016/j.gtc.2022.12.002 | oa_other |
==== Front
Vaccine
Vaccine
Vaccine
0264-410X
1873-2518
Elsevier Ltd.
S0264-410X(22)01533-X
10.1016/j.vaccine.2022.12.019
Article
Cold-adapted SARS-CoV-2 variants with different temperature sensitivity exhibit an attenuated phenotype and confer protective immunity
Faizuloev Evgeny ad⁎
Gracheva Anastasiia a
Korchevaya Ekaterina a
Smirnova Daria a
Samoilikov Roman a
Pankratov Andrey b
Trunova Galina b
Khokhlova Varvara b
Ammour Yulia a
Petrusha Olga a
Poromov Artem ae
Leneva Irina a
Svitich Oxana ac
Zverev Vitaly ac
a I.I. Mechnikov Research Institute of Vaccines and Sera, Moscow, Russia
b FSBI NMRRC of the Ministry of Health of the Russian Federation, P.A. Hertsen Moscow Oncology Research Institute, Moscow, Russia
c I.M. Sechenov First Moscow State Medical University (Sechenov University), F.F. Erisman Institute of Public Health, Moscow, Russia
d Russian Medical Academy of Continuous Professional Education, Moscow, Russia
e Peoples' Friendship University of Russia, Department of Biochemistry, Moscow, Russia
⁎ Corresponding author at: I.I. Mechnikov Research Institute of Vaccines and Sera, Moscow, Russia.
13 12 2022
13 12 2022
11 8 2022
28 11 2022
9 12 2022
© 2022 Elsevier Ltd. All rights reserved.
2022
Elsevier Ltd
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
As novel SARS-CoV-2 Variants of Concern emerge, the efficacy of existing vaccines against COVID-19 is declining. A possible solution to this problem lies in the development of a live attenuated vaccine potentially able of providing cross-protective activity against a wide range of SARS-CoV-2 antigenic variants. Cold-adapted (ca) SARS-CoV-2 variants, Dubrovka-ca-B4 (D-B4) and Dubrovka-ca-D2 (D-D2), were obtained after long-term passaging of the Dubrovka (D) strain in Vero cells at reduced temperatures. Virulence, immunogenicity, and protective activity of SARS-CoV-2 variants were evaluated in experiments on intranasal infection of Syrian golden hamsters (Mesocricetus auratus). In animal model infecting with ca variants, the absence of body weight loss, the significantly lower viral titer and viral RNA concentration in animal tissues, the less pronounced inflammatory lesions in animal lungs as compared with the D strain indicated the reduced virulence of the virus variant. Single intranasal immunization with D-B4 and D-D2 variants induced the production of neutralizing antibodies in hamsters and protected them from infection with the D strain and the development of severe pneumonia. It was shown that for ca SARS-CoV-2 variants, the temperature-sensitive (ts) phenotype was not obligate for virulence reduction. Indeed, the D-B4 variant, which did not possess the ts phenotype but had lost the ability to infect human lung cells Calu-3, exhibited reduced virulence in hamsters. Consequently, the potential phenotypic markers of attenuation of ca SARS-CoV-2 variants are the ca phenotype, the ts phenotype, and the change in species specificity of the virus. This study demonstrates the great potential of SARS-CoV-2 cold adaptation as a strategy to develop a live attenuated COVID-19 vaccine.
Keywords
SARS-CoV-2
Cold adaptation
Attenuation
Temperature-sensitive phenotype
Live vaccine
Immunogenicity
Protective immunity
==== Body
pmc1 Introduction
The COVID-19 pandemic has become the main medical challenge of the 21st century. Almost all vaccines for the specific prevention of COVID-19 that have been or are being evaluated in clinical trials are based on replication-defective viral vectors, self-replicating RNA molecules, recombinant or native viral antigen preparations [1], [2], [3], [4]. These technological platforms allow the rapid development of safe vaccines capable of inducing a protective immune response. The development and widespread use of vaccines has significantly reduced the incidence of hospitalization and mortality from the disease [1], [4]. However, licensed vaccines generally have high production costs, include a limited number of protective viral antigens, provide a short-lived immune response, and their effectiveness declines when novel SARS-CoV-2 Variants of concern (VOC) appear [5], [6] since SARS-CoV-2 is evolving rapidly. Indeed, the Delta (B.1.617.2) VOC replaced the Alpha, Beta and Gamma variants due to increased infectivity and was less neutralized by the serum obtained from COVID-19 convalescents caused by other SARS-CoV-2 variants [7], [8], [9]. Delta VOC was replaced by highly contagious Omicron (B.1.1.529) VOC, which by February 2022 had occupied the dominant position, constituting over 95% of all the strains characterized by sequencing (https://www.gisaid.org/). The Omicron variant has several deletions in the genome and more than 30 amino acid substitutions in the S-protein, which have led not only to increased infectivity of the virus, but also the ability to evade the neutralizing antibodies of COVID-19 convalescents and vaccinated individuals [10], [11], [12], [13], [14]. Therefore, the monoclonal antibodies used in COVID-19 therapy also proved to be less effective against the Omicron variant [15]. Consequently, there is an urgent need to develop a safe and effective vaccine with cross-protective activity against a wide range of SARS-CoV-2 VOCs. Live attenuated COVID-19 vaccines may be considered as a potential highly effective strategy to fight the threat posed by SARS-CoV-2 [16], [17].
A long history of successful use of live attenuated viral vaccines has proven their ability to generate a long-lasting cellular and humoral immune response and cross-protection against different antigenic virus variants [18], [21]. However, according to the WHO data (22.07.2022), out of 169 vaccines against COVID-19, licensed or in clinical trials, only two vaccines (1.2%) were based on live attenuated strains constructed by codon deoptimization, COVI-VAC (Codagenix/Serum Institute of India, India) and MV-014-212 (Meissa Vaccines, Inc, USA) [19].
Previously, it was shown that adaptation of viruses to growth at suboptimal low temperature leads to a temperature sensitive (ts) phenotype (reducing viral replication at 37 °C or higher) associated with attenuation of virulence for a normal host [20]. In this case, the cold-adapted (ca) attenuated virus provides safe and effective protection against wild-type virus infection [20], [21]. Recently, scientific groups from Japan, Korea and Iran reported ca attenuated SARS-CoV-2 strains exhibiting a ts phenotype [22], [23], [24]. In this work, we generated two ca live attenuated SARS-CoV-2 clones with different temperature sensitivity and evaluated their virulence, immunogenicity, and protective activity in a Syrian golden hamster model of coronavirus pneumonia.
2 Materials and methods
2.1 Viruses
The laboratory SARS-CoV-2 Dubrovka (D) strain and its variants: Dubrovka-37 (D-37), Dubrovka-ca (D-ca), Dubrovka-ca-B4 (D-B4), and Dubrovka-ca-D2 (D-D2) (Supplementary Table S1), were isolated or generated in our laboratory previously and used in this study. The D strain (GenBank number MW514307.1, clade GR according to the GISAID classification, line B.1.1.317 according to the Pangolin classification), phylogenetically close to strain Wuhan-Hu-1 (GenBank number NC_045512.2), was obtained and characterized in summer 2020 in Moscow (Russia) by isolation in Vero cells from a clinical sample of a patient with COVID-19 [25]. Variants of D strain, D-37 and D-ca, were obtained by propagating of the D strain in Vero cells for 42 passages [26]. The D-37 variant was adapted to a constant cultivation temperature of 37 °C. The D-ca variant (cold-adapted) was gradually adapted from 37 °C to 23 °C according to the following scheme: 10 passages at a temperature of 37 °C, then the cultivation temperature was lowered by 1 °C every two passages, the final 6 passages were carried out at a temperature of 23 °C (a total of 42 passages) [26]. D-B4 and D-D2 variants were generated by three-fold cloning of the D-ca variant at 23 °C by limiting dilution method (Supplementary Fig. S1). The D strain revealed a 27 nucleotide deletion in the N-terminal region of S-gene (encodes 9 amino acids from 68 to76 a.a. – YMSLGPMVL in the S-protein) appeared already on the 1st passage and persisted with prolonged cultivation in all variants.
SARS-CoV-2 strains belonging to Delta and Omicron VOC isolated in Vero cells in the Moscow region (Russia) were used in the viral neutralization test: Podolsk strain (collection date: 2021–10-08, GenBank ID ON032860.1, Delta B.1.617.2.122); Otradnoe strain (collection date: 2022–01-25, GenBank ID ON032857.1, Omicron BA.1.1).
2.2 Cells and virus cultivation
Virus cultivation was performed on African green monkey kidney epithelial cells Vero CCL81 (ATCC), Vero cells, and human lung cancer cells Calu-3 HTB-55 (ATCC), Calu-3 cells. Cells were cultured at 37 °C in DMEM medium complemented with Earle’s balanced salt solution (PanEco, Russia), 5% fetal bovine serum (FBS) (ThermoFisher Scientific, USA), L-glutamine (300 µg/ml, PanEco), and gentamicin (40 µg/ml, PanEco) in an atmosphere of 5% CO2. A three-day monolayer of Vero or Calu-3 cells was infected with the SARS-CoV-2 virus at different multiplicity of infection (MOI). After 60 min of viral adsorption at 37 °C, 0% FBS maintaining medium was added and cells were incubated at 23 °C to 39 °C for 3–8 days (depending on viral variant) in an atmosphere of 5% CO2. To study the kinetics of viral replication, the culture medium was collected daily within 3–6 days after infection and stored at −80 °C until use. Vero cells were tested for the absence of mycoplasma contamination with the “Myco Real-Time” (Evrogen, Russia) kit based on real-time PCR.
2.3 Animals
4-week-old 40–50 g female Syrian golden hamsters (Mesocricetus auratus) were kept under sterile conditions for SPF-animals (Research Institute of Laboratory Animals, IBC RAS, Russia). The hamsters were screened for the absence of viruses, as well as bacterial infections and parasites following the recommendations of the European Laboratory Animal Science Association. Hamsters were arbitrarily assigned to study groups, had free access to food and sterilized tap water, and were kept on a 12-h light/dark cycle. All studies with animals were carried out in accordance with the National Research Council's Guide for the Care and Use of Laboratory Animals [27] and approved by the Mechnikov Research Institute of Vaccines and Sera Institutional Animal Care and Use Committee.
2.4 Virus titration
The SARS-CoV-2 virus titers were determined by the cytopathic effect endpoint method (CPE) in Vero cells as described earlier [26]. The virus titer was calculated as described by Ramakrishnan M.A. et al [28] and expressed as log10 TCID50/ml.
2.5 Quantification of SARS-CoV-2 RNA
Real-time RT-PCR was performed as described earlier [29]. To detect viral RNA we used primers and the probe designed for the nucleocapsid N gene of the SARS-CoV-2 virus, proposed by Chan J. et al [30]. Samples obtained by successive ten-fold dilutions of synthetic oligonucleotide COVN-PC (Table S2) with known concentrations were used to construct a calibration curve.
2.6 SARS-CoV-2 genome sequencing
NEBNext® ARTIC SARS-CoV-2 library preparation kit (New England Biolabs, USA) was used to obtain a pool of amplicons for subsequent genome-wide sequencing. This kit was designed to perform the SARS-CoV-2 whole-genome sequencing based on the “SARS-CoV-2 McGill Nanopore sequencing protocol SuperScript IV_42C_ArticV3″ (dx.https://doi.org/10.17504/protocols.io.bjajkicn). Ligation Sequencing kit 1D and Native Barcoding Kit 1D (Oxford Nanopore Technologies, UK) were used to prepare the resulting pool. Nanopore sequencing was performed in a Flow Cell R9.4 using MinKNOW software (Oxford Nanopore Technologies, UK). Genome assembly was performed in Minimap2 v. 2.24 (https://github.com/lh3/minimap2).
2.7 Evaluation of the ts phenotype of SARS-CoV-2 ca variants
Vero cells were infected with ca variants of SARS-CoV-2 and the D strain at a multiplicity of infection (MOI) 0.001 or 0.00001 and incubated at 37 °C or 39 °C in an atmosphere of 5% CO2 for 3 days. Supernatants were collected daily and stored at −80 °C until use. Viral titers and viral RNA concentration were determined in the collected samples. A 4.0 log10 or greater difference in viral titer or viral RNA concentration compared to infection with the parental D strain was considered as the ts phenotype of the virus as described by Larionova N.V. et al [31].
2.8 Evaluation of virulence and protective activity of SARS-CoV-2
Virulence and efficacy were assessed according to the scheme (Supplementary Fig. S2). Syrian hamsters were divided into four groups of nine animals each. Each animal received intranasally 4.0 log10 TCID50 of the D strain (passage 17) or its variants, D-B4 or D-D2. When determining infectious dose we based on Sia SF et al [32]. Infectious dose in 4.0 log10 per animal was established empirically before the start of the study - this dose of the D strain reproducibly led to significant weight loss compared to uninfected animals and the development of severe lobar pneumonia. Before intranasal procedures, animals were anesthetized and held in an upright position for viral infection. The negative control group received an equivalent amount of PBS. Hamsters were observed daily and weight control was performed every 2 days. Four days after infection, 4 animals from each group were euthanized. Hamsters were randomly selected and sacrificed during experiments regardless of the weight and condition of the animals. Lung, brain, and other organ tissues were collected, homogenized in DMEM medium with gentamicin (40 µg/ml, PanEco) using a Tissue Lyser LT homogenizer (Qiagen, Netherlands), and centrifuged at 10 000 rpm for 5 min at 4 °C. Supernatants were collected to measure virus titers and viral RNA concentration. The absence of body weight loss, death, the significantly lower viral titer and viral RNA concentration in animal tissues, and the less pronounced inflammatory lesions in animal lungs as compared with the D strain indicated the reduced virulence of the virus variant, thus, the attenuated (att) phenotype. To evaluate the protective activity 21 days after immunization, each animal (5 animals per group) received 4.0 log10TCID50 of the D strain intranasally. Hamsters were observed daily and weight control was performed at day 0 and day 4. Four days after infection, animals were euthanized. Animal tissues were prepared for determination of viral titer, viral RNA concentration, and histological examination as described above.
2.9 Lung histological examination.
The right hamster lung was fixed in 10% neutral buffered formalin for 24 h, dehydrated, then embedded in Histomix paraffin medium (BioVitrum, Russia) and used for histological study. The lung tissue was cut into 3–5 µm sections by Leica RM 2125 RTS rotary microtome (Leica, Germany), then stained with hematoxylin and eosin solution and embedded in Canada balsam (Sigma-Aldrich). Histological preparations were visualized under a BX 51 light microscope (Olympus, Japan).
2.10 ELISA
Determination of antibodies to SARS-CoV-2 in hamster sera was performed using BioKit ELISA reagent kit (Bioservice, Russia) according to the instruction. Inactivation of SARS-CoV-2 by UV-light was performed as described earlier [29]. For use in the ELISA, a 45 ml centrifuged clarified UV-inactivated virus-containing supernatant (≥8.5 log10 TCID50/ml) was passed through a 100 kD Amikon MWCO centrifuge filter (Millipore, Ireland) at 4000 rpm. The virus preparation collected on the filter was diluted to 4.5 ml with sterile PBS (pH 7.2), achieving a 10-fold concentration of SARS-CoV-2 virions. Before use, the preparation was processed on an MSE ultrasonic disintegrator (UK) at amplitude 2 for 2 min. The native ultraviolet (UV) inactivated viral antigen (D strain) in a dilution of 1:100 was sorbed on to wells of an immunoassay plate.
Double dilutions of the sera were analyzed by ELISA, starting at a dilution of 1:50. Anti-HAMSTER IgG (H + L)-Peroxidase antibody produced in goat (Sigma-Aldrich) was used in a dilution of 1:10000 for detection of hamster antibodies. The reciprocal value of the last dilution at which the OD value of the sample was higher than the cut-off threshold in each assay was taken as the titer of SARS-CoV-2 antibodies. The OD value for the negative serum multiplied by 2 was taken as the cut-off threshold.
2.11 Viral neutralization test
Measurement of SARS-CoV-2 neutralizing antibodies was performed in Vero cells according to the protocol described earlier [25]. D (Wuhan-like), Podolsk (Delta) and Otradnoe (Omicron) SARS-CoV-2 strains were used to determine the neutralizing activity of sera for different antigenic variants of the virus. The neutralizing titer was considered the reciprocal value of the last dilution, in which no signs of CPE were detected in two or more wells.
2.12 Statistical analysis
Statistical processing was performed using Graphpad Prism v.5.03 software. The data were presented as the mean ± standard deviation (SD) and mean ± standard error (SE) on the plots. The normality was checked based on the Shapiro-Wilk Test. The differences in hamsters body weights of Syrian hamsters and log10-transformed viral titres and quantitative viral RNA in different organs between strain variants and over time were compared using two-way ANOVA followed by Tukey’s multiple-comparison test or Kruskal Wallis test with Dunn’s Multiple Comparison Test. The Holm-Bonferroni correction for multiple testing was applied for primary analysis. The differences in hamsters body weights of Syrian hamsters over time (before and after challenge)were compared using paired sample T-test. Differences were considered to be significant at p < 0.05.
2.13 Work safety requirements
All work with the SARS-CoV-2 virus was carried out under conditions of Biosafety Level-3 laboratory.
3 Results
3.1 Genetic characterization of SARS-CoV-2 variants
Previously, we obtained D-37, D-ca, D-B4, and D-D2 variants of SARS-CoV-2 by long-term passaging of the Dubrovka strain in Vero cells [26] (Supplementary Table S1, Fig. S1). Their complete genome sequences (GenBank numbers ON380441.1, ON040960.1, ON059701.1, and ON040961.1, respectively) were determined. Genome analysis of the variants revealed a significant number of nucleotide substitutions, most of which were nonsynonymous (Supplementary Table S3, S4). In the genome of the D-37 variant, 7 nucleotide substitutions occurred after prolonged passaging in Vero cells at 37 °C, 5 of which led to amino acid substitutions. Following a cold adaptation in Vero cells, the genome of the D-ca variant collected 17 nucleotide substitutions, 16 of which led to amino acid substitutions. In the genomes of ca clones, D-B4 and D-D2, 16 and 20 nucleotide substitutions were determined resulting in 14 and 17 amino acid substitutions, respectively. The greatest number of nonsynonymous substitutions was localized in the S gene: 2 in the D-37 genome, while 5, 6, and 7 in the D-ca, the D-B4, and the D-D2 genomes, respectively.
3.2 Evaluation of virulence of SARS-CoV-2 variants
In hamsters infected intranasally with ca variants, D-B4 and D-D2, no body weight loss and behavioral changes were observed compared to uninfected animals. However, when infected with the D strain, there was a significant delay in the weight gain at day 2–6p.i. reaching its maximum values on day 4p.i. of 13.4% (P < 0.001) and day 6p.i. of 10,1% (P < 0.01) (Fig. 1 A, B), coupled with other clinical signs including reduced appetite, lethargy, and somnolence.Fig. 1 Evaluation of virulence of SARS-CoV-2 D strain and D-B4 and D-D2 variants.
Each animal received 4.0 log10 TCID50 of the virus intranasally. The negative control group (K-) received an equivalent amount of PBS. Weight controls were performed every 2 days (from the 0th to the 4th day - n = 9/group, from the 6th to the 8th day - n = 5/group). Four days after infection, animals were euthanized; lungs, brain, and other animal tissues were homogenized and the viral titer and the concentration of viral RNA was measured (n = 4/group). Bars = SEM. A. Weight of the infected hamsters from day 0 to day 8p.i. B. Weight distribution of hamsters at day 4p.i. C. Concentration of viral RNA in organs of infected hamsters. Limit of detection was 3.0 log10 RNA copies/ml. D. Viral titer in lung and brain of infected hamsters. Limit of detection was 2.0 log10 TCID50/ml. «n.d.» - not detected.
The replication of D-B4 and D-D2 variants in lungs, brain, and other organs of Syrian hamsters on day 4 after infection was significantly lower compared to the D strain (Fig. 1 C, D). The lowest concentration of viral RNA in the lungs was observed upon infection with the D-D2 variant, 6.5 log10 RNA copies/ml, which was 1.6 log10 lower compared to the control group (p = 0.004). The replication of D-B4 and D-D2 variants in the brain decreased more significantly, by 2.2 and 3.2 log10, respectively. In liver, heart and blood of hamsters infected by D-B4 and D-D2 variants viral RNA was not detected. Infectious viral titers in the lungs of animals on the fourth day after infection with D-B4 and D-D2 variants was 1.2 log10 lower than in the control group (p < 0.05). No infectious virus was detected in the brain upon infection with ca variants, whereas upon infection with the D strain it reached a titer of 5.0 log10 TCID50/ml. It should be pointed out, that tissues homogenates were toxic to Vero cells in which titration was performed, hence, reducing the sensitivity limit to 2 log10 TCID50/ml.
On the fourth day after intranasal infection, inflammatory lesions developed in the lungs of Syrian hamsters in all groups (Fig. 2, Fig 3, Fig. 4 ). However, there were significant differences in the nature, severity, and extent of inflammatory damages between the groups. Thus, when infected with the D strain, lobar interstitial pneumonia developed in hamster lungs, accompanied by pronounced inflammatory changes: formation of extensive confluent airless pneumonia foci; desquamation and death of respiratory epithelium; formation of peribronchial and perivascular lymphohistiocytic infiltration; inflammatory infiltration of interalveolar septa circulatory system disorders (marked vascular and microvascular congestion, perivascular edema, interaalveolar and interstitial edema, interaalveolar hemorrhages) (Fig. 2). In all lobes, extensive confluent airless areas and areas with reduced airiness occupying most of the slice area were observed.Fig. 2 Morphological characterization of hamster lungs infected with the D strain.
Fig 3 Morphological characteristics of hamster lungs infected with the D-B4 variant.
A, B - arrows indicate foci of alveolitis; C - peribronchial foci of alveolitis: parenchymal airiness is reduced, the alveolar lumen is narrowed, interalveolar septa are thickened due to inflammatory infiltration, microvessel fullness. A, B - ×40, C - ×200. Hematoxylin and eosin staining.
Fig. 4 Morphological characteristics of hamster lungs infected with the D-D2 variant.
A - in the lower left corner of the microphotograph there are areas of parenchyma with reduced airiness (alveolitis foci); B - alveolitis foci (black arrow) bordered by alveoli without inflammatory changes (red arrow); C - fragment of histological section of a lung lobe of a healthy animal. B, C - ×40, B - ×200. Hematoxylin and eosin staining.
A - confluent foci of pneumonia; B - section of lung parenchyma with reduced airiness located peribronchiolar (black arrow indicates bronchiole, a lumen of which contains single cells of desquamated epithelium, macrophages, epithelial lining preserved, single cells with dystrophic changes; weak inflammatory infiltration of the bronchial wall; red arrow indicates pulmonary artery, diffuse inflammatory infiltrate located around it, perivascular edema; asterisks indicate areas of parenchyma with reduced airiness, thickened interalveolar septa, slotted lumen of alveoli); C - fragment of airless pneumonia focus located peribronchial (arrow - bronchial wall; asterisk - pneumonia focus, in which interalveolar septa and alveolar lumen are not defined). A - ×40, B - ×200, C - ×400. Hematoxylin and eosin staining
When hamsters were infected with D-B4 and D-D2 variants, a morphological picture of focal interstitial pneumonia was observed in the lungs, the prevalence of which was significantly lower than in the D strain group (Fig 3, Fig. 4). The histological structure of the lungs in the × 10 objective field of view corresponded to that in hamsters of the control group. The lumens of all bronchi and bronchioles were free, containing single desquamated epitheliocytes. Areas of alveolitis occupied a small part of the slice area and contained small airless foci, which were often located around the vessels. In the respiratory tract, there were no signs of circulatory disturbances (edema, interaalveolar hemorrhages) and pronounced damage to interalveolar septa. No pathological changes were found in the lungs of one of the two hamsters infected with the D-D2 variant (Fig. 4 C).
No pathological changes were detected in the lungs of uninfected animals (Fig. 5 ).Fig. 5 Morphological characterization of the lung of an uninfected hamster. A – a histological section of a lung lobe: bronchi of different generations, bronchioles, pulmonary arteries veins, acini profiles; lumen of bronchi and bronchioles free, organ parenchyma are airy; B - bronchiole lumen free, epithelial lining preserved, bronchiole wall contains single lymphocytes; alveoli, alveolar passages, and sacs are uniformly airy, interalveolar septa are thin, the interstitium is scanty, vessels and capillaries are moderately full of blood. A - ×40, B - ×200. Hematoxylin and eosin staining.
3.3 Identification of possible markers of SARS-CoV-2 attenuation in vitro.
Since the markers of attenuation of cold-adapted viruses are the ca and ts phenotype [20], we evaluated the presence of these markers in D-B4 and D-D2 variants. D-B4 and D-D2 variants possessed the ca phenotype because they replicated efficiently in Vero cells at 23 °C, reaching a titer of 6.0 to 7.0 log10 TCID50/ml on day 5, whereas the parental D strain and the D-37 variant did not replicate under these conditions (Fig. 6 A).Fig. 6 Identification of possible markers of SARS-CoV-2 attenuation in vitro.
Vero cells were infected with the D strain and D-B4 and D-D2 variants. Supernatants were collected daily and viral titers or viral RNA concentration were determined. Limit of detection was 1.0 log10 TCID50/ml and 3.0 log10 RNA copies/ml. Mean values from two independent experiments. Bars show the difference between two individual values. «n.d.» - not detected. A. Replication kinetics of SARS-CoV-2 variants at 23 °C in Vero cells. MOI = 0.001. B. Viral titer in Vero cells at day 3p.i. at different MOI at 39 °C. C. Viral RNA concentration in infected Vero cells at 37 °C. MOI = 0.001. D. Viral RNA concentration in infected Vero cells at 39 °C. MOI = 0.001.
At 37 °C, the replication of D-B4 and D-D2 variants in Vero cells was comparable to that of the D strain (Fig. 6 C). At 39 °C, the D strain and the D-B4 variant replicated efficiently, as indicated by the increase in viral RNA concentration from day 0 to day 3p.i. (Fig. 6 D). The D-D2 variant did not replicate at 39 °C, exhibiting a distinct ts phenotype (Fig. 6 B, D). The D-B4 variant exhibited weakly expressed signs of ts phenotype only at low MOI (0.00001) and temperature 39 °C, the difference in viral titer with the D strain was 3.0 log10 at day three p.i. (Fig. 6 B).
Since both ca variants of the virus, D-B4 and D-D2, had reduced virulence for hamsters regardless of the presence of ts phenotype, we hypothesized that not only ca phenotype and temperature sensitivity are possible markers of virus attenuation. To assess changes in species and tissue specificity, we examined the replication of SARS-CoV-2 variants in Calu-3 human lung cancer cells and Vero monkey kidney cells. D-37 and D-B4 variants did not replicate in Calu-3 cells, whereas D-D2 replicated, but slower compared to the D strain (Fig. 7 A, B).Fig. 7 Replication of SARS-CoV-2 variants in Calu-3 cells at 37 °C.
Calu-3 cells were infected with the virus variants at MOI = 0.001. Supernatants were collected daily and viral titers or viral RNA concentration were determined. Limit of detection was 1.0 log10 TCID50/ml and 3.0 log10 RNA copies/ml. Mean values from three independent experiments. Bars = SEM. A. Viral RNA concentration from day 1 to day 4p.i. B. Viral titer at day 3p.i.
3.4 Immunogenicity and efficacy of SARS-CoV-2 variants.
Twenty-one days after a single intranasal immunization of hamsters with the D strain or D-B4 or D-D2 variants, the IgG titers to structural SARS-CoV-2 antigens reached 51200 ± 31353, 8960 ± 3505 or 20480 ± 7011, respectively, in animals sera (Fig. 8 A). The virus-neutralizing activity of hamsters sera after immunization with the D-B4 or D-D2 variants (neutralizing antibodies titer 1012 ± 740 and 1408 ± 701) was comparable to sera of the group of animals infected with the D strain (2304 ± 572) (Fig. 8 B).Fig. 8 Humoral immune response 21 days after single immunization of hamsters with SARS-CoV-2 variants.
Hamsters received a dose of 4.0 log10 TCID50 per animal with the D strain or variants D-B4 or D-D2 intranasally. The negative control group received an equivalent amount of PBS. After 21 days, animal blood was collected, and total and neutralizing antibodies to SARS-CoV-2 were determined in sera (n = 5/group; bars = SEM). A. Total IgG titer to SARS-CoV-2 by ELISA. B. Viral neutralizing antibody titer against Wuhan-like D strain. C. Viral neutralizing antibody titer against Podolsk strain (Delta) and Otradnoe strain (Omicron).
Additionally, the virus neutralizing activity of the obtained sera was studied against virus strains related to Delta (Podolsk strain) and Omicron (Otradnoe strain) VOC. The neutralizing activity of hamster sera immunized with the D-D2 variant was reduced by 2.6 times in relation to the Delta variant (p = 0.03) and by more than 60 times in relation to the Omicron variant (p = 0.0014) (Fig. 8 C) compared to Wuhan-like strain D.
Single intranasal immunization with D-B4 or D-D2 variants fully protected hamsters from infection with the D strain as evidenced by the absence of viral replication in lungs and brain (Fig. 9 A, B). Remarkably, the hamsters immunized with the D strain did not develop sterile immunity, as viral RNA and infectious virus titer 3.45 ± 2.9 log10 TCID50/ml were detected in the lungs. In the organs of non-immunized animals, viral RNA was detected with the highest virus load in the lungs, 7.83 ± 7.7 log10 RNA copies/ml and 5.55 ± 5.5 log10 TCID50/ml.Fig. 9 Efficacy of intranasal immunization with SARS-CoV-2 variants.
Hamsters immunized with the D strain or D-B4 or D-D2 variants and the negative control group were challenged with the D strain at a dose of 4.0 log10 TCID50 per animal after 21 days p.i. Weight control was performed at days 1 and 4. Four days after challenge, animals were euthanized; lungs and brain were homogenized and viral titer and viral RNA concentration were determined (n = 5/group; bars = SEM). Limit of detection was 2.0 log10 TCID50/ml and 3.0 log10 RNA copies/ml. A. Virus titer in lung. B. Concentration of viral RNA in lungs and brain. C. Weight change of the infected hamsters.
After experimental infection with the D strain, immunized animals gained weight 4 days after infection on average from 5.8 to 7.6 g, while non-immunized animals lost 5.1 g (Fig. 9 C).
On the fourth day after infection, hamster lungs developed inflammatory changes expressed in different degrees. In the control group of unimmunized hamsters, the morphological picture corresponded to lobar viral interstitial pneumonia in the exudation phase, and extensive confluent airless areas and areas with reduced airiness were observed (Supplementary Fig. S3). The lumen of bronchi and bronchioles located in pneumonia foci were predominantly free, some of them contained small layers of the desquamated epithelium. Adjacent parenchyma represented airless fields, in which alveoli lumen was not determined, and interalveolar septa were destroyed due to inflammatory infiltrate, edema, and death of respiratory epithelium. Alveolar capillaries were in a state of acute profundity, dilated, and stasis of erythrocytes was noted in their lumens.
The severity of inflammatory changes in the lungs of immunized hamsters on day four after infection with the D strain was significantly lower than in the control group (Supplementary Fig. S4, S5, S6). The histological structure of the lungs in the majority of the objective field of view (×10) was consistent with the normal structure. However, histological sections of all hamster lung lobes identified small areas of pulmonary parenchyma with inflammatory changes, usually located peribronchial correspondingly to focal alveolitis in the recovery stage. At visual assessment foci of alveolitis in hamsters immunized by D-B4 or D-D2 variants occupied small areas of lung slices (Supplementary Fig. S5, S6).
4 Discussion
Live viral vaccines included in the national immunization schedules made it possible to eliminate smallpox on a global scale and bring such diseases as polio, measles, rubella, and mumps to the brink of eradication [21]. Live attenuated vaccines are similar to natural infectious agents; they induce strong, cross-protective, and long-lasting immune response [21]. High immunological efficacy coupled with relatively simple and low-cost manufacturing of live viral vaccines could potentially legitimate their use [21]. The currently used mRNA vaccines and adenovirus vectored vaccines encode only the spike protein, therefore limiting the immune response against only this viral antigen [1]. However, live attenuated vaccines can induce immunity to several structural and non-structural viral proteins, enhancing the chances of protection [21], [33]. While novel SARS-CoV-2 VOCs evade the immune response produced by approved vaccines [7], [8], [9], [10], [11], [12], [14], [15] development of vaccines against COVID-19 based on live attenuated viruses seems particularly attractive, as they activate all branches of the host immune system: humoral, innate, and cellular [16], [17]. Additionally, intranasal administration of live vaccine may induce of mucosal immunity, stimulate IgA production, which is capable not only neutralize the virus at the entry gate of infection but also limit the spread of the respiratory virus [35], [36], [37], [38], [39].
One of the basic principles of developing live attenuated vaccines is to maintain a balance between attenuating the virulence of the vaccine strain and maintaining the ability to induce a protective immune response. In this regard, the safety and protective activity profile of the SARS-CoV-2 ca variants we obtained is the focus of attention.
In experimentally infected Syrian hamsters, D-B4 and D-D2 variants demonstrated a decrease in virulence according to all parameters analyzed: the animal body weight gain was not slowed down, the concentration of viral RNA and content of infectious virus in organs was significantly lower than when infected with the D strain, the animals retained activity and a good appetite. Histological examination of the lungs of hamsters infected with ca variants revealed relatively reduced focal inflammatory changes, whereas lobar interstitial pneumonia with extensive lesion area developed in hamsters infected with the virulent D strain. According to the previous works, attenuated SARS-CoV and SARS-CoV-2 can slightly replicate in the lungs of model animals and cause inflammatory changes with minimal histopathological damages [17], [22], [34], [40], [41]. Even limited virus replication in the lungs of model animals is certainly undesirable, but this does not exclude the possibility of clinical application of attenuated vaccine. The lowest replication efficiency in vivo was observed in the temperature sensitive D-D2 variant. Furthermore, no infectious virus was detected in the brains of Syrian hamsters infected with the ca variants, whereas when infected with the virulent D strain, the viral titer reached 5.0 log10 TCID50/ml. Given the known neurovirulence of SARS-CoV-2 for humans [42], the reduction in the replication efficiency of ca variants of the virus in the hamster brain when administered intranasally reduces the probability of neurological damages in vivo.
Previously, S.H. Seo et al., S. Okamura et al. and M. Abdoli et al reported cold-adapted and temperature sensitive SARS-CoV-2 strains as vaccine candidates [22], [23], [24]. In the present study, we have shown that for ca variants of SARS-CoV-2, the ts phenotype is not mandatory for virulence reduction. Both non-ts D-B4 variant and ts D-D2 variant exhibited att phenotype for hamsters. Compared to parental strain D and the D-B4 variant, the D-D2 variant lost the ability to replicate at 39 °C (ts phenotype). Non-ts D-B4 lost the ability to infect human lung cells of Calu-3 compared to the D strain and the D-D2 variant. Thus, along with the ca and ts phenotype, the altered species specificity of the virus is a probable phenotypic marker of virus attenuation for Syrian hamsters.
Single intranasal immunization with D-B4 and D-D2 variants induced the production of neutralizing antibodies in Syrian hamsters and protected them from infection with the D strain and consequent development of severe pneumonia. This is consistent with the results of similar studies [22], [23], [24], [34] revealing high protective activity of attenuated SARS-CoV-2 strains by intranasal immunization of Syrian hamsters or hACE-2 (K18-hACE2) transgenic mice.
However, in the present study, the efficacy of immunization with the ca variants has only been studied against infection with the homologous parental D strain closely related to Wuhan-Hu-1 (GenBank number NC_045512.2). The decrease in the neutralizing activity of serums of hamsters immunized with the Wuhan-like D-D2 variant in relation to the heterologous Omicron variant (Fig. 8 C) reflects only the strength of the humoral immunity. The question of whether such immunization can protect against later emerging VOCs, such as Delta (B.1.617.2) and Omicron (B.1.1.529), as well as variants that will inevitably appear in the future, remains open. The potential for the cross-protective activity of live vaccines is determined by the fact that reinfection with SARS-CoV-2 is rare (absolute rate 0%-1.1%) [43], [44]. Pulliam JRC et al. found no evidence of increased risk of reinfection associated with circulating Beta-(B.1.351) or Delta-(B.1.617.2) variants in South Africa, and showed that the risk of SARS-CoV-2 reinfection increased slightly at the peak of fourth wave (period of Omicron variant dominance) [45]. In a retrospective study conducted in Italy (follow-up period to mid-February 2022), 729 cases of reinfection were identified among 119,266 previously infected patients, representing 0.61%. Although the marked increase of the reinfection rates during the Omicron wave is concerning, the risk of secondary severe disease or death remained close to zero [44]. Reinfections have become common since emergence of Omicron and further evolution of this variant [46], [47]. A study conducted in Qatar shows that SARS-CoV-2 infection with the original virus or pre-Omicron variants elicited less than 60% protection against reinfection with Omicron subvariants [48]. According to Chemaitelly H. et al effectiveness of pre-Omicron primary infection against Omicron reinfection was 38.1% (95% CI: 36.3–39.8%) and declined with time since primary infection. The effectiveness of primary infection against severe, critical, or fatal COVID-19 reinfection was 97.3% (95% CI: 94.9–98.6%), irrespective of the variant of primary infection or reinfection, and with no evidence for waning [49]. The extremely low proportion of severe and lethal COVID-19 reinfection cases gives hope that live attenuated COVID-19 vaccines will be able to provide cross-protection against different VOCs.
Sera from hamsters immunized by the D strain and the D-D2 variant (both are Wuhan-like) poorly neutralized Omicron BA.1-like virus in vitro (Fig. 8 C). The results obtained are in good agreement with the ability of Omicron-like viruses to evade the neutralizing antibodies of pre-Omicron COVID-19 convalescents and vaccinated individuals [10], [11], [12], [13], [14]. This indicates a potentially low efficacy of the humoral immune response against the Omicron-like virus when immunizing with D strain derived attenuated virus. Consequently, the development of temperature sensitive Omicron-like strain is a promising research direction that would allow obtaining vaccine strains that effectively induce both cellular and humoral immunity against emerging virus variants.
The obtained ca variants, D-B4 and D-D2, contain a large number of mutations in protein sequences compared with the parental D strain and among themselves (Supplementary Table S4) determining phenotypic differences between the variants. Switching species tropism and/or tissue specificity of the D-B4 and D-D2 variants is consistent with identified amino acid substitutions in the S-protein responsible for binding to host receptors. In addition, recently it has been shown that S-protein can have active and inactive states at different temperatures. In particular, the receptor binding motif (RBM) on the receptor binding domain (RBD) S1 is temperature sensitive and loses its ability to bind to the ACE2 receptor at 40 °C [50]. Consequently, it cannot be excluded that conformational changes of S protein of ca SARS-CoV-2 mutants are associated not only with host switch but also with a cold adaptation of the virus. This is indirectly evidenced by the fact that the D-37 variant, which is unable to replicate at 23 °C in Vero cells and has lost its ability to infect human Calu-3 cells, has only 2 amino acid substitutions in the S protein, whereas the ca D-B4 and D-D2 variants have 6 and 7, respectively. The role of detected amino acid substitutions in non-structural proteins nsp3, nsp4, nsp5, nsp6, nsp14, and nsp16, found in the D-D2 variant, but absent in the non-ts D-B4 variant (Supplementary Table S4), could potentially determine ts phenotype of the D-D2 variant. However, further studies are needed to reliably determine the role of these and other mutations.
It is very difficult to establish infectivity, reactogenicity, immunogenicity (including the absence of the hyper-attenuation effect) and efficacy of the obtained virus variants for humans without conducting studies on higher primates or clinical trials. Thus, the results we obtained on the Syrian hamster model are the first step towards understanding the potential of SARS-CoV-2 cold adaptation in the production of live vaccines against COVID-19.
Currently, the majority of the global adult population has markers for COVID-19 or has been vaccinated. Therefore, a strategy for the safe use of live attenuated vaccines against COVID-19 in adults may involve “booster” immunization of only individuals with markers of new coronavirus infection and/or previously immunized with inactivated vaccine. Such a vaccination schedule is applied in several countries, where the WHO recommendation includes administering at least 1 dose of inactivated polio vaccine followed by a series of immunizations with live oral polio vaccine to avoid the risk of reversion to virulence [51]. When considering the possible clinical application of live attenuated vaccine, it is also important to take into account the low susceptibility of children to SARS-CoV-2 variants phylogenetically close to the Wuhan virus [52] suggesting the avirulence for children of ca attenuated SARS-CoV-2 strains.
4.1 Limitations of research
1. The lack of objective, quantitative histopathology scoring. Histological examination of the lungs was carried out only for qualitative morphological characteristics of pathological changes.
2. Relatively small number of animals per group (4 or 5) used in experiments for evaluation of virulence, immunogenicity and efficacy of cold-adapted virus variants.
5 Conclusions
In the present study, attenuated for Syrian hamsters cold-adapted SARS-CoV-2 variants were obtained. The variants had different temperature sensitivity and provided protective immunity against infection with a virulent strain upon single intranasal immunization. The virulence and immunogenicity data of ca variants of SARS-CoV-2 obtained in an animal model are difficult to directly extrapolate to humans without clinical studies. Preclinical testing in animal models only provides an approximation to understanding the safety of clinical use and human susceptibility to live vaccine strains. However, despite the limitations of the present study noted above, the results revealed a potential for cold-adaptation of SARS-CoV-2 as a strategy for development a live attenuated vaccine against COVID-19.
Ethics statement
All applicable international, national, and/or institutional guidelines for the care and use of animals, including the Guide for the Care and Use of Laboratory Animals [27], were followed. This study was approved by the Medical Ethics Review Committee of the I. I. Mechnikov Research Institute of Vaccines and Sera (Ethics Committee Decision No 2 dated May 24, 2021).
Funding
The study was carried out with the financial support of the Ministry of Science and Higher Education of the Russian Federation (Theme No. FGFS-2022-0004) using equipment of the Collective Usage Center “I. I. Mechnikov NIIVS”, Moscow, Russia (Agreement No. 075-11-2021-676 dated 28.07.2021). Genetic characterization of SARS-CoV-2 variants was performed with the financial support of the Russian Foundation for Basic Research, No. 20–04-60079.
Author contributions
All authors contributed to the study’s conception and design. Experimental work, data collection, artwork and analysis were performed by EF, AG, EK, DS, OP, AP, and RS. Histology was performed by AP, GT and VK. The manuscript was written by EF, YA, and revised by IL, OS, and VZ.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Appendix A Supplementary data
The following are the Supplementary data to this article:Supplementary data 1
Data availability
Data will be made available on request.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.vaccine.2022.12.019.
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| 0 | PMC9744683 | NO-CC CODE | 2022-12-15 23:17:56 | no | Vaccine. 2022 Dec 13; doi: 10.1016/j.vaccine.2022.12.019 | utf-8 | Vaccine | 2,022 | 10.1016/j.vaccine.2022.12.019 | oa_other |
==== Front
Vaccine
Vaccine
Vaccine
0264-410X
1873-2518
Elsevier Science
S0264-410X(22)01458-X
10.1016/j.vaccine.2022.11.045
Article
Transmission potential of vaccinated and unvaccinated persons infected with the SARS-CoV-2 Delta variant in a federal prison, July—August 2021
Salvatore Phillip P. a⁎
Lee Christine C. b
Sleweon Sadia c
McCormick David W. d
Nicolae Lavinia e
Knipe Kristen f
Dixon Thomas g
Banta Robert h
Ogle Isaac i
Young Cristen j
Dusseau Charles k
Salmonson Shawn l
Ogden Charles m
Godwin Eric n
Ballom TeCora o
Ross Tara p
Tran Wynn Nhien q
David Ebenezer r
Bessey Theresa K. s
Kim Gimin t
Suppiah Suganthi u
Tamin Azaibi v
Harcourt Jennifer L. w
Sheth Mili x
Lowe Luis y
Browne Hannah z
Tate Jacqueline E. aa
Kirking Hannah L. ab
Hagan Liesl M. ac
a SM – CDC COVID-19 Response Team
b CDC COVID-19 Response Team Laboratory Leadership Service
c MPH – CDC COVID-19 Response Team
d MPH – CDC COVID-19 Response Team Epidemic Intelligence Service
e CDC COVID-19 Response Team
f CDC COVID-19 Response Team
g Bureau of Prisons, U.S. Department of Justice
h MSN – Bureau of Prisons, U.S. Department of Justice
i MSN – Bureau of Prisons, U.S. Department of Justice
j Bureau of Prisons, U.S. Department of Justice
k Bureau of Prisons, U.S. Department of Justice
l Bureau of Prisons, U.S. Department of Justice
m MPH – Bureau of Prisons, U.S. Department of Justice
n Bureau of Prisons, U.S. Department of Justice
o DO – Bureau of Prisons, U.S. Department of Justice
p Bureau of Prisons, U.S. Department of Justice
q MS – CDC COVID-19 Response Team
r CDC COVID-19 Response Team
s CDC COVID-19 Response Team
t CDC COVID-19 Response Team
u CDC COVID-19 Response Team
v CDC COVID-19 Response Team
w CDC COVID-19 Response Team
x CDC COVID-19 Response Team
y MS, MPH – CDC COVID-19 Response Team
z CDC COVID-19 Response Team
aa CDC COVID-19 Response Team
ab MD – CDC COVID-19 Response Team
ac MPH – CDC COVID-19 Response Team
⁎ Corresponding author.
13 12 2022
13 12 2022
27 9 2022
19 11 2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Background
The extent to which vaccinated persons who become infected with SARS-CoV-2 contribute to transmission is unclear. During a SARS-CoV-2 Delta variant outbreak among incarcerated persons with high vaccination rates in a federal prison, we assessed markers of viral shedding in vaccinated and unvaccinated persons.
Methods
Consenting incarcerated persons with confirmed SARS-CoV-2 infection provided mid-turbinate nasal specimens daily for 10 consecutive days and reported symptom data via questionnaire. Real-time reverse transcription-polymerase chain reaction (RT-PCR), viral whole genome sequencing, and viral culture was performed on these nasal specimens. Duration of RT-PCR positivity and viral culture positivity was assessed using survival analysis.
Results
A total of 957 specimens were provided by 93 participants, of whom 78 (84%) were vaccinated and 17 (16%) were unvaccinated. No significant differences were detected in duration of RT-PCR positivity among vaccinated participants (median: 13 days) versus those unvaccinated (median: 13 days; p=0.50), or in duration of culture positivity (medians: 5 days and 5 days; p=0.29). Among vaccinated participants, overall duration of culture positivity was shorter among Moderna vaccine recipients versus Pfizer (p=0.048) or Janssen (p=0.003) vaccine recipients. In post-hoc analyses, Moderna vaccine recipients demonstrated significantly shorter duration of culture positivity compared to unvaccinated participants (p=0.02). When restricted to participants without reported prior infection, the difference between Moderna vaccine recipients and unvaccinated participants was more pronounced (medians: 3 days and 6 days, p=0.002).
Conclusions
Infectious periods for vaccinated and unvaccinated persons who become infected with SARS-CoV-2 are similar and can be highly variable, though some vaccinated persons are likely infectious for shorter durations. These findings are critically important, especially in congregate settings where viral transmission can lead to large outbreaks. In such settings, clinicians and public health practitioners should consider vaccinated, infected persons to be no less infectious than unvaccinated, infected persons.
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pmc1 Introduction
COVID-19 vaccines are highly effective in preventing severe illness and death from SARS-CoV-2 (the virus that causes COVID-19). However, because COVID-19 vaccines are not 100% effective in preventing infection, some infections among vaccinated persons are expected to occur. As global vaccination coverage increases, the role of vaccinated persons in transmission will be a critical determinant of the pandemic’s future trajectory.[1] The extent to which vaccinated persons who become infected contribute to transmission of SARS-CoV-2 is not yet well understood. Some preprint manuscripts have reported comparable indicators of transmission potential regardless of vaccination status,[2] while others have reported reduced viability of virus isolated from vaccinated persons.[3]
The B.1.617.2 (Delta) variant was associated with a peak in COVID-19 cases in the United States beginning in July 2021 that included large outbreaks among vaccinated and unvaccinated persons in crowded settings.[4], [5], [6] These findings are of particular concern for congregate living environments such as correctional and detention facilities because of the potential for rapid transmission of SARS-CoV-2 and the high prevalence of underlying health conditions associated with severe COVID-19.[7], [8], [9]
In an outbreak involving the Delta variant in a federal prison in Texas, the cumulative incidence of infection in two affected housing units was 74%; it was 93% and 70% among unvaccinated and vaccinated incarcerated persons, respectively.[6] Using serial mid-turbinate nasal specimens collected from a subset of incarcerated persons infected during this outbreak, this report assesses reverse transcription-polymerase chain reaction (RT-PCR) and viral culture characteristics as surrogate markers of transmission potential over time among vaccinated and unvaccinated persons. This report is one of the first longitudinal investigations of viral shedding from vaccinated persons infected with the Delta variant and contributes to the evidence base guiding infection prevention and control procedures across a variety of settings.
2 Methods
2.1 Investigational Setting
On July 12, 2021, an outbreak of SARS-CoV-2 among vaccinated and unvaccinated persons was detected in a federal prison in Texas. Staff from the Centers for Disease Control and Prevention (CDC) and Federal Bureau of Prisons (BOP) deployed to the prison to investigate the outbreak as previously reported.[6] As part of this outbreak investigation, a subset of incarcerated persons provided serial mid-turbinate nasal specimens which were analyzed to evaluate the potential role of infected vaccinated and unvaccinated persons in transmission of SARS-CoV-2. This activity was reviewed and approved by the BOP Research Review Board and CDC and conducted consistent with applicable federal law and CDC policy.*
2.2 Participant Enrollment and Serial Specimen Collection
Incarcerated persons living in four housing units where COVID-19 cases had been identified were invited to participate in serial swabbing. Persons were eligible to enroll if they had tested positive for SARS-CoV-2 between July 12 (the start of the outbreak) and August 4, 2021. Staff members who tested positive during the outbreak were not invited to participate in the investigation; per CDC guidelines, they were restricted from entering the facility during their home isolation period. CDC and BOP staff held information sessions to explain the purpose of the project and to answer questions, including privacy protections and how results of the study would be made available to participants. All persons who chose to participate signed consent forms, which were provided in English and Spanish.
Specimen collection occurred during July 19—August 9, 2021. CDC and BOP staff collected one nasal mid-turbinate specimen daily for 10 consecutive days from participants who had tested positive for SARS-CoV-2. Specimen collection began on July 19 for known cases; for cases identified after July 19 collection began on the date of participants’ first positive test. All incarcerated persons residing in housing units where cases were identified were placed under quarantine precautions. To assist in case-finding, consenting persons who were quarantined were tested every other day beginning on July 19 or on their first full day of quarantine; those who tested positive during quarantine were invited to participate in the 10 consecutive days of specimen collection for persons who had tested positive. All participants were asked to provide an eleventh specimen on August 6, which corresponded to a late timepoint in infection for most participants, to provide additional data on viral shedding (Figure 1 ).Figure 1 Timelines and results of nasal mid-turbinate specimens collected from enrolled participants, Federal prison, Texas, July 12—August 9, 2021. The timelines of specimen collection and laboratory results for 95 included participants are represented diagrammatically, indexed by the day of onset. Onset was determined to be either a) date of first onset of self-reported symptom(s) meeting the case definition of COVID-19 or b) date of first positive diagnostic SARS-CoV-2 test, whichever occurred first. Each participant is represented by a horizontal line corresponding to the investigation sampling period during their time-course of illness. Participants who were unvaccinated (including 2 participants who received only the first dose of a two-dose COVID-19 vaccine series) are depicted at the top of the figure, while vaccinated participants are depicted at the bottom. RT-PCR results are represented by solid circles (positive results) or open circles (negative results). For specimens with positive RT-PCR results for which viral culture was performed, culture results are indicated by overlaid blue boxes (positive culture results) or red boxes (negative culture results). Specimens with positive RT-PCR results with a cycle threshold (Ct) value greater than 35 for which viral culture was not performed are indicated by overlaid orange boxes (indicated a presumptive negative viral culture result). Some participants provided specimens during case-finding testing while in quarantine and may have RT-PCR negative specimens collected prior to onset.
On the tenth day of specimen collection, participants were asked to complete a paper-based questionnaire to report COVID-19-like symptoms during the course of their illness, including date of symptom onset and symptom duration. Information on demographic characteristics, COVID-19 vaccination history, previous positive SARS-CoV-2 diagnostic tests, and underlying medical conditions was extracted from BOP electronic medical records for all participants.
2.3 Laboratory Methods
Specimens were collected using nylon flocked minitip swabs, transferred into universal viral transport media (VTM) (Becton Dickinson, Franklin Lakes, NJ), immediately stored at 2-8°C and frozen at -20°C or below within 72 hours, and sent to CDC for RT-PCR testing using the CDC Influenza SARS-CoV-2 Multiplex Assay. Remnant aliquots were stored at -70°C or below for viral culture. Due to capacity limitations, viral culture was performed on a subset of specimens. Specimens were included for viral culture if they had been collected 0, 3, 5, 7, or 9 days since onset and had an accompanying positive RT-PCR test with cycle threshold (Ct) value <35. For verification that this selected Ct cutoff did not exclude specimens containing culturable virus, viral culture was also performed on 25 of 102 specimens with Ct≥35. (25/25 of these specimens were culture negative.) For more granular detail across the time-course of infection, viral culture was also performed on a subset of specimens collected on other days (see Supplemental Figure 1, Figure 2 for details on specimens included for viral culture).Figure 2 SARS-CoV-2 RT-PCR test positivity survival curves for enrolled participants, Federal prison, Texas, July 12—August 9, 2021. Panels illustrate the results of Turnbull estimation survival functions with a primary endpoint of last positive reverse transcription-polymerase chain reaction (RT-PCR) test result. Solid lines indicate nonparametric maximum likelihood estimates and shaded regions correspond to 95% confidence intervals estimated through modified bootstrap. Survival functions are plotted by Turnbull interval midpoints. Onset was determined to be either a) date of first onset of self-reported symptom(s) meeting the case definition of COVID-19 or b) date of first positive diagnostic SARS-CoV-2 test, whichever occurred first. Panel A depicts RT-PCR positivity by vaccination status. Panel B depicts positivity by vaccine product among vaccinated participants. Panel C depicts positivity according to the time from completion of a COVID-19 vaccine/series to onset. Panel D depicts positivity according to history of known prior SARS-CoV-2 infection.
Specimens selected for culture were used to perform limiting-diluting inoculation of Vero CCL-81 cells expressing TMPRSS2, and cultures showing evidence of cytopathic effect were tested by RT-PCR for the presence of SARS-CoV-2 RNA. Viral recovery was conducted as previously described.[10] Whole genome sequencing (WGS) was performed for one RT-PCR-positive specimen per participant with Ct<30 (per sequencing laboratory standard protocols).
2.4 Statistical Methods
Onset (used as time 0 in longitudinal analyses below) was defined to be either a) date of first onset of self-reported symptom(s) meeting the case definition of COVID-19,[11] or b) date of first positive diagnostic SARS-CoV-2 test, whichever occurred first. In two instances where a participant without symptoms had an initial positive test followed by at least 3 negative tests before subsequent positive tests, the date of second positive test was used.
Participants were considered vaccinated if ≥14 days had elapsed since they had completed all recommended doses of a COVID-19 primary vaccine series before the start of the outbreak. (No participant had completed a primary vaccine series <14 days before the outbreak.) At the time of this investigation, additional/booster doses of COVID-19 vaccines were not recommended. Participants were considered unvaccinated if they had not received any doses; persons who had started but not completed a primary vaccine series were excluded from the analysis. Demographic characteristics of participants stratified by vaccination status were assessed using Fisher’s exact tests.
Three surrogate markers for assessing transmission potential were analyzed as primary outcomes: RT-PCR positivity (an indicator of current/recent infection), RT-PCR Ct value (a semi-quantitative indicator of relative level of viral nucleic acid), and viral culture positivity (an indicator of viable/infectious virus). Dichotomous laboratory results (RT-PCR positivity and viral culture positivity) were analyzed longitudinally with time 0 defined as the date of onset and the primary endpoints defined by a participant’s last positive test. Specimens for which viral culture was not performed were presumed to be culture negative if an accompanying RT-PCR test was negative or was positive with Ct≥35. To account for variation in the interval between onset and enrollment, and intermittent participation in specimen collection by some participants (which can result in interval and right censoring), survival analyses were performed using Turnbull estimation using the “interval” package implementation in R.[12] Hypothesis testing of survival functions was performed using the generalized Wilcoxon-Mann-Whitney method for interval-censored data.
As a post-hoc evaluation of potential interactions between vaccination status, vaccine product, recency of vaccination, and known prior SARS-CoV-2 infections, stratified pairwise comparisons of survival functions were performed between vaccinated and unvaccinated participants in each subgroup (e.g., those vaccinated with known prior infection vs. those unvaccinated with known prior infection) using the generalized Wilcoxon-Mann-Whitney method.
Non-dichotomous laboratory results (RT-PCR Ct values) were characterized by days since onset using medians and interquartile ranges (IQRs). Because Ct values are semi-parametric, distributions were compared non-parametrically using the Mann-Whitney U test with ties (for dichotomous variables) or the Kruskal-Wallis test (for categorical variables with more than 2 levels); negative RT-PCR results were assigned higher ranks than any Ct value from positive RT-PCR results. To account for multiple hypothesis testing across days, α thresholds were adjusted using Bonferroni correction. All hypothesis tests of Ct values are detailed in Supplementary Tables 1 and 2. All statistical analyses were performed in R version 4.0.2 (R Core Team, Vienna, Austria).
3 Results
3.1 Population Characteristics
Among 189 persons with SARS-CoV-2 infection eligible to enroll, a total of 96 persons (51%) consented to participate in serial specimen collection; one participant had a single positive diagnostic test (Ct=36.2) followed by seven negative diagnostic tests and reported no symptoms and was excluded as a non-case, and two participants who had received single doses of a two-dose primary series were also excluded. Of the 93 included participants, 78 (84%) were documented as being vaccinated against SARS-CoV-2 and 15 (16%) were unvaccinated (Table 1 ). Among vaccinated participants, a majority (57/78, 73%) received the Pfizer vaccine; smaller proportions received the Moderna vaccine (14/78, 18%) or Janssen vaccine (7/78, 9%). A majority (47/78, 60%) of vaccinated participants completed their vaccination series more than 120 days prior to the start of the outbreak (IQR: 81-140 days prior to start). Recipients of Pfizer vaccines completed their series earlier (IQR: 131-131 days) than recipients of Moderna (IQR: 81-82 days prior to start) or Janssen (IQR: 46-70 days prior to start) vaccines (p<0.001). A small number of participants (2/78 vaccinated, 3%, and 2/15 unvaccinated, 13%, p=0.10) had a documented prior SARS-CoV-2 infection. Based on symptom self-report at the end of sampling, 68% of participants reported at least one symptom in the COVID-19 case definition. The most commonly reported symptoms were runny or stuffy nose (59%), loss of smell or taste (54%), and cough (45%). Of 93 specimens from 93 participants for which sequencing was attempted, 64 were successfully sequenced and passed quality metrics; all 64 (100%) belonged to the B.1.617.2 (Delta) lineage and AY.3 sublineage.Table 1 Characteristics of enrolled participants who tested positive for SARS-CoV-2, Federal prison, Texas, July 12—August 9, 2021
All participants Vaccinated Unvaccinated* p-value†
n % n % N %
Total 93 100% 78 84% 15 16%
Sex
Male 93 100% 78 84% 15 16%
Age 0.5
18-29 5 5% 3 4% 2 13%
30-39 22 23% 19 24% 3 20%
40-49 26 29% 22 28% 4 27%
50-59 25 26% 20 26% 5 33%
≥ 60 15 16% 14 18% 1 7%
Race/Ethnicity 0.01
American Indian/Alaska Native 2 2% 2 3% 0 0%
Asian 1 1% 1 1% 0 0%
Black 15 17% 8 10% 7 47%
Hispanic 12 13% 10 13% 2 13%
White 63 67% 57 73% 6 40%
Country of birth 0.5
Non US-born 4 4% 3 4% 1 7%
US-born 89 96% 75 96% 14 93%
Vaccination status
Vaccinated 78 82% 78 100% 0 0%
Unvaccinated* 15 16% 0 0% 15 100%
Vaccine product received
Janssen 7 7% 7 9% 0 0%
Moderna 14 15% 14 17% 0 0%
Pfizer 57 60% 57 74% 0 0%
Time from full vaccination to outbreak (if vaccinated)
≤120 days 31 33% 31 33% 0 0%
>120 days 47 49% 47 61% 0 0%
Medical comorbidities
Overweight‡ 31 33% 24 31% 7 46% 0.2
Obesity‡ 46 49% 42 54% 4 26%
Severe obesity ‡ 7 7% 6 8% 0 0%
History of smoking 45 48% 42 54% 3 20% 0.02
Hypertension 42 45% 38 49% 4 26% 0.1
Diabetes 15 16% 14 18% 1 6% 0.3
Moderate/severe asthma 10 11% 8 10% 2 12% 0.7
Chronic obstructive pulmonary disease 6 6% 6 8% 0 0% 0.6
Cancer 1 1% 1 1% 0 0% 1.0
Chronic kidney disease 2 2% 2 3% 0 0% 1.0
Immunocompromised state 2 2% 2 3% 0 0% 1.0
HIV 0 0% 0 0% 0 0%
Serious cardiac conditions 0 0% 0 0% 0 0%
Liver disease 0 0% 0 0% 0 0%
Documented prior SARS-CoV-2 infection 0.1
No 89 96% 76 97% 13 87%
Yes 4 4% 2 3% 2 13%
COVID-19 disease outcomes
Hospitalization 2 2% 1 1% 1 6%
Death 0 0% 0 0% 0 0%
Reported Symptoms
Reported any symptoms in CSTE case definition§ 64 68% 54 69% 10 67% 1.0
Reported any symptoms 70 75% 59 76% 11 73% 0.4
Runny/Stuffy Nose 54 59% 48 62% 6 47% 0.3
Loss of Smell or Taste 50 54% 43 55% 7 47% 1.0
Cough 43 45% 35 45% 7 47% 0.8
Headache 40 43% 33 42% 6 40% 1.0
Muscle Aches 38 41% 30 38% 8 53% 0.1
Subjective Fever 34 36% 27 35% 6 40% 0.5
Measured Fever 10 11% 6 8% 4 27% 0.04
Chills 28 30% 21 27% 7 47% 0.09
Sore Throat 22 24% 21 27% 1 7% 0.2
Shortness of Breath 19 20% 14 18% 5 33% 0.1
Abdominal Pain, Nausea, Vomiting 17 18% 12 15% 5 33% 0.1
Diarrhea 15 16% 11 14% 4 27% 0.2
Other 6 6% 6 8% 0 0% 1.0
None Reported ¶ 23 25% 19 24% 4 27% 1.0
*Unvaccinated participants include 15 who have not received any dose of a SARS-CoV-2 vaccine.
†P-values correspond to results of Fisher’s exact tests.
‡Overweight was defined as a body mass index (BMI) >25 kg/m2 but <30 kg/m2; obesity was defined as BMI ≥30 kg/m2 but <40 kg/m2; severe obesity was defined as BMI ≥40 kg/m2.
§The COVID-19 case definition of the Council of State and Territorial Epidemiologists (CSTE) includes fever, chills, muscle aches, headache, sore throat, nausea/vomiting, diarrhea, fatigue, stuffy/runny nose, cough, shortness of breath, or loss of taste or smell.
¶ 8 participants (5 vaccinated and 3 unvaccinated) declined to report symptoms in addition to 15 (14 and 1, respectively) who reported that they had no symptoms
3.2 RT-PCR Positivity
From the 93 included participants, 957 specimens were collected for RT-PCR testing (825/957, 86% from vaccinated participants). Specimens were collected ranging from 13 days prior to onset (among participants tested during quarantine prior to diagnosis) to 32 days following onset. See Figure 1 for a diagrammatic representation of RT-PCR specimen collection from participants, and see Supplemental Figure 1 for details of specimen collection by day since onset (stratified by vaccination status). A median of 6 days elapsed between onset and enrollment among vaccinated participants, compared with a median of 7 days among participants who were unvaccinated (p=0.45).
No significant differences in time to last RT-PCR positive test were found. Median duration of RT-PCR positivity was 13 days among vaccinated participants versus 17 days among participants who were unvaccinated (p=0.32; Figure 2); and 10 days among participants with known history of prior SARS-CoV-2 infection (regardless of vaccination) versus 13 days among participants without any known prior infection (p=0.14). Among vaccinated participants, median duration of positivity was 10 days among Moderna vaccine recipients versus 13 days among Pfizer recipients and 13 days among Janssen recipients (p=0.39); and 13 days among participants vaccinated more than 120 days prior to the outbreak versus 11 days among participants vaccinated 120 days or less prior to the outbreak (p=0.32).
3.3 Ct Values
Ct values from specimens testing positive by RT-PCR increased with the number of days since onset (Figure 3 ). Among specimens from vaccinated participants, Ct values increased from a median of 26.4 (IQR: 23.5-28.4) on the day of onset to a median of 32.9 on day 10 (IQR: 30.5-34.6), while Ct values from specimens from participants who were unvaccinated increased from a median of 28.5 (IQR:24.8-31.8) on the day of onset to a median of 31.9 on day 10 (IQR:28.9-34.9). Across the time-course of infection, no statistically significant difference was observed among Ct values by vaccination status on any day after Bonferroni correction (all p>0.0026, the Bonferroni-corrected α threshold). Additionally, no significant differences were observed among Ct values when stratified by vaccine product, time since vaccination, or known prior SARS-CoV-2 infection. While not statistically significant, lower Ct values were observed early in the time-course of infection among Janssen vaccine recipients (day 3 median: 17.9; IQR: 17.6-19.4) than among Moderna (day 3 median: 27.4; IQR: 23.7-28.1) or Pfizer recipients (day 3 median: 24.8; IQR: 23.1-26.8; p=0.016 while Bonferroni α=0.0026).Figure 3 RT-PCR Cycle Threshold distributions for enrolled participants with confirmed SARS-CoV-2 infection, Federal prison, Texas, July 12—August 9, 2021. Panels illustrate daily medians and interquartile ranges (IQRs) for reverse transcription-polymerase chain reaction (RT-PCR) cycle threshold (Ct) values among specimens with positive RT-PCR results. Solid lines indicate median Ct values and shaded regions indicate IQRs. Percentages at the top of each panel indicate the proportion of specimens with negative RT-PCR results each day. Onset was determined to be either a) date of first onset of self-reported symptom(s) meeting the case definition of COVID-19 or b) date of first positive diagnostic SARS-CoV-2 test, whichever occurred first. Panel A depicts RT-PCR positivity by vaccination status. Panel B depicts positivity by vaccine product among vaccinated participants. Panel C depicts positivity according to the time from completion of a COVID-19 vaccine/series to onset. Panel D depicts positivity according to history of known prior SARS-CoV-2 infection.
3.4 Viral Culture Positivity
Of the 957 specimens collected, viral culture was performed on 283 (30%); an additional 538 (56%) were included as presumptive negative viral culture results due to an accompanying negative RT-PCR test (n=461) or a positive RT-PCR test with a Ct value greater than 35 (n=77). Viral culture capture by day since onset stratified by vaccination status is detailed in Supplementary Figure 2. Among the 821 specimens with a viral culture result, 75 (9%) had a positive viral culture. Virus was recovered from 57/690 (8%) of specimens from vaccinated participants, compared with 18/131 (14%) of specimens from participants who were unvaccinated (p=0.07).
No statistically significant difference was detected in the duration of viral culture positivity (Figure 4 ) between participants who were vaccinated (median: 5 days) compared with those who were unvaccinated (median: 6 days; p=0.192). (Viral culture results are illustrated as a function of days since onset and grouped by RT-PCR result in Supplementary Figure 4). Cumulative hazard functions indicate overall shorter culture positivity for vaccinated participants who received the Moderna vaccine than those who received Pfizer (p=0.048) or Janssen vaccines (p=0.003), but there was no significant difference between recipients of Pfizer and Janssen vaccines (p=0.12). No statistically significant differences in duration of culture positivity were detected when stratified according to time since vaccination (p=0.79) or known prior infection (p=0.99).Figure 4 SARS-CoV-2 viral culture test positivity survival curves for enrolled participants, Federal prison, Texas, July 12—August 9, 2021. Panels illustrate the results of Turnbull estimation survival functions with a primary endpoint of last positive viral culture test result. Specimens were included as presumptive negative results if no culture was performed but were accompanied by negative RT-PCR results or positive RT-PCR results with Ct>35. Solid lines indicate nonparametric maximum likelihood estimates and shaded regions correspond to 95% confidence intervals estimated through modified bootstrap. Survival functions are plotted by Turnbull interval midpoints. When Turnbull intervals are bounded by positive infinity (resulting from right-censoring in subgroups), survival functions are truncated by open points at the rightmost non-infinite intervals. Onset was determined to be either a) date of first onset of self-reported symptom(s) meeting the case definition of COVID-19 or b) date of first positive diagnostic SARS-CoV-2 test, whichever occurred first. Panel A depicts viral culture positivity by vaccination status. Panel B depicts positivity by vaccine product among vaccinated participants. Panel C depicts positivity according to the time from completion of a COVID-19 vaccine/series to onset. Panel D depicts positivity according to history of known prior SARS-CoV-2 infection.
3.5 Post-Hoc Pairwise Testing
Due to the high degree of correlation between vaccine product, recency of vaccination, and history of known prior infection, subgroup identifiability limits the use of multivariate models to examine interactions between these factors. Instead, a series of post-hoc pairwise comparisons were performed across identifiable subgroups (Supplemental Table 3). In these comparisons (Figure 5 ), duration of viral culture positivity was significantly shorter among Moderna vaccine recipients compared to unvaccinated participants (medians: 3 days vs. 6 days; p=0.02); this difference was more pronounced when restricted to participants with no known history of prior infection (medians: 3 days vs. 6 days; p=0.002). Additionally, among unvaccinated participants, persons with known prior infection were positive for significantly shorter than those without a known prior infection (medians: 2 days vs. 6 days; p=0.019). Duration of culture positivity was not significantly different between vaccinated participants with no known history of prior infection and unvaccinated participants with known prior infection (medians: 3 days vs. 2 days; p=0.162).Figure 5 Subgroup analysis of SARS-CoV-2 viral culture test positivity survival curves for enrolled participants, Federal prison, Texas, July 12—August 9, 2021. Panels illustrate the results of Turnbull estimation survival functions with a primary endpoint of last positive viral culture test result. Specimens were included as presumptive negative results if no culture was performed but were accompanied by negative RT-PCR results or positive RT-PCR results with Ct>35. Solid lines indicate nonparametric maximum likelihood estimates and shaded regions correspond to 95% confidence intervals estimated through modified bootstrap. P-values of differences in survival functions (using the generalized Wilcoxon-Mann-Whitney method) are displayed at the bottom of each panel. Survival functions are plotted by Turnbull interval midpoints. When Turnbull intervals are bounded by positive infinity (resulting from right-censoring in subgroups), survival functions are truncated by open points at the rightmost non-infinite intervals. Onset was determined to be either a) date of first onset of self-reported symptom(s) meeting the case definition of COVID-19 or b) date of first positive diagnostic SARS-CoV-2 test, whichever occurred first. Panel A depicts viral culture positivity between Moderna vaccine recipients and unvaccinated participants. Panel B restricts this analysis to participants with no known prior infection, comparing positivity between Moderna vaccine recipients and unvaccinated participants Panel C restricts to unvaccinated participants and compares positivity between participants with and without known prior infection. Panel D compares positivity between vaccinated participants (any full primary series) without know prior infection versus unvaccinated participants with known prior infection.
4 Discussion
During a high-transmission outbreak of the SARS-CoV-2 Delta variant in a prison setting, we failed to find different durations of RT-PCR positivity, Ct values, or durations of viral culture positivity between persons who had received any primary series vaccine and persons who were unvaccinated. However, persons who had specifically received the Moderna vaccine demonstrated shorter duration of viral culture positivity than unvaccinated persons. In our data, outcomes varied by vaccine product as persons who received the Moderna vaccine had a shorter duration of culture positivity compared with Pfizer or Janssen vaccine recipients. Finally, among unvaccinated participants, the duration of viral culture positivity was shorter among those with prior infection than those without a known prior infection.
Collectively, our findings suggest that potential infectiousness may be decreased in some vaccinated persons with SARS-CoV-2 infection and in some unvaccinated persons with prior infection. However, vaccination with a primary series does not guarantee decreased infectiousness in those who become infected, and many vaccinated persons in our analysis demonstrated longer duration of viral culture positivity than some unvaccinated persons. As illustrated in this outbreak (in which 74% of incarcerated persons in affected housing units became infected), introduction of infection into congregate and correctional settings can accelerate rapidly and result in hospitalizations and deaths.[6] In such settings, clinicians and public health practitioners should consider vaccinated persons who become infected as not significantly less infectious than unvaccinated persons for the purposes of public health action.
As viral infections in vaccinated persons can result from either a failure to mount a protective immune response following initial vaccination or a gradual waning of immunological protection following initially robust protection, the infectiousness of vaccinated persons may be variable. It is plausible that some participants in this investigation who became infected despite vaccination had weak or waning vaccine-induced protection and were therefore similar to unvaccinated persons in the markers of transmission potential that we evaluated.
This report adds to a limited body of scientific literature evaluating the transmission potential of SARS-CoV-2 infections in vaccinated persons. Reports of infections in vaccinated persons have found mixed results using markers of transmission potential, and no longitudinal studies of viral culture characteristics in vaccinated persons with Delta infections have been published. A multi-site serial testing investigation involving Alpha (B.1.1.7) and Gamma (P.1) infections found that duration of culture positivity was shorter among vaccinated persons compared with unvaccinated persons.[13], [14] One report using surveillance data found lower Ct values among unvaccinated persons, but this difference was only observed for two of three RT-PCR probes and only during one of three months.[15] One cross-sectional report found no difference in Ct value by vaccination status.[2] However, extrapolating from cross-sectional and surveillance data may be challenging without data to account for timing of specimen collection in the course of infection. Nevertheless, this finding is corroborated by analysis of a clinical convenience sample which found vaccination did not impact Ct values and reduced viral recovery of Alpha variant but did not reduce recovery of Delta variant virus;[16] similar findings were mirrored by two retrospective health-system cohorts.[17], [18] A report of health system workers found that viral culture positivity was reduced in vaccinated persons despite similar Ct values as those in unvaccinated persons.[3] A separate report found that early in the clinical course of infection, Ct values were comparable between vaccinated and unvaccinated persons, but among individuals who presented to care later in their course of illness, Ct values were higher in vaccinated persons.[19] A study of household transmission of Delta infections found similar peak viral loads regardless of vaccination status, but noted faster declines in vaccinated persons.[20] Cumulatively, available data have not clearly or consistently identified markers of reduced transmission potential in vaccinated persons with SARS-CoV-2 infection. This report, which to our awareness represents the first longitudinal investigation of viral culture characteristics of vaccinated persons with Delta variant infections, further demonstrates the potential of vaccinated persons to contribute to SARS-CoV-2 transmission.
While our investigation found mixed evidence of reduced transmission potential from vaccinated persons with infection, vaccination is known to reduce the risk of infection,[6], [21] which prevents secondary transmission. In addition, vaccination remains a strongly protective factor against morbidity and mortality due to SARS-CoV-2.[22] Protection against infection, morbidity, and mortality underscores the importance of maximizing vaccination coverage, particularly in settings where challenges to physical distancing can result in rapid, widespread transmission when infections do occur.
The evidence that vaccinated persons can transmit SARS-CoV-2 to others suggests that there is continued risk of widespread outbreaks when the virus is introduced into congregate settings, even when vaccination coverage is high. While quarantine is not recommended after exposure to someone with COVID-19 in general settings, some high-risk congregate settings may still choose to use quarantine protocols to limit transmission, especially when the population has a high prevalence of underlying health conditions associated with severe COVID-19.[7], [8] Our findings suggest that when facilities use quarantine as a COVID-19 prevention strategy, they should implement it for anyone who is exposed, regardless of vaccination status.
This report is subject to several limitations. Due to the small proportion of participants who were unvaccinated (16%), statistical comparisons on the basis of vaccination status were underpowered, and negative findings reported here warrant cautious interpretation. Only four participants had known prior infection, of which a higher proportion occurred in those unvaccinated; therefore, these participants may appear to have slightly greater immunological protection than those without prior infection. On average, unvaccinated participants enrolled earlier in the outbreak and later in their course of infection than vaccinated participants; we utilized Turnbull estimation in survival analyses to account for the possibility of interval censoring in this population. All symptom data was self-reported and collected at the end of the specimen collection period, which may have impacted the accuracy of participants’ recall related to the date of symptom onset. Ct values are semi-quantitative indicators of viral RNA levels and cannot be interpreted as quantitative markers of viral load or infectiousness. To avoid drawing quantitative conclusions around Ct values, we conservatively utilized non-parametric rank-based statistics (Mann-Whitney and Kruskal-Wallis) with Bonferroni correction to describe Ct values in this investigation. Information on prior SARS-CoV-2 infection was obtained from medical records; persons with earlier infections that were undiagnosed or diagnosed prior to incarceration and not documented in the BOP medical record may not have been correctly characterized. We did not attempt viral culture for 561 specimens with Ct>35 and classified them as presumptively negative. This decision was based on negative viral culture results from 25/25 specimens with Ct>35 for which viral culture was performed during this investigation, as well as previously published findings demonstrating an inability to recover viable virus from specimens that were RT-PCR negative.[23] Finally, our investigation took place in a setting and time in which prior infections were less common, vaccine boosters were not yet recommended, hybrid immunity (i.e., vaccination and prior infection) was uncommon, and the Delta variant was predominant, factors which may limit the generalizability of our findings to future outbreaks.
In this investigation, we found mixed evidence of reductions in transmission potential between vaccinated persons and persons who were unvaccinated. While recipients of a Moderna primary series demonstrated reduced viral culture positivity, recipients of other vaccines did not. Therefore, our findings indicate that prevention and mitigation measures should be applied without regard to vaccination status for persons in high-risk settings or those with significant exposures. Our data add to a growing body of evidence characterizing transmission potential from vaccinated persons. Future studies of transmission potential from vaccinated persons with infection, incorporating similar laboratory-based markers as well as evidence of transmission from secondary attack rates and network analysis, may help to further describe the contributions of vaccinated persons in chains of transmission as the pandemic evolves and new variants emerge.
5 Footnotes
* 45 C.F.R. part 46, 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501 et seq.
Disclaimer. The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of Centers for Disease Control and Prevention (CDC).
Uncited reference
[24].
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data availability
Data will be made available on request.
Acknowledgements
Mario Cordova, Torrey Haskins, Jennifer Jackson, Joshua Jett, Barbara Swopes, Tammy Winbush, Federal Bureau of Prisons.
==== Refs
References
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2 Riemersma KK, Grogan BE, Kita-Yarbro A, Halfmann PJ, Segaloff HE, Kocharian A, et al. Shedding of Infectious SARS-CoV-2 Despite Vaccination. medRxiv. 2021: 2021.07.31.21261387. 10.1101/2021.07.31.21261387.
3 Shamier MC, Tostmann A, Bogers S, de Wilde J, IJpelaar J, van der Kleij WA, et al. Virological characteristics of SARS-CoV-2 vaccine breakthrough infections in health care workers. medRxiv. 2021: 2021.08.20.21262158. 10.1101/2021.08.20.21262158.
4 Brown CM, Vostok J, Johnson H, Burns M, Gharpure R, Sami S, et al. Outbreak of SARS-CoV-2 Infections, Including COVID-19 Vaccine Breakthrough Infections, Associated with Large Public Gatherings - Barnstable County, Massachusetts, July 2021. MMWR Morb Mortal Wkly Rep. 2021; 70(31): 1059-62. 10.15585/mmwr.mm7031e2.
5 Centers for Disease Control and Prevention. COVID Data Tracker. Atlanta, GA. US Department of Health and Human Services. Accessed October 16, 2021. [Available from: https://covid.cdc.gov/covid-data-tracker/#trends_dailycases.
6 Hagan L.M. McCormick D.W. Lee C. Sleweon S. Nicolae L. Dixon T. Outbreak of SARS-CoV-2 B.1.617.2 (Delta) Variant Infections Among Incarcerated Persons in a Federal Prison - Texas, July-August 2021 MMWR Morb Mortal Wkly Rep. 70 38 2021 1349 1354 10.15585/mmwr.mm7038e3 34555009
7 Hagan L.M. Williams S.P. Spaulding A.C. Toblin R.L. Figlenski J. Ocampo J. Mass Testing for SARS-CoV-2 in 16 Prisons and Jails - Six Jurisdictions, United States, April-May 2020 MMWR Morb Mortal Wkly Rep. 69 33 2020 1139 1143 10.15585/mmwr.mm6933a3 32817597
8 Maruschak L. Bronson J. Alper M. Medical problems reported by prisoners, survey of prison inmates, 2016 2021 DC. US Department of Justice, Bureau of Justice Statistics Washington Available from: https://bjs.ojp.gov/sites/g/files/xyckuh236/files/media/document/mprpspi16st.pdf
9 McMichael T.M. Clark S. Pogosjans S. Kay M. Lewis J. Baer A. COVID-19 in a Long-Term Care Facility - King County, Washington, February 27-March 9, 2020 MMWR Morb Mortal Wkly Rep. 69 12 2020 339 342 10.15585/mmwr.mm6912e1 32214083
10 Harcourt J. Tamin A. Lu X. Kamili S. Sakthivel S.K. Murray J. Severe Acute Respiratory Syndrome Coronavirus 2 from Patient with Coronavirus Disease United States. Emerg Infect Dis. 26 6 2020 1266 1273 10.3201/eid2606.200516 32160149
11 Council of State and Territorial Epidemiologists. Update to the standardized surveillance case definition and national notification for 2019 novel coronavirus disease (COVID-19). Accessed October 15, 2021. [Available from: https://cdn.ymaws.com/www.cste.org/resource/resmgr/21-ID-01_COVID-19_updated_Au.pdf.
12 Fay MP, Shaw PA. Exact and Asymptotic Weighted Logrank Tests for Interval Censored Data: The interval R package. J Stat Softw. 2010; 36(2). 10.18637/jss.v036.i02.
13 Ke R. Martinez P.P. Smith R.L. Gibson L.L. Achenbach C.J. McFall S. Longitudinal analysis of SARS-CoV-2 vaccine breakthrough infections reveal limited infectious virus shedding and restricted tissue distribution medRxiv. 2021 10.1101/2021.08.30.21262701
14 Ke R. Martinez P.P. Smith R.L. Gibson L.L. Mirza A. Conte M. Daily sampling of early SARS-CoV-2 infection reveals substantial heterogeneity in infectiousness medRxiv. 2021 10.1101/2021.07.12.21260208
15 Griffin JB, Haddix M, Danza P, Fisher R, Koo TH, Traub E, et al. SARS-CoV-2 Infections and Hospitalizations Among Persons Aged ≥16 Years, by Vaccination Status - Los Angeles County, California, May 1-July 25, 2021. MMWR Morb Mortal Wkly Rep. 2021; 70(34): 1170-6. 10.15585/mmwr.mm7034e5.
16 Luo C.H. Morris C.P. Sachithanandham J. Amadi A. Gaston D. Li M. Infection with the SARS-CoV-2 Delta Variant is Associated with Higher Infectious Virus Loads Compared to the Alpha Variant in both Unvaccinated and Vaccinated Individuals medRxiv. 2021 10.1101/2021.08.15.21262077
17 Christensen PA, Olsen RJ, Long SW, Subedi S, Davis JJ, Hodjat P, et al. Delta variants of SARS-CoV-2 cause significantly increased vaccine breakthrough COVID-19 cases in Houston, Texas. medRxiv. 2021: 2021.07.19.21260808. 10.1101/2021.07.19.21260808.
18 Eyre DW, Taylor D, Purver M, Chapman D, Fowler T, Pouwels KB, et al. The impact of SARS-CoV-2 vaccination on Alpha & Delta variant transmission. medRxiv. 2021: 2021.09.28.21264260. 10.1101/2021.09.28.21264260.
19 Chia PY, Xiang Ong SW, Chiew CJ, Ang LW, Chavatte J-M, Mak T-M, et al. Virological and serological kinetics of SARS-CoV-2 Delta variant vaccine-breakthrough infections: a multi-center cohort study. medRxiv. 2021: 2021.07.28.21261295. 10.1101/2021.07.28.21261295.
20 Singanayagam A, Hakki S, Dunning J, Madon KJ, Crone M, Koycheva A, et al. Community transmission and viral load kinetics of SARS-CoV-2 Delta (B.1.617.2) variant in vaccinated and unvaccinated individuals. Preprint Available at SSRN: https://ssrncom/abstract=3918287 or http://dxdoiorg/102139/ssrn3918287. 2021.
21 Pouwels K.B. Pritchard E. Matthews P.C. Stoesser N. Eyre D.W. Vihta K.D. Effect of Delta variant on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK Nat Med. 2021 10.1038/s41591-021-01548-7
22 Tenforde M.W. Patel M.M. Ginde A.A. Douin D.J. Talbot H.K. Casey J.D. Effectiveness of SARS-CoV-2 mRNA Vaccines for Preventing Covid-19 Hospitalizations in the United States Clin Infect Dis. 2021 10.1093/cid/ciab687
23 Ford L. Lee C. Pray I.W. Cole D. Bigouette J.P. Abedi G.R. Epidemiologic Characteristics Associated With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antigen-Based Test Results, Real-Time Reverse Transcription Polymerase Chain Reaction (rRT-PCR) Cycle Threshold Values, Subgenomic RNA, and Viral Culture Results From University Testing Clin Infect Dis. 73 6 2021 e1348 e1355 10.1093/cid/ciab303 33846714
24 Centers for Disease Control and Prevention. Interim guidance on management of coronavirus disease 2019 (COVID-19) in correctional and detention facilities. Atlanta, GA. US Department of Health and Human Services. Accessed October 29, 2021. [Available from: https://www.cdc.gov/coronavirus/2019-ncov/community/correction-detention/guidance-correctional-detention.html.
| 0 | PMC9744684 | NO-CC CODE | 2022-12-15 00:01:53 | no | Vaccine. 2022 Dec 13; doi: 10.1016/j.vaccine.2022.11.045 | utf-8 | Vaccine | 2,022 | 10.1016/j.vaccine.2022.11.045 | oa_other |
==== Front
Journal of Traditional Chinese Medical Sciences
2095-7548
2589-0395
Beijing University of Chinese Medicine. Production and hosting by Elsevier B.V.
S2095-7548(22)00108-9
10.1016/j.jtcms.2022.11.003
Article
Acupuncture for olfactory dysfunction in infected COVID-19 patients: study protocol for a randomized, sham-controlled clinical trial
Zhong Linda Lidan a∗
Wong Yiping a
Leung Choryin a
Choy Chifung b
Cho Hungwai c
Wong Alan Yatlun d
Yau Kaming d
Wong Rowena Howwan e
Ng Bacon Fungleung e
Bian Zhaoxiang a
a School of Chinese Medicine,Hong Kong Baptist University,Hong Kong 999077,China
b Tseung Kwan O Hospital,Hong Kong Hospital Authority,Hong Kong 999077,China
c Department of Ear,Nose and Throat (ENT),Tseung Kwan O Hospital,Hong Kong 999077,China
d Haven of Hope,Chinese University of Hong Kong Chinese Medicine Clinic Cum Training and Research Centre (Sai Kung District),Hong Kong 999077,China
e Chinese Medicine Department,Hong Kong Hospital Authority,Hong Kong 999077,China
∗ Corresponding author.
13 12 2022
13 12 2022
23 9 2022
25 11 2022
26 11 2022
© 2022 Beijing University of Chinese Medicine. Production and hosting by Elsevier B.V.
2022
Beijing University of Chinese Medicine
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Objective
Olfactory dysfunction (OD) is a common symptom of Corona Virus Disease 2019 (COVID-19). It is defined as the reduced or distorted ability to smell during sniffing (orthonasal olfaction) and represents one of the early symptoms in the clinical course of COVID-19 infection. A large online questionnaire-based survey has shown that some post-COVID-19 patients had no improvement 1 month after discharge from the hospital. Therefore, this clinical trial was designed to explore the efficacy of acupuncture for OD in COVID-19 infected patients and to determine whether acupuncture could have benefits over sham acupuncture for OD in post-COVID-19 patients.
Methods
This is a single-blind, randomized controlled, cross-over trial. We plan to recruit 40 post-COVID-19 patients with smell loss or smell distortions lasting for more than 1 month. Qualified patients will be randomly allocated to the intervention group (real acupuncture) or the control group (sham acupuncture) at a 1:1 ratio. Each patient will receive 8 sessions of treatment over 4 weeks (Cycle 1) and a 2-week follow-up. After the follow-up, the control group will be subjected to real acupuncture for another 4 weeks (Cycle 2), and the real acupuncture group will undergo the 4-week sham acupuncture. The primary outcomes will be the score changes on the questionnaire of olfactory functioning and olfaction-related quality of life at week 6, 8, 12, and 14 from the baseline. The secondary outcomes will be the changes in the olfactory test score at week 6 and 12 from the baseline measured by using the Traditional Chinese version of the University of Pennsylvania Smell Identification Test (UPSIT-TC).
Discussion
The results of this trial will help to determine the effectiveness of acupuncture for OD in post-COVID-19 patients. This may provide a new treatment option for patients.
Keywords
Olfactory dysfunction
Smell loss
Smell distortions
COVID-19
Acupuncture
Chinese Medicine
UPSIT
==== Body
pmcPeer review under responsibility of Beijing University of Chinese Medicine.
| 0 | PMC9744685 | NO-CC CODE | 2022-12-15 00:01:53 | no | 2022 Dec 13; doi: 10.1016/j.jtcms.2022.11.003 | utf-8 | null | null | null | oa_other |
==== Front
Eur J Intern Med
Eur J Intern Med
European Journal of Internal Medicine
0953-6205
1879-0828
European Federation of Internal Medicine. Published by Elsevier B.V.
S0953-6205(22)00433-2
10.1016/j.ejim.2022.12.004
Review Article
The spike effect of acute respiratory syndrome coronavirus 2 and coronavirus disease 2019 vaccines on blood pressure✰
Angeli Fabio ab⁎
Zappa Martina a
Reboldi Gianpaolo c
Gentile Giorgio d
Trapasso Monica e
Spanevello Antonio ab
Verdecchia Paolo f
a Department of Medicine and Surgery, University of Insubria, Varese, 21100, Italy
b Department of Medicine and Cardiopulmonary Rehabilitation, Maugeri Care and Research Institute, IRCCS Tradate, 21049, Italy
c Department of Medicine, and Centro di Ricerca Clinica e Traslazionale (CERICLET), University of Perugia, Perugia, 06100, Italy
d College of Medicine and Health. University of Exeter, Exeter, United Kingdom and Department of Nephrology, Royal Cornwall Hospitals NHS Trust, Truro, United Kingdom
e Dipartimento di Igiene e Prevenzione Sanitaria, PSAL, Sede Territoriale di Varese, ATS Insubria, Varese, 21100, Italy
f Division of Cardiology, Hospital S. Maria della Misericordia, Perugia, and Fondazione Umbra Cuore e Ipertensione-ONLUS, Perugia, 06100, Italy
⁎ Corresponding author at: Department of Medicine and Surgery, University of Insubria, Department of Medicine and Cardiopulmonary Rehabilitation, Istituti Clinici Scientifici Maugeri, IRCCS Tradate, Varese, Italy.
13 12 2022
13 12 2022
11 10 2022
7 12 2022
12 12 2022
© 2022 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
2022
European Federation of Internal Medicine
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Among the various comorbidities potentially worsening the clinical outcome in patients hospitalized for the acute respiratory syndrome coronavirus-2 (SARS-CoV-2), hypertension is one of the most prevalent. However, the basic mechanisms underlying the development of severe forms of coronavirus disease 2019 (COVID-19) among hypertensive patients remain undefined and the direct association of hypertension with outcome in COVID-19 is still a field of debate.
Experimental and clinical data suggest that SARS-CoV-2 infection promotes a rise in blood pressure (BP) during the acute phase of infection. Acute increase in BP and high in-hospital BP variability may be tied with acute organ damage and a worse outcome in patients hospitalized for COVID-19. In this context, the failure of the counter-regulatory renin-angiotensin-system (RAS) axis is a potentially relevant mechanism involved in the raise in BP. It is well recognized that the efficient binding of the Spike (S) protein to angiotensin converting enzyme 2 (ACE2) receptors mediates the virus entry into cells. Internalization of ACE2, downregulation and malfunction predominantly due to viral occupation, dysregulates the protective RAS axis with increased generation and activity of angiotensin (Ang) II and reduced formation of Ang1,7. Thus, the imbalance between Ang II and Ang1–7 can directly contribute to excessively rise BP in the acute phase of SARS-CoV-2 infection. A similar mechanism has been postulated to explain the raise in BP following COVID-19 vaccination (“Spike Effect” similar to that observed during the infection of SARS-CoV-2). S proteins produced upon vaccination have the native-like mimicry of SARS-CoV-2 S protein's receptor binding functionality and prefusion structure and free-floating S proteins released by the destroyed cells previously targeted by vaccines may interact with ACE2 of other cells, thereby promoting ACE2 internalization and degradation, and loss of ACE2 activities.
Graphical abstract
Image, graphical abstract
Keywords
SARS-CoV-2
COVID-19
Blood pressure
Hypertension
Vaccines
COVID-19 vaccination
ACE2
Renin-angiotensin system
Spike protein
==== Body
pmc1 Introduction
Data accrued over the last 2 years reported that specific comorbidities are associated with increased risk of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and worse outcomes with development of increased severity of lung injury and mortality [1], [2], [3], [4], [5].
The most frequent comorbidity in patients with coronavirus disease 2019 (COVID-19) is hypertension [1], [2], [3]. Despite some reports seem to support the notion that hypertension represents a risk factor for susceptibility to SARS-CoV-2 infection, a more severe course of COVID-19, and increased COVID-19-related deaths [6], [7], [8], [9], [10], [11], [12], [13], the exact mechanisms explaining the development of severe forms of COVID-19 among hypertensive patients remain undefined.
Recent investigations demonstrated that SARS-CoV-2 infection may promote a significant rise in blood pressure (BP) during the acute phase of infection [14], [15], [16], [17] and that in-hospital acute increase of BP and the development of high BP variability might be associated with acute organ failure and unfavorable outcome in patients with COVID-19 [16].
More recently, reports on safety of COVID-19 vaccines included a significant rise in BP following vaccination as potential adverse reaction [18], [19], [20]. In this context, some investigations argued a specific effect of COVID-19 vaccines on the renin-angiotensin system (RAS) as mediated by the interaction between free floating Spike (S) proteins produced upon vaccination and angiotensin (Ang) converting enzyme 2 (ACE2) receptors (the “Spike effect) [18,20,21].
The main aim of our narrative review was to summarize available evidences on the effect of SARS-CoV-2 infection and COVID-19 vaccines on BP. For this purpose, we identified clinical and experimental studies according to established methods [22,23]. Literature searches were conducted using Google Scholar, Scopus, PubMed, EMBASE, and Web of Science databases. We searched for eligible studies using research Methodology Filters [22,23]. The following research terms were used: “COVID-19, SARS-CoV-2, blood pressure, hypertension, high blood pressure, vaccines, and vaccination”.
2 SARS-CoV-2 infection and blood pressure
Several comorbidities may worsen the clinical outcomes in patients hospitalized for SARS-CoV-2 [6,7,9,10]. Among risk factors that have been linked with COVID-19 [24], hypertension is one of the most common [6], [7], [8], [9], [10] and its direct association with outcome in COVID-19 is a field of debate [3,25,26]. A systematic overview and meta-analysis of 7 clinical studies analyzing data of 1576 COVID-19 patients demonstrated that the most prevalent comorbidity was hypertension (21.1%, 95% confidence interval [CI]: 13.0–27.2%) [27]. Furthermore, hypertension was associated with an increased risk of severe COVID-19 (odds ratio [OR]: 2.49; 95% CI: 1.98–3.12) and death (OR: 2.42; 95% CI: 1.51–3.90) [28].
On the other hand, in-hospital acute rise in BP and increased BP variability are frequently observed during hospitalization for COVID-19 and they seem to be significant independent predictors of bad outcome in COVID-19 patients [14,15]. More specifically, an observational clinical study in COVID-19 showed that an exaggerated cardiovascular response due to persistently elevated and unstable BP occurring during hospitalization are independently associated with in-hospital death, intensive care unit (ICU) admission, and worsening heart failure [14]. In this retrospective cohort study involving 803 hypertensive patients, 8.3% were admitted to ICU, 3.7% had respiratory failure, 3.2% had heart failure, and 4.8% died. After adjustment for several confounders, average systolic BP (hazard ratio [HR] per 10 mmHg: 1.89; 95% CI: 1.15-3.13) and pulse pressure (HR per 10 mmHg: 2.71; 95% CI: 1.39-5.29) were independent predictors of heart failure. Moreover, the standard deviations of systolic and diastolic BP were independently associated with mortality and ICU admission.
To investigate the effect of COVID-19 on BP during short term follow-up, Akpek and co-workers [29] analyzed data of 153 consecutive COVID-19 patients. Mean age of study population was 47 ± 13 years and the main study outcome was the development of new onset hypertension according to current Guidelines [29]. Both systolic (121 ± 7 mmHg vs 127 ± 15 mmHg, p<0.001) and diastolic BP (79 ± 4 vs 82 ± 7 mmHg, p <0.001) were significantly higher in the post COVID-19 period than on admission. Notably, a new diagnosis of hypertension was observed in 18 patients at the end of the observation [29].
Similarly, the clinical data of 366 hospitalized COVID-19-confirmed patients without prior hypertension showed an incidence of rise in BP during hospitalization equal to 8.42%, with a significantly increased level of troponin, procalcitonin, and Ang II [30].
More recently, a prospective case-control study from our group analyzed BP changes among hospitalized patients with confirmed diagnosis of SARS-CoV-2 infection.
The infection was established by RNA reverse-transcriptase-polimerase-chain-reaction (PCR) assays from nasopharyngeal swab specimens. All patients had imaging features for COVID-19 pneumonia. The clinical outcome was the development of a persistent increase in BP (as defined by BP values ≥ 140 mmHg systolic or 90 mmHg diastolic for at least two consecutive days) requiring a new or intensified anti-hypertensive treatment during hospitalization [17]. A control group of patients with bacterial pneumonia (diagnostic tests for SARS-CoV-2 infection were negative along the entire hospitalization period) was also enrolled and used to analyze the differences in BP with COVID-19 pneumonia. Notably, age, BP at admission, main clinical features and in-hospital management, demographic data, and prevalence of risk factors and comorbidities were similar between cases with COVID-19 pneumonia and controls with bacterial pneumonia. Systolic (126 vs 118 mmHg, p = 0.016) and diastolic (79 vs 70 mmHg, p<0.0001) BP values recorded during the acute phase were significantly different between the two groups. Overall, a persistent increase in BP was detected in 28 patients. Specifically, 25 and 3 patients met the primary endpoint among COVID-19 and bacterial pneumonia, respectively (p = 0.001). Estimating the effects of covariates with multivariable regression models, COVID-19 pneumonia was associated with a 7-fold higher risk of uncontrolled hypertension when compared with bacterial pneumonia (OR: 6.99; 95% CI: 1.89 to 25.80; p = 0.004), even after adjustment for confounders (Fig. 1 ).Fig. 1 Probability of persistent raise in BP during hospitalization for COVID-19 according to type of pneumonia, age, and number of comorbidities (see text for details). Legend: BP=blood pressure.
Fig 1
Results of the aforementioned clinical studies support the notion that a significant increase in BP may be used to identify patients at increased risk of adverse outcome when recorded in the early phase of hospitalization. Indeed, the development of severe forms of COVID-19 may be linked to hypotension, as recorded during acute heart failure, myocardial infarction, and arrhythmias. Other clinical conditions (including fever, dehydration, acute kidney injury, in-hospital over-infections, weight loss, physical inactivity, and acute respiratory failure) may affect BP values [9,13,31].
3 Raise in blood pressure following COVID-19 vaccination
After the first report by Meylan and co-workers who described a case series of 9 patients (8 were symptomatic) with stage III hypertension following COVID-19 vaccination [32], a number of studies evaluated the rate of increased BP as potential adverse reaction to vaccination.
Sanidas and co-workers [33] evaluated the effects of COVID-19 vaccination on BP in patients with history of controlled hypertension (defined as systolic/diastolic BP <140/90 mmHg) and healthy controls. Overall, 100 patients were enrolled [33]. All patients had BP measurements (both home and ambulatory) between the 5th and the 20th day after fully COVID-19 vaccination [33]. Patients with history of controlled hypertension showed a mean home and 24-h ambulatory BP equal to 175/97 mmHg and 177/98 mmHg, respectively [24]. Moreover, healthy controls showed a home BP of 158/96 mmHg and a 24-h ambulatory BP equal to 157/95 mmHg [33].
Ch'ng and coworkers [34] evaluated 4906 healthcare workers, recording BP when the staff members arrived at the vaccination site, immediately after vaccination, and 15–30 min later. Mean pre-vaccination systolic/diastolic BP was 130.1/80.2 mmHg and the mean changes after vaccination were +2.3/+2.4 mmHg for systolic/diastolic BP [34].
Pharmacovigilance databases were also used to evaluate this phenomenon, showing proportions of abnormal or increased BP after vaccination ranging from 1% to 3% [35], [36], [37]. Among these, a retrospective analysis involving 21,909 subjects, exhibited the largest proportion of this phenomenon [38]. Specifically, Bouhanick and co-workers investigated the BP profile of vaccinated patients and healthcare workers after the first and the second dose of COVID-19 vaccine [38]. Overall, 8121 subjects (37%) exhibited systolic and/or diastolic BP above 140 and/or 90 mmHg after the first dose. Interestingly, the majority (64%) of subjects with abnormal BP after the first injection showed a persistent abnormal BP after the second one [38].
Surveys specifically designed to evaluate BP changes following vaccination showed an incidence of raise in BP after COVID-19 vaccination ranging from 1% to 5% (5% in the analysis by Tran and co-workers [39] and Zappa and co-workers [40], and about 1% among subjects enrolled in the study by Syrigos and co-workers [41]). Just recently, Simonini and co-workers evaluated data from a large cohort of 1866 vaccinated healthcare workers [42]. They documented a BP increase in 153 subjects (8%) [42]. BP alterations presented with greater frequency at the 2nd or booster dose [42]. Furthermore, in 39 subjects (2%) a diagnosis of hypertension was done after vaccination, and among subjects already on antihypertensive therapy, 11% had to increase therapy [42]. The same Authors also recorded a significant proportion (4%) of subjects reporting a decrease in BP [42]. Nonetheless, the lack of definition and magnitude of BP decrease does not permit to evaluate the influence of conditions such as masked hypertension [42].
A systematic overview and meta-analysis including 6 studies (for a total of 357,387 subjects and 13,444 events) showed a pooled estimated proportion of abnormal/increased BP after vaccination equal to 3.91% (95% CI: 1.25 – 11.56, Fig. 2 – upper panel). A similar pooled proportion (3.20%; 95% CI: 1.62 – 6.21) was computed after the exclusion of 2 studies identified as statistical outliers (Fig. 2, lower panel) [21]. Notably, the proportion of cases of clinically significant increase in BP (stage III hypertension, hypertensive urgencies, and hypertensive emergencies) was 0.6% [21].Fig. 2 Proportions of increased BP after vaccination in a meta-analysis of 6 studies, for a total of 357,387 subjects and 13,444 adverse events [21].
Fig 2
4 Mechanisms
4.1 The role of ACE2
Although hypertension seems to be linked to the pathogenesis of COVID-19 and acute elevations in BP during the acute phase of infection seem to be related with SARS-CoV-2 replication [14], the exact mechanism is still debated.
The failure of the counter-regulatory RAS axis, characterized by the decrease of generation of the protective Angiotensin1,7 (Ang1,7) and ACE2 receptors expression [43], [44], [45], appears to be the most relevant causative mechanism implicated in the raise of BP and worse outcome of COVID-19 [46], [47], [48], [49], [50]. Indeed, recent investigations demonstrated the development of an “Angiotensin II storm” [51] or “Angiotensin II intoxication” [52] during the acute phase of SARs-CoV-2 infection [10,16,46,47,53,54].
It is well recognized that the virus entry into cells is mediated by the efficient binding of the Spike (S) protein (which comprises S1 and S2 subunits) to ACE2 receptors (Fig. 3 ) [49,55]. ACE2 receptors are ubiquitary expressed in human tissues [56] and they are composed by 805 amino acids. ACE2 are responsible for the cleavage (using a single extracellular catalytic domain) of an amino acid from Ang I to form Ang1,9 and to remove an amino acid from Ang II to form Ang1–7 (Fig. 4 ) [57].Fig. 3 Steps of SARS-CoV-2 entry process. The main step after the invasion of SARS-CoV-2 is binding to membranal ACE2 receptor; see text for details. Legend: ACE2=angiotensin-converting enzyme 2 receptor.
Fig 3
Fig. 4 Angiotensin1,7 formation. Angiotensin1,7 is formed by the action of the angiotensin-converting enzyme 2 (and other angiotensinases, including POP and PRCP) by the cleavage of an amino acid from Angiotensin II. Legend: ACE2=angiotensin-converting enzyme 2 receptor; POP=prolyl oligopeptidase; PRCP=prolyl carboxypeptidases.
Fig 4
ACE2 downregulation/internalization, and malfunction predominantly due to viral occupation (as mediated by the binding between S proteins and ACE2), dysregulates the protective RAS axis with reduced formation of Ang1,7 and increased generation and activity of Ang II (Fig. 5 ) [46], [47], [48].Fig. 5 The effect of binding of the Spike protein to ACE2 on the dysregulation of the renin-angiotensin system with increased generation and activity of Ang II (loss of ACE2 activity). Legend: ACE2=angiotensin-converting enzyme 2 receptor; Ang=angiotensin.
Fig 5
Notably, Ang II is directly involved in BP regulation and inflammatory pathways (which are both disturbed in COVID-19 [58], [59], [60]), and the imbalance between Ang II and Ang1–7 can directly contribute to development of high BP in the acute phase of SARS-CoV-2 infection [19].
In this context, Wu and co-workers demonstrated a significant raise in Ang II levels among COVID-19 patients [61]. More specifically, they evaluated whether the plasmatic activity of Ang II is dysregulated in COVID-19 patients. They demonstrated increased Ang II levels in the majority (90%) of COVID-19 patients, and a direct association between plasma Ang II levels and COVID-19 severity [61].
Similar results were obtained in the aforementioned study by Chen and co-workers [30].
Furthermore a clinical study investigating disease severity in SARS-CoV-2 infected patients, found that plasmatic Ang II levels were significantly increased and linearly associated with lung damage and viral load [62].
The picture is further complicated analyzing the phenomenon of raised BP following COVID-19 vaccination. However, a “Spike Effect” similar to that observed during the infection of SARS-CoV-2 may be postulated.
Recent observations demonstrated that S proteins produced upon vaccination have the native-like mimicry of SARS-CoV-2 S protein's receptor binding functionality and prefusion structure [20,63]. Free-floating S proteins released by the destroyed cells previously targeted by COVID-19 vaccines may interact with ACE2 receptors of other cells, thereby promoting degradation, internalization, and loss of catalytic activities of ACE2 receptors [20,64]. These mechanisms may enhance the imbalance between Ang II overactivity and Ang1–7 deficiency, contributing to an increase in BP (Fig. 6 ) [40,65].Fig. 6 Schematic mechanism of action of COVID-19 vaccines and their potential cardiovascular effects throughout the interaction between free-floating Spike proteins and ACE2 receptors. Legend: ACE2=angiotensin-converting enzyme 2 receptor; SARS-CoV-2= severe acute respiratory syndrome coronavirus-2.
Fig 6
The role of RAS in the biology of COVID-19 support the hypothesis that its pharmacological modulation may favorably impact organ dysfunction and illness severity. After the concern at the beginning of the pandemic on the susceptibility to infection and disease severity enhanced by ACE-inhibitors (ACE-Is) and angiotensin type-1 receptor blockers (ARBs) [66], some reports provided data on the potential benefit of angiotensin receptor modulators in COVID-19 [67], [68], [69]. Just recently, a prospective study specifically tested the prognostic value of exposure to RAS modifiers among 566 hypertensive patients with COVID-19 [54]. During hospitalization 66 patients died and exposure to RAS modifiers was associated with a significant reduction (−46%, p = 0.019) in the risk of in-hospital mortality when compared to other BP-lowering strategies [54]. Exposure to ACE-Is was not significantly associated with a reduced risk of in-hospital mortality when compared with patients not treated with RAS modifiers; conversely, ARBs users showed a 59% lower risk of death (p = 0.016) even after allowance for several prognostic markers [54]. Furthermore, the discontinuation of RAS modifiers during hospitalization did not exert a significant effect (p = 0.515) [54].
Nonetheless, recent randomized trials consistently show neither benefit nor harm from inhibition of RAS [70], [71], [72]. Of note, these trials were conducted in patients with early, mild, or moderate disease and the role of RAS modulation in critically ill COVID-19 remains to be evaluated [70], [71], [72].
4.2 The role of other angiotensinases
In the last few years, other Ang1,7 forming enzymes have been identified [59]. To date, the Ang II-Ang1,7 axis of the RAS includes three carboxypeptidases forming by cleavage Ang1,7 from Ang II: ACE2, prolyl oligopeptidase (POP), and prolyl carboxypeptidases (PRCP) [59]. Specifically, POP cuts at the C-side of an internal proline and cleaves Ang I to form Ang1,7, and Ang II to form Ang1,7 [59,[73], [74], [75]]; similarly, PRCP cleaves the C-terminal amino acid of Ang II [76]. Notably, ACE2 is the main enzyme responsible for Ang II formation in the kidney; Ang1,7 formation in the lungs and circulation is mainly POP-dependent [59]; conversely, PRCP is ubiquitously expressed [77,78], regulating inflammation, oxidative stress, thrombosis, and vascular homeostasis [79], [80], [81] by stimulating the release of nitric oxide and prostaglandin [80,82,83].
Several experimental and clinical studies supported the detrimental role of POP and PRCP deficiency on BP. The genetic absence of POP directly affects BP response (due to the diminished Ang II degradation and Ang1,7 formation) [59,84] and the PRCP gene variant promotes disease progression in hypertensive patients [85]. Finally, PRCP depletion contributes to vascular dysfunction with hypertension and arterial thrombosis [86].
As aforementioned, phenotypes of ACE2 deficiency [43], [44], [45] (including older age, hypertension, diabetes, and previous vascular events) are associated with an increased risk of worse outcome in COVID-19 [1,9,12,[87], [88], [89], [90], [91]]. Conversely, accrued data on the RAS show that aging, inflammation, atherosclerosis, and the development of atherosclerotic risk factors and cardiovascular events are associated with an increased plasmatic activity of POP and PRCP [92,93]. Experimental and clinical studies demonstrated a significant positive association between POP/PRCP and several metabolic and cardiovascular parameters (including blood glucose, body mass index, body weight, and amount of total, visceral and subcutaneous abdominal adipose tissue) [94,95]. Furthermore, intraplaque PRCP levels are upregulated in unstable atherosclerotic plaques compared with stable plaques [96].
In other words, in the cardiovascular disease continuum (from atherosclerosis and cardiovascular risk factors to the development of cardiovascular events) specific changes of angiotensinanes levels exists [97]: in the disease continuum ACE2 activities decrease, whereas PRCP and POP levels increase from the health status to advanced deterioration of the cardiovascular system.
4.2.1 SARS-CoV-2 infection
In the specific area of BP regulation, POP and PRCP may play a specific role in COVID-19 [58], [59], [60]. Indeed, the activities of POP and PRCP remain substantially unchanged during the acute phase of SARS-CoV-2 infection, therefore failing to limit the accumulation of Ang II by ACE2 downregulation and malfunction. A clinical study by Bracke and co-workers investigated the plasma activities of PRCP and POP among patients at the time of hospital admission or during their hospital stay for COVID-19 [98]. The Authors documented that PRCP activity remained stable during hospitalization and did not differ from PRCP activity recorded in healthy controls. Finally, they also supported the recent hypothesis [99] that the elevated POP levels observed in plasma of patients COVID-19 originates from cell damage due to acute lung injury or organ failure [98].
4.2.2 COVID-19 vaccination
Loss of the catalytic activities of ACE2 due to the interaction between these receptors and free-floating S proteins is documented across all the strata of the cardiovascular disease continuum [19,20]. On the other hand, an increased catalytic activity of POP and PRCP is not observed in the young, but more typically pronounced in elderly subjects with comorbidities or previous cardiovascular events.
Thus, the potential adverse reactions to COVID-19 vaccination associated with Ang II accumulation (including increase in BP, enhanced inflammation, and thrombosis) are reasonably expected to be more common in younger and healthy subjects (Fig. 7 , right panel) [19,20]. Conversely, older age, presence of comorbidities and previous cardiovascular events identify phenotypes at lower risk of adverse events (Fig. 7, left panel).Fig. 7 Adverse reactions to COVID-19 vaccination associated with Ang II accumulation. Older age, presence of comorbidities and previous cardiovascular events identify phenotypes at lower risk of adverse events (left panel).Younger and healthy subjects are phenotypes at increased risk of adverse events (right panel). Legend: ACE2=angiotensin-converting enzyme 2 receptor; Ang=angiotensin; CV=cardiovascular; POP=prolyl oligopeptidase; PRCP=prolyl carboxypeptidases; SARS-CoV-2= severe acute respiratory syndrome coronavirus-2.
Fig 7
This potential mechanism is supported by recent clinical and epidemiological studies evaluating the development of adverse events after COVID-19 vaccination.
In a prospective survey of 113 healthcare workers who received COVID-19 vaccine [40], 6 subjects (5.3%) developed an increase in systolic or diastolic BP at home ≥ 10 mmHg during the first five days after the first dose of the COVID-19 vaccine when compared with the five days before the vaccine. Of note, age of patients with uncontrolled hypertension following COVID-19 vaccination ranged from 35 to 52 years [40].
Similarly, Tran and co-workers [39] demonstrated that age of vaccinated subjects was a significant predictor of increased BP after COVID-19 vaccination, as the increase of age was associated with the decrease of this adverse event [39].
In a study published in JAMA Internal Medicine, Simone and co-workers evaluated the incidence of acute myocarditis and clinical outcomes among adults following mRNA vaccination in an integrated health care system in the US (Kaiser Permanente Southern California members) [100]. Among subjects who received COVID-19 mRNA, 54% were women and median age was 49 years [100]. The Authors identified 15 cases of post-vaccination myocarditis (2 after the first dose and 13 after the second) [100]. Of note, all cases occurred in men with a median age of 25 years [100].
Among 530 cases of myocarditis reported after COVID-19 vaccination to Vaccine Adverse Events Reporting System, approximately 65% of subjects were aged 12–24 years [101].
Schultz and co-workers reported findings in five patients in a population of more than 130,000 vaccinated persons who presented with venous thrombosis and thrombocytopenia after receiving the first dose of COVID-19 vaccine (ChAdOx1 nCoV-19 adenoviral vector vaccine) [102]. The patients were health care workers who were 32 to 54 years of age [102].
Similarly, other reports found that subjects with vaccine-induced immune thrombotic thrombocytopenia (VITT) were younger [103,104].
Finally, in a report from the Advisory Committee on Immunization Practices, rates of VITT were similar between males and females in most age brackets, with the exception of females ages 30 to 49 years, in whom rates were higher [105].
5 Conclusions
Recent clinical and experimental advances in the pathophysiology of SARS-CoV-2 infection support the notion that the interaction of the virus (mediated by S proteins) with ACE2 receptors exerts a pivotal role in the development of severe disease [47,53,106,107].
Recent findings further expanded our knowledge on the deleterious effect of Ang II accumulation. Downregulation and internalization of ACE2 receptors (due to viral occupation), and malfunction of other angiotensinases, dysregulates the protective RAS axis with increased generation and activity of Ang II and reduced formation of Ang1,7 [46], [47], [48].
Of note, Ang II plays key roles in BP homeostasis, including the heart, kidney, blood vessels, adrenal glands, and cardiovascular control centres in the brain [108]. Thus, the negative effect of SARS-CoV-2 on BP during and after the acute phase of infection is not entirely unexpected [17].
In this context, the association between increased levels of Ang II and increased BP during hospitalization for COVID-19 support this mechanism. Uncontrolled hypertension during the course of the disease can acutely worsen hypertension-mediated organ damage and adverse outcomes [16]
A similar mechanism has been recently proposed to explain the raise in BP following COVID-19 vaccination [19,20,109]. In other words, the resulting features of COVID-19 vaccination resemble those of active COVID-19 disease.
When vaccinated cells die or are destroyed by the human immune system, the debris may release a large amount of free-floating S proteins [20]. Having the native-like mimicry of SARS-CoV-2 S protein's receptor binding functionality and prefusion structure, S proteins produced upon vaccination may interact with ACE2 receptors, causing internalization, degradation [19,20], and loss of ACE2 activities.
These mechanisms may lead to less Ang II inactivation and Ang1,7 generation, with consequent Ang II overactivity which may trigger a variable raise in BP [46], [47], [48].
Stress response (white-coat effect) and the role of some excipients might explain the high prevalence of increased BP values recorded immediately after vaccination [21,32]. However, data from surveys and pharmacovigilance databases which expanded the observation some days after vaccination demonstrated that a persistent raise in BP after COVID-19 vaccination is not unusual [21,40]. Further research taking into account the potential effects of confounders and long-term clinical data are urgently needed in this area.
✰ None of the authors of this study has financial or other reasons that could lead to a conflict of interest.
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| 0 | PMC9744686 | NO-CC CODE | 2022-12-15 23:17:55 | no | Eur J Intern Med. 2022 Dec 13; doi: 10.1016/j.ejim.2022.12.004 | utf-8 | Eur J Intern Med | 2,022 | 10.1016/j.ejim.2022.12.004 | oa_other |
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Res Pract Thromb Haemost
Res Pract Thromb Haemost
Research and Practice in Thrombosis and Haemostasis
2475-0379
Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis.
S2475-0379(22)02184-7
10.1016/j.rpth.2022.100009
100009
Original Article
Immune thrombocytopenia and COVID-19 vaccination: outcomes and comparisons to pre-pandemic patients
Young-Ill Choi Philip MBBS, PhD 12∗
Hsu Danny MBBS 34
Tran Huyen Anh MBBS, PhD 5
Tan Chee Wee MBBS, PhD 67
Enjeti Anoop MBBS, PhD 8
Yee Chen Vivien Mun MBBS, PhD 9
Merriman Eileen MBBS, PhD 10
Yong Agnes S.M. MBBS, PhD 1112
Simpson Jock MBBS 13
Gardiner Elizabeth PhD 2
Cherbuin Nicolas PhD 14
Curnow Jennifer MBBS, PhD 1516
Pepperell Dominic MBBS 17
Bird Robert MBBS 18
1 The Canberra Hospital, Canberra, ACT, Australia
2 John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
3 Liverpool Hospital (NSW Health Pathology), Liverpool, NSW, Australia
4 University of NSW, Australia
5 The Alfred Hospital, Melbourne, VIC, Australia
6 Royal Adelaide Hospital, SA Pathology, Adelaide, SA, Australia
7 University of Adelaide, Adelaide, SA, Australia
8 Calvary Mater Hospital, Newcastle, NSW, Australia
9 ANZAC Research Institute, University of Sydney, NSW, Australia
10 Waitemata DHB, Department of Haematology, New Zealand
11 Department of Haematology, Royal Perth Hospital, Perth, WA, Australia
12 School of Medicine, The University of Western Australia, Perth, WA, Australia
13 Port Macquarie Base Hospital, NSW, Australia
14 National Centre for Epidemiology and Population Health, Australian National University, Canberra, ACT, Australia
15 Westmead Hospital, Sydney, NSW, Australia
16 Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
17 Fiona Stanley Hospital (PathWest), Murdoch, WA, Australia
18 Princess Alexandra Hospital, Brisbane, Queensland, Australia
∗ Corresponding author: Dr Philip Choi, BA BSc(Med) MBBS PhD FRACP FRCPA, Senior Staff Specialist, Haematology Department, Canberra Region Cancer Centre, Level 5, Building 19, The Canberra Hospital, Yamba Drive, Garran, ACT 2605, Phone +612 5124 8444; Fax +612 5124 5544;
13 12 2022
13 12 2022
10000930 6 2022
1 10 2022
7 10 2022
© 2022 Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Background
Immune thrombocytopenia (ITP) has been reported following COVID-19 vaccination. After index case fatalities, there was concern amongst patients both with and without a prior history of ITP in Australia.
Objectives
Describe treatment outcomes of ITP after COVID-19 vaccination, and compare relapsed vs historical pre-COVID-19 ITP cohorts.
Methods
We collected ITP cases in Australia within six weeks of receiving any COVID-19 vaccination as part of primary vaccination (up to 17th October 2021). Secondly, we reviewed platelet charts in a historical ITP cohort to determine whether platelet variability was distinct from relapsed ITP after vaccination.
Results
We report on 50 cases (37 de novo, 13 relapsed ITP) vaccinated 22nd March 2021 to 17th October 2021. Although there was one fatality, bleeding was otherwise mostly minor: (70%) WHO <2. De novo ITP was more likely after ChAd (89%) than BNT (11%). Most patients responded quickly: median 4 days, complete response 40/45 (89%).Historical cohort - only six of 47 patients exhibited platelet variability (>50% fall and platelets <100x109/L), but median platelet nadir was significantly higher than vaccination relapse (27 vs 6x109/L, P=0.005**).
Conclusions
ITP was more frequently reported after ChAd than BNT vaccination. Standard ITP treatments remain highly effective for de novo and relapsed ITP (96%). Although thrombocytopenia can be severe after vaccination, bleeding is usually mild. Despite some sampling bias, our data does not support a change in treatment strategies for ITP patients after vaccination.
Keywords
Immune Thrombocytopenia
ChAdOx1 nCov-19
BNT162 Vaccine
COVID-19 Vaccines
Treatment Outcome
Vaccination
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pmcEssentials
1. Immune thrombocytopenia (ITP) has been reported after COVID-19 vaccinations.
2. Fifty cases of ITP post vaccination were reviewed for distinguishing features and treatment outcomes.
3. Most cases (36/50) in our study presented after first dose ChAdOx1 (AstraZeneca) vaccination.
4. ITP after vaccination presents with infrequent bleeding and responds well to conventional treatments.
| 0 | PMC9744687 | NO-CC CODE | 2022-12-15 00:01:53 | no | Res Pract Thromb Haemost. 2022 Dec 13;:100009 | utf-8 | Res Pract Thromb Haemost | 2,022 | 10.1016/j.rpth.2022.100009 | oa_other |
==== Front
Journal of Hazardous Materials Advances
2772-4166
2772-4166
The Author(s). Published by Elsevier B.V.
S2772-4166(22)00173-5
10.1016/j.hazadv.2022.100217
100217
Article
Mega-scale desalination Efficacy (Reverse Osmosis, Electrodialysis, Membrane Distillation, MED, MSF) during COVID-19: Evidence from salinity, pretreatment methods, temperature of operation
Parsa Seyed Masoud ⁎
Centre for Technology in Water and Wastewater, School of Civil and Environmental Engineering, University of Technology Sydney, Sydney, NSW 2007, Australia
⁎ Corresponding author
13 12 2022
13 12 2022
100217© 2022 The Author(s). Published by Elsevier B.V.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
The unprecedented situation of the COVID-19 pandemic heavily polluted water bodies whereas the presence of SARS-CoV-2, even in treated wastewater in every corner of the world is reported. The main aim of the present study is to show the effectiveness and feasibility of some well-known desalination technologies which are reverse osmosis (RO), Electrodialysis (ED), Membrane Distillation (MD), multi effect distillation (MED), and multi stage flashing (MSF) during the COVID-19 pandemic. Systems’ effectiveness against the novel coronavirus based on three parameters of nasopharynx/nasal saline-irrigation, temperature of operation and pretreatment methods are evaluated. First, based on previous clinical studies, it showed that using saline solution (hypertonic saline >0.9% concentration) for gargling/irrigating of nasal/nasopharynx/throat results in reducing and replication of the viral in patients, subsequently the feed water of desalination plants which has concentration higher than 3.5% (35000ppm) is preventive against the SARS-CoV-2 virus. Second, the temperature operation of thermally-driven desalination; MSF and MED (70-120°C) and MD (55-85°C) is high enough to inhibit the contamination of plant structure and viral survival in feed water. The third factor is utilizing various pretreatment process such as chlorination, filtration, thermal/precipitation softening, ultrafiltration (mostly for RO, but also for MD, MED and MSF), which are powerful treatment methods against biologically-contaminated feed water particularly the SARS-CoV-2. Eventually, it can be concluded that large-scale desalination plants during COVID-19 and similar situation are completely reliable for providing safe drinking water.
Graphical abstract
Image, graphical abstract
Keywords
Water Desalination
Novel Coronavirus
SARS-CoV-2
Environmental Contamination
Nasopharynx Irrigation
Viral Inactivation
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pmc1 Introduction
In the light of emerging the novel coronavirus form the beginning of 2020, the public health (at the forefront of this battle) was not the only sector which adversely affected but other sectors are severely get under pressure. Apparently, the huge environmental barriers as the results of the pandemic are one of these side effects which elucidated from different aspects from air/water/soil pollution to plastic wastes (Rume and Islam, 2020, Saadat, Rawtani, and Mustansar, 2020). However, direct and indirect effects of contaminating water bodies via SARS-CoV-2 is more concerning and more dangerous since it directly related to the human health from different aspects, because the viral RNA is release to the environment through wastewater and it can be remain viable from days to weeks. Importantly, presence of the SARS-CoV-2 in water bodies would be threatening for millions of people who rely on water treatment and desalination systems to provide their drinkable water needs. In the context of providing safe drinking water with small-scale desalination systems such as solar distillations from biologically contaminated water a limited number of efforts have been made to realize the effectiveness of them (particularly small-scale systems) against pathogens (Malaeb et al., 2017). Ayoub et al. (Ayoub, Dahdah, and Alameddine, 2015) examine the possibility of cross contaminating two pathogens of Escherichia coli and Enterococcus faecalis in desalination units to distilled water for different temperature ranges of 40-45°C and 50-55°C. The results of indoor experiments revealed that both pathogens are transmitted via vapor from desalination unit to the distilled water. Similarly, transfer of three other pathogens of Klebsiella pneumonia, Escherichia coli and Enterococcus faecalis in analogous solar desalination units in the absence of solar UV were examined to understand the mechanism of pathogens transfer through three parameters of water temperature (30-50°C), pathogens’ particle size, and type of sample water (Ayoub et al., 2014). The findings revealed that all pathogens are capable to transmit via vapor of desalination units while the highest rate of transfer occurred at 40°C. Furthermore, it was showed that particle size has direct effect on the pathogens transmission in which Enterococcus faecalis (particle size < 1µm) has the highest concentration in distilled water. However, the aforementioned studies focused on the bacteria rather viruses. Recently, Parsa (Parsa, 2021), presented a theory on the possibility of novel coronavirus (SARS-CoV-2) transmission via vapor of solar desalination units and concluded that under the most of conditions in various types of solar desalination configurations the novel coronavirus would be transfer via vapor to the collected droplets. As our main focus in this review is the novel coronavirus in desalination plant rather than other pathogens (because of the SARS-CoV-2 virus is greatly impacted various sectors of environment) one crucial question that should be answered is arise here; Is it possible to be infected by the novel coronavirus if it exist in the drinking water? In another word: Does presence of the SARS-CoV-2 in consumable water of people dangerous and threatening? To answer this vital question we need to know that the main transmission route of any disease is not the only way to result in infection but other routes are completely plausible. Numerous instances for transmission via off-centered routes are reported. Transmission via an off-centered route for a number of pathogens such as Ebola virus (Petrosillo et al., 2015, Vetter et al., 2016, Lalle et al., 2019), Vibrio Cholera (Kjær et al., 2020), Influenza A (Hinshaw, Webster, and Turner, 1979) to name a few is reported. Interestingly, the risk of infection by contaminated water during the ongoing pandemic is also suggested in numerous studies. In a broader prospect, the first detection of SARS-CoV-2 in gastrointestinal tract rise many concerns about another route of spreading the virus called fecal-oral transmission (Xiao et al., 2020) whereas using numerical methods such as QMRA elucidated and further boosted the potential transmission of the virus via water media to human (Tyagi, Gurian, and Kumar, 2022). Importantly, Bilal et al. (Bilal et al., 2020) brought the potential of water matrices as the source of SARS-CoV-2 transmission into the spotlight and concluded that various water matrices including groundwater and drinking water resources should be safe (particularly from SARS-CoV-2) enough in order to prevent another route of the virus spreading to human. Shutler et al. in a preprint (Shutler et al., 2020) put one step forward and proposed that there is no substantial difference in virus temporal survival and infection risk between freshwater and seawater whereas gathering data from 39 countries showed that considering SARS-CoV-2 as the waterborne disease to the human via rivers is serious concern (Shutler et al., 2021). Jiao et al. (Jiao et al., 2021) in a non-human model proved that the gastrointestinal tract can be considered as a transmission route of the SARS-CoV-2. Surprisingly, in a recent study published in Nature Communication, Giobbe et al. (Giobbe et al., 2021) showed that SARS-CoV-2 virus can efficiently replicated in stomach of persons and leading to infections. Conclusively, due to the infection of gastric epithelium they concluded that the virus play an important role in fecal-oral transmission. Although many studies highlighted the effectiveness of various pretreatment methods such as ozonation, UV, chlorination, electrochemical process (Zahmatkesh, Amesho, and Sillanpää, 2022, Zahmatkesh and Sillanpää, 2022), mix matrix membrane (Zahmatkesh, Rezakhani, and Gholamzadeh, 2023) and biological treatment such as algae-based methods in wastewater treatment plants (Zahmatkesh and Pirouzi, 2020), the number of researches in the context of large-scale desalination plants during the ongoing pandemic is rare and those limited studies that could be related to the desalination technologies is focused on the role of some of the pretreatment methods against SASR-CoV-2. Nevertheless, some researches have been performed in the context of thermal desalination technologies by focusing on the use of nanomaterial as antibacterial agents for biological contamination, but they limited to the small-scale desalination (Parsa et al., 2020) system and the feasibility for large-scale plants has not been realized.
Thus, the main aim of this review is to realize the effectiveness of different desalination technologies for providing safe drinking water during the COVID-19 pandemic. To do this we are about to evaluate reliability of large-scale desalination technologies via three parameters which are effect of feed water salinity, temperature of operation, and various pretreatment methods that used in desalination technologies. Regarding the interdisciplinary approach of the review and to realize the main goal of study, the paper organized in several sections to follow a rational path in order to easily comprehend by readers in the field.
1.1 The road map of present study
As it mentioned above the present study separated in several section due to the multidisciplinary nature of the topic. Since the main route of entering biological contamination to water resources is wastewater, in the first section, contamination of water bodies via wastewater is briefly discussed. Afterwards, this section followed by presence and survival of the different viruses as well as SARS-CoV-2 in seawater because large-scale desalination technologies mainly used huge water bodies like seawater. In the next section mechanism and characteristics of NACL solution as an antiviral agent is discussed and it followed by more discussion on effectiveness of nasopharynx saline irrigation against the novel coronavirus. The aim of this section is to elucidate the sensitivity of the novel coronavirus to salinity (in different concentration) because the feed water of desalination plants is saline. In the next step principle of desalination plants briefly explained. It should be mentioned that an in-depth and detailed technical discussion about desalination plants was not performed in this section because the aim is to highlight the important principle of systems such as temperature of operation. In the next section various types of pretreatment methods associated with desalination plants are presented. Finally, in the last section, reliability of mega-scale desalination plants in providing safe drinking water regarding three aforementioned parameters which are temperature of operation, salinity of feed water, and pretreatment methods thoroughly discussed.
2 Contamination of water bodies
Human activities have a drastic effect on the aquatic environment whether on water bodies or biodiversity of a certain type of aquatic animals (Su et al., 2021). Although one third of the world's population lived in vicinity of rivers/banks/ floodplains, variety of environmental contaminations through the anthropogenic activities forced to these regions. Water bodies contaminated via different sources but the two most important factors that paly the key roles are the nutrients and pathogens produced (i.e. various bacteria, viruses, etc.) by human wastes. The origination of these pollutions are varied but wastewater is known as one of the major reasons that lead to these two source of contaminations (Best, 2019). The critical role of wastewater in contamination of water bodies stepped more into the spotlight when we consider that some of the huge transcontinental rivers and basins in the world such as Ganges, Amazon, Congo, Parana, Nile, Yenisey, Lena, Zambezi, Niger, Amur, Indus, Mekong, and Salween are polluted by various pathogens of wastewater (Transboundary River Basins: Status and Trends (UNEP-DHI, UNEP, TWAP, 2016) 2016). Figure 1 a-b shows various routes of contaminating water bodies during the pandemic.Figure 1 (a) The likelihood of COVID-19 contaminating the urban and rural water cycle with potential human exposure (Bhowmick et al., 2020). (b). Transmission routes of SARS-CoV-2 virus to natural water bodies. WWTP = Wastewater treatment plant (Yusoff et al., 2021). Figures reprinted from open sources
Figure 1
2.1 Seawater contamination by various wastewater sources
Oceans and seawaters are subjected to contaminate by sewages and urban/industrial/hospital wastewaters in recent years. These contaminations are more prevalent in developing countries where there are not effective sanitation networks. However, the problem of contamination by wastewater in some of the industrialized countries with developed economy is reported too (Parsa et al., 2021). Numerous examples of contaminating seawater and ocean throughout the world were reported. Contamination of Venezuela's center coastal in the Caribbean region by two different protozoa is scrutinized (Betancourt et al., 2014). Improper residential waste management, discharging sewage, wastewater, and ineffective sewer system are introduced as the main reasons of pollution. Furthermore, contamination of Tunisia coastlines in the Mediterranean Sea by industrial and domestic wastewater is observed (Houda et al., 2011). Also, it was reported that pharmaceutical/hospital and urban wastewater is the source of pollution in the Mahdia coastline in the Mediterranean Sea region (Afsa et al., 2020). Over 500 sewage-derived contaminations in the Atlantic Ocean due to urban wastewater were reported by Pablo and co-workers. They declared that these contaminations are identified at 50 Km far away from the shoreline and in the depth deeper than 500 m. This surprising findings revealed the fact that contaminations of water bodies not only adversely impacted the costal lines but in a massive water body such as the Atlantic Ocean various type of contaminations are detected at such distances and depths too (Lara-Martín et al., 2020). The other pollution path of oceans and seawater is through indirect via contaminated surface water and groundwater by wastewater and sewage. It is interesting to be noted that contamination of natural water bodies (that many of them can connected with the huge water resources such as seawater and oceans) (Kumar et al., 2021, Buonerba et al., 2021), rivers (Shutler et al., 2021), groundwater (Huo et al., 2021), and freshwater environment (Mahlknecht et al., 2021) via the SARS-CoV-2 are disclosed.
2.2 Presence of viruses in seawater
Coastlines and seawater always subjected to enter various types of microorganisms and pathogens such as bacteria, fungi, and viruses (Santhiya et al., 2011). Presence of different types of viruses in aquatic environment has been extensively explained in plenty of studies. However, a brief discussion about various types of these pathogens in seawater is presented. The most well-known viruses that have high potential for waterborne outbreak in human are Rotavirus, Calicivirus, Astrovirus, and some enteric adenoviruses (Leclerc, Schwartzbrod, and Dei-Cas, 2002). Leveque et al. warned about transmitting of enteroviruses to human by swimming in contaminated seawater (Leveque and Laurent, 2008) while Aller expressed the upper layer of sea (micro-layer) as the source of viruses and bacteria that enrich marine aerosols (Aller et al., 2005). Rebollo et al. examined the persistence of Lymphocystivirus in different types of seawater for temperature range of 18-22°C. Findings showed that the virus can remain viable between 2-242 days depending on the type of water media and temperature (Leiva-Rebollo et al., 2020). Dancer et al. also reported human Norovirus under simulated cold season conditions (temperature at 8°C and available UV 1 mW/cm2) can tolerated up to 140 hours (Dancer et al., 2010) whereas Tsai et al. declared that Poliovirus in seawater at both low and room temperatures (i.e., 4 and 23°C) is detected after three weeks (Tsai, Tran, and Palmer, 1995). Contaminated samples of seawater of various viruses including Hepatitis A, poliovirus and somatic Salmonella bacteriophages from different coastal sites in California, Hawaii, and North Carolina were collected by Callahan and co-workers. Their findings revealed that 4log10 reduction of Hepatitis A, poliovirus and somatic salmonella bacteriophages was achieved by around 4, 1, and 10 weeks respectively (Callahan, Taylor, and Sobsey, 1995). Furthermore, it was disclosed that Hepatitis A viruses in synthetic seawater at temperature of 4, 19, and 25°C remains stable by around 92, 24, and 11 days respectively (Crance et al., 1998). Dale et al. reported haemorrhagic septicaemia virus (HSV) outbreak in seawater that results in death of rainbow trout species in Norwegian sea (Dale et al., 2009) while Weli et al. examined the presence of salmonid Alphavirus in Norwegian sea in Oslofjord (Weli et al., 2021). Also Griffin et al. (Griffin et al., 2000) realized that more 90% of canals and near waters from 19 locations that poured to the Florida Keys have been positive tests for at least one group of enteroviruses. Interestingly, Wetz et al. evaluated the persistence of Poliovirus in different types of seawater at Florida Keys and found that temperature, concentration of pathogen/salt, and type of seawater play significant role in inactivation the pathogen (Wetz et al., 2004). Furthermore, in the context of COVID19, the SARS-CoV-2 can easily enter to oceans/seawater and contaminated the aquatic environment. This is not only an unlike statement but is a fact when we consider in a country like India with a dense population, nearly 60% of sewage without any treatment is directly discharged into environment (Bhowmick et al., 2020). This can increase the risk of pneumonia of aquatic mammalians (Nabi and Khan, 2020) and it would be more disturbing when consider this fact that cetaceans herds are migrated to long distances regardless of political/geographical boundaries (Van Bressem et al., 2014). Hence. it can be another route for transmitting pathogens to other sites via these secondary hosts.
3 Nasal and nasopharynx irrigation by antiviral solutions against SARS-CoV-2
Since the viral load of novel coronavirus in nasal and nasopharynx is high, nasal and nasopharynx irrigation by various antiviral agents proposed as a proper solution to reduce (if not eliminate) the viral load in these areas and diminish its viability. Researchers proposed different liquid-based solutions for irrigating/gargling such as Copper (Ramezanpour et al., 2020), Povidone Iodine (Etievant et al., 2020, Frank et al., 2020), hydrogen peroxide, Corticosteroids, Chlorpheniramine, Listerine, Chlorhexidine, and NaCl (Stathis et al., 2021, Go et al., 2021). However, there are controversial arguments about the use of these compounds against the SARS-CoV-2 because of different reasons. For instance, in the case of copper not only the toxicity of element is of great concern but releasing ROS (i.e., reactive oxygen species) or free radicals which damage cell structure is also highly preventive factor (Ameh and Sayes, 2019). Furthermore, the long-term use of povidone iodine results in damage to ciliary function due to the risk of dilution error, because povidone iodine is not always available as ready-to-use compounds in all regions (Nasal Saline Irrigations in the COVID-19 Pandemic—Reply 2021). Interestingly, the side-effects of hydrogen peroxide (which is well-known for its virucidal/bactericidal effect) irrigation of the nasal and nasopharynx is still unknown in the case of COVID-19 because of the lack of trial evidence on its safety (Higgins et al., 2020). Among three types of the saline gargling and irrigation which are liquid direction, powder direction, and the traditional method; the liquid-based is the most effective method among other methods. However, the effective use of saline solution for nasal irrigation and the health of respiratory system is proven before (Santoro, Kalita, and Novak, 2021). Figure 2 illustrates the anatomy of nasopharynx, oropharynx, and hypopharynx of human.Figure 2 Anatomy of nasopharynx and oropharynx
Figure 2
3.1 Effectiveness of NaCl as an antiviral agent and mechanism for pulmonary phagocytic/non-phagocytic cells
Until now, the direct effect of NaCl on the SARS-CoV-2 is not proven yet and it is previously stated that saline solution (i.e., at low concentrations of 0.5-3%) have not a direct virucidal effect on other virus. However, it enhances the innate immunity system. This effect is mainly arise through the Cl- ions rather than Na+ ions, because Phagocyte myeloperoxidase (MPO) turns Cl- (as well as other halides such as bromide, iodide (Kettle and Winterbourn, 1997, Klebanoff et al., 2013, Kettle et al., 2011)) and hydrogen peroxide into hydrogen hypochlorite (HOCl) in phagosome. Its worthy to be noted that HOCl is the uttermost dominant mammalian germicidal suppresses viruses, probably via chlorination (Ramalingam et al., 2018). MPO is amply presents in neutrophil granulocytes (It is a sub-type of white blood cells) and in lower proportions in other cells such as respiratory system cells whereas an MPO-reliant augment in intracellular HOCl increases antiviral immunity in respiratory system. Therefore, the Cl- augments the antiviral innate immunity of phagocytic/non-phagocytic cells in human respiratory systems. Phagocytes are located in alveolar/airways surface liquid and constantly mobilized Cl- of their vicinities (Ramalingam et al., 2018) subsequently the lack (or scantiness) of chloride could threaten viral inhibition by epithelial cells. Ramalingam et al. showed that the presence of NaCl can effectively reduce the load of various virus including Influenza A, MHV68 and RSV (Ramalingam et al., 2018) whilst saline supply enhances mucociliary clearance (Robinson et al., 1997) . NaCl treatment induces cell membrane depolarization, Na+ influx, increased cytosolic Ca2+ and a low energy state (high ADP/ATP ratio), impairing SARS-CoV-2 replication (Machado et al., 2020). Thus, increasing saline availability may be essential to triggering and maintaining antiviral innate immunity in the human respiratory system.
3.2 Nasal/nasopharynx saline irrigations and gargling against the SARS-CoV-2
Performing isotonic/hypertonic saline irrigation against the novel coronavirus was firstly proposed by Farrell et al. (Farrell, Cristine, and S. John, 2020) in Washington University. Since there is not a scientific evidence about the effectiveness of saline solutions against the SARS-CoV-2, their conclusion was based on previous studies on saline irrigation (especially hypertonic solutions) that can be helpful against the viral load in nasal and nasopharyngeal. Rosati et al. (Rosati, Giordano, and Concato, 2020) were the second research group that proposed the hypertonic saline irrigating of nasal and nasopahrynx as an affordable and even cost-free method that can be used by individuals to reduce the viral load of the SARS-CoV-2 in nasal and nasopahrynx. They reported a single case that used hypertonic saline for irrigation and gargling (3-4% NACL) during the time of quarantine. The patient's RT-PCR tests after 3, 10 and 14 days of the positive test were negative, showing the effectiveness of hypertonic saline. In the ELVIS (Edinburgh & Lothians Viral Intervention Study) center, series of trials are conducted on effectiveness of hypertonic saline nasal irrigating/gargling on patients infected by coronavirus. Their findings indicated that duration of illness in patients which used hypertonic saline irrigating/gargling is nearly 2 days lower (as well as lower symptoms) than those not used the method. They emphasized that these results suggested the hypertonic saline irrigation as an affordable method against SARS-CoV-2, but further trial studies should be performed (Ramalingam et al., 2020). Notably, Suzy et al. (Suzy, Levi, and Guido, 2021) in a review on effectiveness of saline solutions on the nasal and respiratory system was reported that while the saline solution has not a direct effect on the SARS-CoV-2 but it inhibited the viral replication in the respiratory system. Importantly, it is stated that viral replication for an isotonic saline at concentration of 0.9% and 1.5% reduced by around 50% and 100% respectively (Machado et al., 2020). Casale et al. (Casale et al., 2020) suggested the nasal irrigation and oral rinsing with saline solution diminished the viral load in cavities, results in decreasing the rate of transmission as these regions are known as portals for entering the virus. Chatterjee et al. (Chatterjee) conducted a clinical trial on two groups of patients that 62 of them was study group and 63 patients are controlled group (for comparison) to show the effect of nasal saline spraying/gargling on patients infected by the novel coronavirus. Their findings revealed that the RT-PCR test of 48% of study group are negative while for control group this stand just on 25%. Furthermore, it was revealed that due to the use of saline solution for irrigating/gargling around 91% of the study group showed improvement in inhibiting sever score in their lungs which brings the importance of saline solution irrigation into the spotlight against the SARS-CoV-2. Although utilizing saline solution has not completely realized by scientific community, it was examined that gargling of throat by saline solution can reduce the viral concentration in oropharynx which can consider as a cost-free method against rapid spread of the virus in poor regions with dense population (Tsai and Wu, 2020). It worthy to be noted that the SARS-CoV-2 viral load in nasopharynx swab is higher than oropharynx swab (Wang et al., 2020).
Bale et al. (Bradley Field Bale, 2020) suggested hypertonic saline gargling/irrigation with 3% concentration to enhance the innate immune system. It consider as a suppression method to prevent the spread of COVID-19 patients without asymptomatic while reducing the progress of infection in early stages. Furthermore, it was reported that throat gargling by warm saline (temperature 56-60°C) at 3% concentration 2-4 times a day results in inactivation of the SARS-CoV-2 (Mukundan, 2019). Panta et al. (Panta, Chatti, and Andhavarapu, 2021) also proposed saline gargling and irrigating of nasal as an appropriate therapy against the progress of novel coronavirus. They emphasized that while there is lack of sufficient clinical trials on the effectiveness of saline gargling/irrigating but this method due to its harmlessness nature could implement. Kimura et al. (Kimura et al., 2020) conducted a clinical trial on non-hospitalized patients that their RT-PCR tests were positive to elucidate the effect of three different saline irrigation solutions which are: hypertonic saline, saline with surfactant, and hypertonic saline with surfactant. Their results elucidated that the efficacy of hypertonic saline irrigation on symptoms and progression of the virus was substantial. Interestingly, early healing of nasal congestion and headache by around 7-9 days was observed in the intervention group. Indeed, using hypertonic and isotonic saline can be consider as the first-line cost-free intervention against the virus for patient in symptomatic and asymptomatic phases.
4 Large-scale desalination technologies
The problem of providing safe drinking due to increasing population size and industrial and social development always consider as a critical issue among governments since it is directly related to human health (Parsa et al., 2020, Sonawane et al., 2022) whereas it anticipated that by 2025 nearly 25% people around the world confronted by severe water shortage (Parsa et al., 2019). The importance of this issue is so vital that it has come up in the last 20 years by several action plans (MDGs and SDGs) in the UN (Parsa et al., 2022, Parsa et al., 2020). For decades, mega-scale desalination technologies (RO, MED, MSF, ED) (Parsa et al., 2021) have been used to provide drinking water for large cities mainly near to seas, oceans, and gulfs. Principle of these systems, mechanisms, and their characteristics are presented in previous studies (Burn et al., 2015, Mathioulakis, Belessiotis, and Delyannis, 2007, El Saliby, Gorjian and Ghobadian, 2015, Parsa et al., 2020). Thus, we are not about to discuss each system extensively, instead, a brief explanation about each system presented.
It is of great importance to remind that, besides introducing principles and systems’ mechanism, the main aim of this section is to highlight the temperature of operation (particularly thermally-driven) in various large-scale desalination technologies. Figure 3 shows the share of desalination technologies through the world.Figure 3 Share of various desalination technologies through the world
Figure 3
4.1 Multi stage flash (MSF)
The highest share of large-scale thermal desalination technologies in the world is possessed by MSF system. Among two configurations of the MSF plants, the brine recycling approach is more attractive since it recovers a part of rejected heat brine and improves the performance of plant. Briefly, MSF process derived with steam flow that provided by a steam turbine. The steam stream increases the temperature of seawater (feed water) between 90-120°C (which defined as the top brine temperature) and the process at the first stage starts (Hanshik et al., 2016, Nair and Kumar, 2013).The number of stages in MSF plants can be up to 40 stages (Nair and Kumar, 2013). After flashing the brine in the first stage, the temperature of leaving brine at the next stage is decreases, subsequently, the pressure of the intended is also decrease to vapor of the seawater at lower temperature.
4.2 Multi effect desalination (MED)
Among thermal desalination technologies, MED plants have remarkable advantages before the advent of MSF systems in 1960. The principle of MED is based on the series of evaporative and condenser chamber that located inside of series of connected vessels known as “effect”. The prominent advantage of MED over MSF is their capability and effectiveness to operate with high saline (such as gulfs water) feed water while it requires less energy per produced water. Briefly, MED process exploited the advantage of using condensation enthalpy of the generated vapor in the previous effect for preceding a new evaporation process in the next effect. This cycle is repeating until the last effect. Generally, MED units worked at low temperature between 60-70°C (Zhang et al., 2017, Parsa et al., 2021, Rostamzadeh, 2021, Kariman et al., 2020), however, by utilizing some modifications it can worked at higher temperature up to 125°C (Ortega-Delgado, García-Rodríguez, and Alarcón-Padilla, 2017, Zhou et al., 2015).
4.3 Reverse Osmosis (RO)
Mega-scale desalination based on the Reverse osmosis is the dominant method through the world. In some cases RO plants can produce hundreds of thousands cubic meter of drinking water per day. Reverse osmosis is on the basis of membrane process and it not require to alter the phase of feed water. In RO plants, a pressure above the osmotic pressure of solute (saline water) by an external pump applied, which result in passing water from semi-permeable membrane. The concentrate brine remains on the other side. The RO have many configurations and it can be coupled with other thermal desalination systems including MED and MSF. Salinity of the feed is among the most important parameters in RO which can determine the electrical consumption of the pump (Nair and Kumar, 2013). Temperature of operation in RO plants is between 15-40°C; however, temperature of water has not a substantial effect on the performance RO plants.
4.4 Electrodialysis (ED)
The Electrodialysis-based desalination is mostly appropriate for lower salinities up to 12000 ppm which usually consider as brackish water. The process is based on the passing impure water between series of anionic and cationic stacks that an electrical field is applied to stacks. Most of existing salts in water being ionic and move to electrodes with opposite electrical charged. The anionic and cationic membranes arrays are arranged continually and a sheet spacer is located between each set of membranes. While the electrodes are charged, the existing anions of water are absorbed by the positive electrode. The anions and cations are moving to the anion-selective and cation-selective membranes respectively. By this configuration, diluted and concentrated solutions are generated in the space between membranes. Eventually, by bounding the spaces by two membranes the cells are introduced in the electrodialysis process. The ED systems are made by hundreds of these cells pair that bounded together with electrodes which called as the membrane stacks (Nair and Kumar, 2013).
4.5 Membrane distillation (MD)
Another attractive membrane-based desalination technology introduced as membrane distillation (MD) which is thermal-driven separating process. In MDs the difference between temperatures of the both sides of membrane leads to vapor pressure difference which is the driving force of process. Separation of constituents in the MD process is on the basis of liquid-vapor equilibrium. Intrinsically, the term of MD is defined from analogousness of it to traditional distillation process whilst both of them are based on liquid-vapor equilibrium as the basis of molecular separation. Both processes (i.e., MD and traditional distillation) require to enthalpy of vaporization (i.e. latent heat of evaporation) in order to change phase from liquid to vapor. The MD technology has some advantages compare to a dominant membrane-based method such as RO. Importantly, the MD process is not limited by osmotic pressure (because of its thermally-driven nature) and unlike the RO process, this characteristic of MD substantially augmented the water recovery. Temperature of operation in MD would be between 45-85°C and increasing the temperature leading to improve the performance of system (Koo et al., 2015, Zare and Kargari, 2018, Shirazi et al., 2014, Hou et al., 2009).
5 Pretreatment methods in desalination technologies
Pretreatment technologies are inseparable part of the all desalination systems whether it is thermal-based or membrane-based. The role of pretreatment is crucial as it can affect the overall performance of desalination plants (Vedavyasan, 2007). The pretreatment process can affect the thermal-based desalination technologies in a way that enable systems to work at higher top brine temperature, results in higher performance (Zhou et al., 2015, Ayoub, Zayyat, and Al-Hindi, 2014). Also, in membrane-based systems the pretreatment process lead to reducing the fouling phenomenon in membranes which is one of the most challenges in membrane-based technologies (Zhou et al., 2015). There are various types of pretreatment technologies such as microfiltration, ultrafiltration, nanofiltration (Ju et al., 2020), chlorination, coagulation (Ghernaout et al., 2014), electrocoagulation (Bagga, Chellam, and Clifford, 2008, Zahmatkesh et al., 2022), thermally-treatment, precipitation softening and sometimes combination of these methods. Although an extensive discussion is not necessary about the different pretreatment process, a brief explanation in open literature seems imperative. The mechanism of microfiltration (MF), ultrafiltration (UF), and nanofiltartion (NF) is similar and it defined in differences between their membranes pore size. In this regard, nanofiltration has the highest rate of removing organic and inorganic impurities including chemical compounds and pathogens.
Ebrahim et al. (Ebrahim et al., 1997) technically and economically evaluated the microfiltration as pretreatment method for RO and concluded that MF is economically attractive that removes COD and BOD while Lau et al. reviewed integration of the UF as pretreatment method with RO units. They reported that from economic standpoint and quality of water, the UF is an appropriate option but some technical advancement should be carried out on UF to be competitive with conventional methods (Lau et al., 2014). From the beginning of the 21 century, tremendous advances in nanotechnology and developing high-performance membrane, makes the nanofiltration as one of the dominant methods in pretreatment –particularly but not limited- for RO units. Collectively, application of NF as the pretreatment method is wide enough that it can be integrated with all of thermal/membrane-based desalination technologies including MSF, MED, RO, FO, MD, ED, and ion exchange (Zhou et al., 2015). Wang et al. examined the effectiveness of pretreatment by coagulation on the performance of membrane distillation and reported 23% improvement in MD flux (Wang et al., 2008). Friedler and co-workers utilized chlorination as pretreatment method for UF-RO desalination units. Findings indicated that 20 ppm of chlorine results in diminished the bacterial activity while it reduce the fouling of membranes by around 33% (Friedler, Katz, and Dosoretz, 2008). Lee et al. realized the effectiveness of chlorination and MF in RO unit against biological fouling (Lee et al., 2010). Heng et al. showed the effectiveness of combining permanganate with chlorine as pretreatment method against algal bio-fouling in UF membranes (Heng et al., 2008) while integration of coagulation with UF as pretreatment in RO units lead to removing 98% of algal and microbial contamination (Ma, Zhao, and Wang, 2007). Furthermore, Yang et al. (Yang and Kim, 2009) combined coagulation with MF and UF as pretreatment of RO and concluded that coagulation substantially improves the membrane performance, especially, the MF membrane. Hakizimana et al. (Hakizimana et al., 2016) experimentally studied the performance of electrocoagulation pretreatment for feed water of a RO unit and reported complete inactivation of microorganisms in feed water. Ayoub et al. (Ayoub, Zayyat, and Al-Hindi, 2014) proposed the precipitation softening as the pretreatment method to reduce the scaling in RO units. They utilized NaOH/Na2CO3 to alkalized the seawater. The findings at variable PH ranging between 10-12 showed more than 99% removal of Mg and Ca elements while complete inactivation of bacteria was also obtained. Gryta (Gryta, 2010) proposed the thermal softening as the pretreatment method of desalination unit. The results showed that increasing the feed water's temperature up to 100°C for 15 min improves the performance of desalination units while it decrease the sedimentation and fouling of membranes. It should be noted that, there are some other pretreatment methods such as ozonation (Soo et al., 2009), utilizing hydrogen peroxide (Lakretz et al., 2018), and UV irradiance (Jin et al., 2018), that consider as advance pretreatment processes and are highly powerful against biological contaminations, however, these methods are not widely used because of economic barriers in some regions. Figure 4 depicts various pretreatment methods. It is important to mention that some of these pretreatment/ post-treatment methods also applied in wastewater treatment plants (Teymoorian et al., 2021).Figure 4 Various pretreatment methods of desalination technologies
Figure 4
5.1 Performance of pretreatment methods against various viruses and the SARS-CoV-2
As the SARS-CoV-2 is lethal pathogen, specific and complicated conditions procedures needs for scientific testing which is expensive and time-consuming process. Therefore, pathogen surrogates in some experiments are used instead of dangerous microbes (Lesimple et al., 2020). Generally, viruses due to their small size could be transmitted by vapor, remain airborne, or easily pass through any porous block except the block with extremely tiny pore size. Figure 5 presents the most common human viruses with respect to their size. Principally, pretreatment methods remove pathogens in contaminated water by damaging to their structure or inhibiting the pathogens to enter to the desalination facilities by filtration. In the context of the ongoing pandemic advance pretreatment methods such as UV and ozonation proposed as appropriate methods against SARS-CoV-2 for water and waste disinfection (Teymourian et al., 2021). For UV, extensive researches highlighted the elimination of the novel coronavirus particularly by UVC wavelengths in different mediums (Raeiszadeh and Adeli, 2020).
Notably, characteristics of the SARS-CoV-2 which has long single-stranded RNA genomes, naturally, make it tremendously vulnerable for UV wavelengths (Avila et al., 2020). Although the number of studies on direct effect of UVC on SARS-CoV-2 in aqueous solution is rare, high energy photons of UVC wavelengths (Specifically in regions 260-265 nm) are highly destructive to cells because of highest UV absorption by nucleic acid. However, Robinson et al. in a preprint and Ma et al. in research paper similarly elucidated that UVC wavelengths can completely eliminate SARS-CoV-2 in aqueous solution (Richard et al., 2021, Ma et al., 2021). Furthermore, ozonation consider as a powerful method against both enveloped and non-enveloped viruses by direct ozone impact and/or indirect effect by generating free radicals such as •OH, O2•-, and H2O2 (Murray et al., 2008). The other prominent advantage of ozonation is the synergistic effect of ozone reaction and generated ROSs with pathogen's constituents such lipid, protein, and amino acid which results in producing other highly oxidative radicals such as RCOO• in chain-like reactions that boost effectiveness of ozonation process against pathogens (Tizaoui, 2020). Chlorination is another disinfection method that widely applied during the pandemic. Fernando et al. in an extensive review highlighted the critical role of chlorine for removal of the SARS-CoV-2 regarding the pros and cons of the method (Richard et al., 2021). The aforementioned methods mainly eliminate the SARS-CoV-2 by damaging to the fragile outer surface of the virus, while in filtration process such as MF, UF, and NF the tiny pore size of membranes rejected the virus. Approximately, the designed pore size (pz) ranges for MF, UF, and NF between 0.1<pz<10 µm, 0.5<pz<0.01 µm, and 5<pz<10 nm respectively. Notwithstanding of emerging NF as an effective method for pathogens removal, UF is at the forefront of membrane-based pretreatment method; particularly for RO (Lesimple et al., 2020). Al-Aani et al. (Al-Aani, Mustafa, and Hilal, 2023) comprehensively reviewed the application of UF for wastewater treatment plant and reported high-reliability of UF for removing pathogens in contaminated water particularly viruses and bacteria. Since the pore size in NF is less than 10 nm, none of the aforementioned human viruses (depicted in Figure 5 ) can cross the NF membranes. This makes NF pretreatment as completely reliable method against pathogens specifically viruses (Lesimple et al., 2020). Furthermore, effectiveness of the NF for a broad range of waterborne pathogens including bacteria, viruses, and protozoa have been extensively reported (Singh et al., 2020). Meanwhile, Venugopal et al. (Venugopal et al., 2020) proposed to utilize electrospun NF fiber membrane not as the pretreatment method but as a monitoring tool for early detection of an unusual accumulation of microorganism (in this case SARS-CoV-2) in water bodies entering to water treatment plants. Figure 6 shows various membranes pore size for water filtration.Figure 5 Common human viruses with the relative size. Reprinted from open source (S.Io.B.S. Viralzone 2020)
Figure 5
Figure 6 Membrane water filtration with respect to their pore size. Reprinted from open source (Ostarcevic et al., 2018)
Figure 6
6 Are mega-scale desalination technologies safe during the pandemic?
Reliability of desalination technologies in the era of COVID-9 still remained unanswered. In this section based on their principles, feasibility and safety of these systems during the ongoing pandemic is discussed. It should be point out that all discussions in this section are based on the medical evidence, clinical trials, laboratory facts, and actual principle of the water desalination technologies. In this regards, an extensive discussion in three sections which are, the impact of feed water's salinity (evidence of nasopharynx/nasal saline solution irrigation/gargling), temperature of desalination technologies, and pretreatment processes to realize the reliability of desalination plants are presented.
6.1 Translation of nasal/nasopharynx saline irrigation and gargling in reliability of desalination technologies (Effect of salinity)
As we previously discussed nasopharynx, throat, and nasal irrigation and gargling by hypertonic and isotonic saline solutions proposed as a preventive method that even it not eliminated the virus, it inhibits of replicating the SARS-CoV-2 in its portals. Furthermore, it was stated that NaCl solutions, especially hypertonic saline solutions that defined with NaCl concentration higher than 0.9% (NaCl>0.9%) is more preferable as the first-line intervention against the SARS-CoV-2. Some researchers used hypertonic saline at higher concentration of 1.5% up to 4% (Machado et al., 2020, Rosati, Giordano, and Concato, 2020). Clinical trial conducted on the saline irrigating/gargling approach (especially ELVISE researcher) and all of them pointed out the effectiveness of salinity on reducing the viral (i.e., SARS-CoV-2) load and inhibiting viral replication in the nasal, nasopharynx, and throat. It is worthy to be reminded that in a meta-analysis it was elucidated that sing hypertonic saline nasal irrigation (less than 5%) shows greater effectiveness than isotonic saline solution for seasonal pathology (Kanjanawasee et al., 2018). On the other hand, feed water of all desalination plants utilized by seawater, oceans and gulfs. Salinity of these water sources may be varied but generally salinity of feed water in all studies is taken as 35000 ppm. Many of these water resources such as the Persian Gulf, Mediterranean Sea, Pacific Ocean, Indian Ocean to name a few, are the home for most of desalination plants throughout the world and have salinity higher than 35000 ppm or 3.5%. Table 1 shows some of the most well-known water bodies with respect to their salinity.Table 1 Water bodies with respect to their salinity
Table 1Water Body Continent Salinity (ppm) Common Type of Desalination
Persian Gulf Asia 40000-41000 RO,MED,MSF,MD
Mediterranean Sea Europe/Africa/Asia 38000-40000 RO,ED
Pacific Ocean All except Arica 32000-37000 RO
Indian Ocean Oceania/Asia 32000-37000 RO
In this regard, the first preventive factor in safety of the large-scale desalination plants is the salinity of feed water. This is not just an assumption but it can be concluded based on concrete pieces of evidence of medical experts’ experiments. When in a small region such as nasal, nasopharynx, or throat with high load of viral RNA the replication process can be inhibited by hypertonic saline, in large saline environments such as seas, oceans, and hyper-saline gulf's waters, replication and the load of the SARS-CoV-2 drastically decreases. Herein, there is an important factor about the minimum infected dose (MID) of disease. Generally, MID can define as the minimum load of pathogen that can lead to the disease. Pathogens have different MIDs which means below the certain MID of pathogen, the disease (or symptoms) will not be appeared in the body. Among pathogens, viruses has higher MID due to their simple structure and higher replication rate compare to bacteria, protozoa, and fungi which justifies why viruses are highly infectious rather than other pathogens. In the case of the novel coronavirus, it seems that the MID of the virus is very low because of high rate of transmission through the world. This fact is justified by its new variants that are more contagious than the previous variants. Nevertheless, researchers in clinical trials observed that the hypertonic saline irrigating/gargling reduce the viral load, reduce symptoms, and length of recovery. It means that presence of NaCl reduces the infection dose of the SARS-CoV-2. By taking into consideration of all the above mentioned discussion, salinity of feed water in large-scale desalination systems is a factor that can inhibited the feed water and the structure of desalination plant gets contaminated. However, some questions are remained unanswered in this context such as the effect seawater salinity on the eliminating the SARS-CoV-2 or the effect of salt concentration on viability of the SARS-CoV-2 with respect to the time.
6.2 Temperature of operation
One of the most important factors that highly affected the survival of SARS-CoV-2 in different environment is temperature. It was showed that viability of the virus has reverse relationship with temperature. While the virus can be survived in temperature of 4°C for almost two weeks (Chin et al., 2020) it completely inactivated at temperature 56°C in 30 minutes (Wang et al., 2020). Figure 7 shows the effect of temperature on the viability of the SARS-CoV-2 (the T90 which defined as the time for eliminating 90% of viral concentration) virus in various water matrices (a detail explanation is presented in our previous study (Parsa, 2021)) in temperature range of 4-37°C (Ahmed et al., 2020). Furthermore, figure 8 illustrated the inactivation of the virus by increasing the temperature in a range between 55-90°C (Batéjat et al., 2021). Indeed, the rate of survival and viability of the virus by increasing the temperature of environment exponentially diminished. On the other hand among the aforementioned desalination technologies the two membrane-based RO and ED are worked on the basis of different pressure and ion-exchange and temperature has not play a significant role in the process while the MED, MSF, and MD are thermally-driven technologies and temperature role is vitally important for performance of the system.Figure 7 The average T90 of the SARS-CoV-2 in various water matrices (Ahmed et al., 2020)
Figure 7
Figure 8 Time for Inactivation of the novel coronavirus by increasing temperature (Batéjat et al., 2021)
Figure 8
Among these three technologies, MSF working temperature is higher than 95°C and it can gets up to 120°C. Likewise, MED range of temperature is varied and it can work at lower top brine temperature as low as 60-70°C but it has potential to work at higher temperature as high as 120°C. Furthermore, the MD process usually driven at temperature higher than 50°C and it worked as high as 85°C. Considering all of the above mentioned range of temperatures for thermally-driven desalinations and susceptibility of the SARS-CoV-2 to temperature regarding figure 8, the MSF desalination units has the highest temperature of operation which indicated this fact that the SARS-VoV-2 cannot remain survive in such hot environment and it will be eliminated during the process. Similarly, the same can be concluded for MED units since it can operate at higher temperature up to 120°C. Although the MED units also can worked at lower temperature between 60-70°C but this temperature range is not high risk for the plant since the viral in such temperature range completely inactivated between 15 to 5 minutes. Thus, the feed water and plant structure would not contaminated by the virus due to thermal inactivation. For MD systems, however, the temperature of operation is not as much as high of MSF or MED and it can work at lower temperature such as 50°C or even lower. Thus, for MD desalination units in the temperature operation higher than 55°C the feed water and the unit will not prone to be contaminated because the SARS-CoV-2 will eliminated in less than 30 minutes, but at lower temperature of operation (i.e. 45-55°C) (Parmar et al., 2021) the inactivation of the SARS-CoV-2 is unknown in the feed water and post-treatment may need to be consider.
6.3 Effectiveness of Pretreatment processes
As it discussed before, pretreatment process is somehow a mandatory part of any desalination technology which utilized to increase the performance of units while it maintains equipment of units from negative effects such as corrosion and so on. Among the available pretreatment process, filtration, especially, NF is widely proposed as a powerful method due to it highly efficacy in separation even particles at nanoscales. On the other, MF and UF also can be used as antibacterial pretreatment methods but for pathogens such as viruses that have particle size is in nanoscale range, MF and UF may not be effective enough. On the other hand, NF can be consider as an strong against biological contamination even viruses with particle size of 10-100 nm since NF membrane usually has pore size between 0.2-10 nm (Ostarcevic et al., 2018, Chuntanalerg et al., 2018). Thus, NF is a powerful method against the SARS-CoV-2 which its particle size is in the range of 60-140 nm. However, using nanofiber membrane for removing the SARS-CoV-2 in wastewater was proposed during the ongoing pandemic (Venugopal et al., 2020). The other pretreatment method is chlorination which always is considered as one of the disinfection methods in wastewater treatment plants. Chlorine compounds consider solely or in combine by other pretreatment methods such as MF (Lee et al., 2010). It was reported that nearly 20 mg/L of chlorine is effective enough to eliminate SARS-CoV-1 (Wang et al., 2005). Therefore, pretreatment by chlorine compounds can be consider the other powerful pretreatment methods against biological contamination, including the SARS-CoV-2. Meanwhile, some pretreatment methods such as precipitation softening may also effective in inactivation of the SARS-CoV-2 since they work at near-extreme pH range higher than 12. Interestingly, it was examined that the SARS-CoV-2 lost infectivity in extreme pH level of 2-3 and 11-12 after 1 day (Chan et al., 2020). Thermal pretreatment also consider as one of the most suitable methods against biologically-contamination feed water since many pathogens are susceptible to increasing temperature including SARS-CoVs. The method that proposed by Gryta (Gryta, 2010) which was based on increasing temperature of water to boiling point can be effective against many bacteria and viruses. Importantly, extensive discussion on performance of pretreatment methods against the novel coronavirus and other pathogens in section 5.1 indicated that pretreatment methods also act as the first-line preventive factor against the biologically-contaminated water in desalination plants. Figure 9 illustrated a flowchart that depicts the approach of this review.Figure 9 Flowchart of the present study
Figure 9
7 Concluding remarks and future studies
Based on the above discussion the following can be summarized:h A high large number of infections results in contaminated of water bodies because of wastewater and human urine and excreta.
h Various types of pathogens including the SARS-CoV-2 contaminated the water media.
h The SARS-CoV-2 can remain viable in various water matrices at low temperature and proper conditions.
h The novel coronavirus is tremendously susceptible to increasing the temperature of its environment whereas the survival of the virus by increasing temperature is exponentially decreases.
h The novel coronavirus in temperature of 56, 65, and 95°C eliminated in 30, 15, and 3 minutes respectively.
h Based on clinical trials saline irrigation/gargling (especially hypertonic saline) of nasal/nasopharynx/throat lead to prevent virus replication and decrease symptoms and reduce the length of illness.
h The salinity of mega-scale desalination technologies is equal or higher than hypertonic saline (>35000 ppm) solution which means by presence of the novel coronavirus in feed water the risk of its viability is very low.
h Temperature of operation for MSF, MED, and MD is between 90-120°C, 60-125°C, and 45-85°C respectively.
h Among thermally-driven desalination technologies temperature operation of MSF and MED are very high for survival of the SARS-CoV-2 which means presence of the SARS-CoV-2 in feed water could not lead to contamination of produced water as well as structure of desalination plants.
h MD units can work at low and medium temperature ranges, thus in the case of the medium working temperature between 55-85°C the structure of system and produced water could not contaminated but at lower temperature of operation (45-55°C) contamination of feed water may have risks for unit and produced water.
h Various pretreatment methods such as filtration, chlorination, thermal/precipitation softening, UV irradiance, ozonation, and hydrogen peroxides can prevent the transmission of biological contamination (including the SARS-CoV-2) in feed water.
h Chlorination and its combination by other methods such as MF, UF and coagulation can be consider as an effective method to decrease the biological contaminated since the use of chlorine compounds for eliminating then SARS-CoV-1 is proven before.
h Among pretreatment methods, nanofiltration membrane is the most emerging technology because of its effective separation and wide application in integrating with all of the large-scale desalination technologies.
h The pore size of the nano-filter membranes is between 0.2-2 nm which means it can inhibit transmitting most of pathogens including the SARS-CoV-2 because of particle size of 60-140 nm.
h The RO units as the dominant method in large-scale desalination technologies are pretty reliable because of various pretreatment methods among them nanofiltartion membranes as the most preferable method.
h Some pretreatment methods such as UV, H2O2, Ozonation are among the powerful methods to eliminate the SARS-CoV-2 but they are rarely used as the pretreatment because technical and economical limitations.
h ED units are not work at high temperatures neither with high salinity water and the units usually is more preferable for low-saline water (brackish water) up to 12000 ppm, therefore the in the case of contaminated feed water by the SARS-CoV-2 it is not clear how could be the performance of the system.
h Survival and viability of the SARS-CoV-2 in different seawater and gulfs with respect to time is an interesting topic worthy to be examined.
h Effect of salt concentration in seawater on the survival of the SARS-CoV-2 is another topic that could be consider by medical researchers and environmental engineering experts.
h Evaluation of the synergistic effect salt concentration with increasing temperature of solution is also an interesting topic worthy to be realized.
8 Conclusion
The ongoing pandemic affected the whole world from different aspects. One of the most barriers of this situation is drop on the shoulders of environment. The high number of infections results in contaminated of water bodies by wastewater and sewage. The high load of viral in water bodies has too many risks to open a new window for transmission of the virus. Although during the COVID-19 the respiratory system is the predominant route of transmission, but it is not the only path of spreading the virus.
In the present study reliability of large-scale desalination technologies during the COVID-19 pandemic is discussed. Five desalination systems that has the highest share of commercial markets are examined. Three important parameters have stepped into spotlight to evaluate the safety of these systems in producing drinking water without biological contamination. The first parameter was salinity of the feed water which it showed that based on medical facts and clinical trials saline solution (especially hypertonic saline) is preventive factor in growing the SARS-CoV-2, indicating that the feed water of large-scale desalination technologies is a not proper environment for the virus to remain viable or replicate. The second factor was temperature of operation in thermally-driven desalination technologies which it is showed that the high temperature of operation for thermal-driven desalination technologies is inhibited the virus to remain infected since the SARS-CoV-2 is highly vulnerable to increasing the temperature. The third preventive factor against biological contamination of feed water was implementing various pretreatment methods especially for RO units. It was revealed that the pretreatment methods especially nanofiltration are powerful method that can eliminated pathogens before entering the feed water to desalination unit.
Eventually, based on the aforementioned discussion, it can be concluded that the large-scale desalination technologies is safe enough during the ongoing pandemic, even if the feed water of the unit is contaminated by the virus. It worthy to be noted that the approach of the present study is not limited to the COVID-19 pandemic but it is true for similar situation in the future whereas the water bodies are contaminated and the pathogen (i.e. most viruses) is susceptible to temperature.
Funding Information
This review has not received funding from any organization
Conflict of Interest
The author declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data Availability
Data will be made available on request.
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J Econ Behav Organ
J Econ Behav Organ
Journal of Economic Behavior & Organization
0167-2681
0167-2681
Published by Elsevier B.V.
S0167-2681(22)00450-4
10.1016/j.jebo.2022.12.007
Article
Anti-social behaviour and economic decision-making: Panel experimental evidence in the wake of COVID-19
Lohmann Paul M. a
Gsottbauer Elisabeth b
You Jing ⁎c
Kontoleon Andreas d
a El-Erian Institute of Behavioural Economics and Policy, University of Cambridge, UK
b Department of Public Finance, University of Innsbruck
c School of Agricultural Economics and Rural Development, Renmin University of China, China
d Department of Land Economy, University of Cambridge, UK
⁎ Corresponding author.
13 12 2022
13 12 2022
31 1 2022
18 11 2022
10 12 2022
© 2022 Published by Elsevier B.V.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
We systematically examine the acute impact of exposure to a public health crisis on anti-social behaviour and economic decision-making using unique experimental panel data from China, collected just before the outbreak of COVID-19 and immediately after the first wave was overcome. Exploiting plausibly exogenous geographical variation in virus exposure coupled with a dataset of longitudinal experiments, we show that participants who were more intensely exposed to the virus outbreak became more anti-social than those with lower exposure, while other aspects of economic and social preferences remain largely stable. The finding is robust to multiple hypothesis testing and a similar, yet less pronounced pattern emerges when using alternative measures of virus exposure, reflecting societal concern and sentiment, constructed using social media data. The anti-social response is particularly pronounced for individuals who experienced an increase in depression or negative affect, which highlights the important role of psychological health as a potential mechanism through which the virus outbreak affected behaviour.
Keywords
Anti-social Behaviour
Coronavirus
Risk Preferences
Time Preferences
Natural Experiment
Panel Data
Social Media Data
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pmc1 Introduction
The novel coronavirus SARS-CoV-2, causing the infectious disease now known as COVID-19, was first reported in China in the city of Wuhan in December 2019.1 In less than three months, the new virus spiralled into a national health crisis and global pandemic. Governments have faced unprecedented challenges to mitigate the spread of the virus and in response have imposed extensive policies that limit social contact and have mandated forms of preventative behaviour.
What are the immediate impacts on social behaviour and economic decision-making of such an unprecedented public health crisis? For example, how does direct exposure to COVID-19 affect people’s proclivity for acting pro-socially, their attitudes towards taking risks or their patience levels. This question is of particular importance as economic preferences have been shown to be an important predictor of people’s willingness to adopt emergency measures at the early critical stages of such a health crisis, including social distancing, hand hygiene and wearing of face masks meant to contain the further spread of the virus (e.g. Nikolov, Pape, Tonguc, Williams, 2020, Müller, Rau, 2021, Campos-Mercade, Meier, Schneider, Wengström, 2021). To manage the pandemic effectively, it is vital to understand factors that drive people’s willingness to comply with confinement measures, especially those that could be significantly affected by the exposure to COVID-19 itself. To shed light on this question, we use a unique dataset of longitudinal experiments to examine the effect of exposure to COVID-19 on anti-social behaviour and economic decision-making. The experiments were conducted in October and December 2019 right before the outbreak and shortly after the first wave of the pandemic in March 2020, relying on a large sample of university students from Beijing. Students were all based in Beijing during the baseline survey and were spread across 183 cities in China during endline survey in March 2020. Unlike other studies on the impacts of COVID-19, our panel data enables identification not only to a higher degree of internal validity, as we were able to track the change in behaviour and preferences of the same individuals before and after the outbreak, but also to larger external validity with wider geographic, epidemic and socioeconomic representation. More broadly, our paper speaks to a sizeable body of empirical literature assessing if negative shocks (e.g., violent conflicts, natural disasters, economics crisis) can bring about systematic changes in economic decision-making and affect the temporal stability of economic preferences (for an overview of largely mixed findings see, Chuang and Schechter (2015)).2 A related literature focuses on the stability of preferences in relation to acute stress events and scarcity, again producing mixed results.3
We also add to a number of papers exploring the impact of COVID-19 on economic and social preferences, including research focusing on risk and time preferences (Angrisani, Cipriani, Guarino, Kendall, Ortiz de Zarate, 2020, Li, Huang, Tam, Hong, 2020, Bu, Hanspal, Liao, Liu, 2020, Drichoutis, Nayga, 2021, Guenther, Galizzi, Sanders, 2021, Harrison, Hofmeyr, Kincaid, Monroe, Ross, Schneider, Swarthout, 2022), social preferences (Branas-Garza, Jorrat, Alfonso, Espin, García, Kovarik, 2022, Buso, De Caprariis, Di Cagno, Ferrari, Larocca, Marazzi, Panaccione, Spadoni, 2020, Grimalda, Buchan, Ozturk, Pinate, Urso, Brewer, 2021) and papers assessing various preference measures (e.g. Alsharawy, Ball, Smith, Spoon, 2021, Bokern, Linde, Riedl, Werner, Shachat, Walker, Wei, 2021). Findings from all of the aforementioned studies on the effect of the outbreak of the pandemic on economic and social preferences are mixed. One reason for these mixed findings might be that these papers cover a broad spectrum of research approaches, amongst others, differing in the use of incentivized and non-incentivized preference measures, sampling among a student or a more general population sample and data collection taking place before and after the outbreak or only after the outbreak of COVID-19. In addition, all of the aforementioned studies were conducted in many different countries and cultural contexts.
The closest of these papers to ours are Shachat et al. (2021), Li et al. (2020b) and Bu et al. (2020) making use of risk and social experimental preference measures elicited among Chinese samples to assess the impact of the first wave of COVID-19 on the stability of these preferences. While we acknowledge that our experimental approach holds many similarities to these papers, there are also some notable differences with respect to research design and identification strategy including the use of a within- instead of between-subject design, additional survey data to study potential mechanisms and a more nuanced analysis with respect to exposure to the virus outbreak through ample geographical variation in virus prevalence. Note that the main sample difference to Shachat et al. (2021) and Bu et al. (2020) is that both studies heavily draw on students located in Hubei province where the majority of Covid-19 cases were reported, while our study relies on geographical variation in students’ location across all of mainland China (only 10 participants, i.e. 1.92% of the sample were located within Hubei province).4 We summarize similarities and differences to these studies in Table A1 in the Appendix.Table 1 Panel Survey Modules
Table 1Wave N Anti-social
Behaviour Risk & Time
Preferences Cognition Well-being Pro-social
Behaviour
1 793 Lottery Choice Task$, Investment Game CES-D, General health Trust Game, Public Good Game
2 650 Joy of Destruction$, Take Game$, Punishment Game$ Convex Time Budget$, Lottery Choice Task$ Raven$, Depletion CES-D, General health, Subjective well-being, PANAS
3 539 Joy of Destruction$, Take Game$, Punishment Game$ Convex Time Budget$, Lottery choice task$, Investment Game Raven$, Depletion CES-D, General health, Subjective well-being, PANAS Trust Game, Public Good Game
Waves 1 & 2 were collected before the COVID-19 outbreak while Wave 3 was collected after. Tasks marked with $ were incentivised. CES-D = Centre for Epidemiologic Studies Depression Scale; PANAS = Positive and Negative Affect Schedule.
Table A3 Baidu Search Terms
Table A3No. English Translation
1 Coronavirus disease (pneumonia caused by the novel coronavirus)
2 Novel coronavirus
3 Real-time Situation of COVID-19
4 The Latest News about pneumonia caused by COVID-19
5 The latest news about COVID-19
6 Coronavirus disease outbreak situation
7 Confirmed cases
8 New cases
9 New cases of pneumonia caused by the novel coronavirus
10 N95 masks
11 How often change n95 mask
12 Antibacterial gel
13 What are the symptoms of pneumonia caused by the novel coronavirus
14 Symptoms of the novel coronavirus
15 Symptoms of coronavirus disease (pneumonia caused by the novel coronavirus)
16 Dry cough
17 What is the temperature of COVID-19
18 Is dry cough a symptom of COVID-19
19 Fever clinic
20 Early symptoms of COVID-19
Table A2 Survey Modules
Table A2Group Measure Description Variable construct
Anti-social Behaviour Joy of Destruction (Abbink and Herrmann, 2011)$23 Binary decision to anonymously destroy a matched player’s endowment as a measure of nastiness. Dummy which takes the value of 1 if the participant decides to destroy another player’s endowment at a cost to him/her-self.
Take Game (Schildberg-Hörisch and Strassmair, 2012)$23 Share of endowment taken from a matched player as a measure of theft. Percentage taken from other player’s endowment
Take Game with Deterrence (Schildberg-Hörisch and Strassmair, 2012) $23 Share of endowment taken from a matched player with a 40% chance of detection resulting in loss of endowment, as a measure of theft with risk. Percentage taken from other player’s endowment
Pro-social Behaviour Dictator Game (Fehr and Fischbacher, 2004) $23 Amount of endowment transferred to a matched player (decision observed by third party). Percentage invested into a public good.
Trust game (Berg et al., 1995) 13 Share of hypothetical endowment entrusted to a hypothetical player, as a measure of trust. Percentage sent to the other player
Public-Goods Game (low return) 13 Share of hypothetical endowment contributed towards a public good, as a measure of cooperation in a low and high return scenario. Percentage given to the other player
Norm-enforcement Third-party punishment game (Fehr and Fischbacher, 2004) $23 Amount of costly punishment imposed on a matched player based on the amount transferred by the matched player in a dictator game. Binary variable: Takes the value of 1 if a participant is willing to punish when the dictator transfers zero credits to the other player.
Extent variable: Amount punished at a cost ratio of 1 Yuan for every 3 Yuan deducted.
Risk & Time Preferences CRRA coefficient (Eckel and Grossman, 2002) $123 Choice between six lotteries (50/50 odds) increasing in variance, absolute pay-off and riskiness. Coefficient of relative risk aversion midpoints (CRRA)
Risk aversion (Gneezy and Potters, 1997) 13 Share of hypothetical endowment not invested in a lottery (50/50 odds). Percentage invested into a lottery
Present Bias (Andreoni et al., 2015) $23 Individual β parameter derived from 24 budget lines across 4 timeframes Dummy which takes the value of 1 if present biasedness parameter beta is greater than 1.
Time Discounting (Andreoni et al., 2015) $23 Individual δ parameter derived from 24 budget lines across 4 timeframes Discount rate (parameter delta)
Cognitive Ability & Well-being Raven’s Standard Progressive Matrices (Bilker et al., 2012) $23 Cognitive ability measured by the number of correctly completed puzzles (out of 9). Score between 0 and 9.
Depression (Andresen et al., 1994) 123 Depression score calculated using the Centre for Epidemiological Studies Depression Scale Short-form (CESD-10). Continuous variable: Depression score between 0 and 30 (sum of ten items). Binary variable: Takes the value of 1 if depression score is greater than 10.
Positive Affect (Thompson, 2007) 23 Assessment of mood on the day of the survey using the international Short-form of the Positive and Negative Affect Schedule (PANAS-ISF) Positive affect score between 5 and 25 (sum of five items).
Negative Affect (Thompson, 2007) 23 Negative affect score between 5 and 25 (sum of five items).
Life Satisfaction23 Self-assessed general life satisfaction Likert scale between 1 and 5
Happiness23 Self-assessed general happiness (enjoying life) Likert scale between 1 and 5
Eudaemonic Well-being23 Self-assessed meaningfulness of life Likert scale between 1 and 5
Depletion 23 Five-item depletion scale adapted from Twenge et al. (2004). Score between - 7 and + 11
General health123 Self-assessed general health status Likert scale between 1 and 5
$ Incentivised tasks; 13 Included in Survey Wave 1 and 3; 23 Included in Survey Wave 2 and 3; 123 Included in Survey Wave 1, 2 and 3
Table A1 Summary of studies on the impact of Covid-19 on economic and social preferences in China
Table A1Paper Population Sample size Same individual over time Time span Games Inc Identification Change Sig
Shachat et al. (2021) Students from Wuhan University N=602 across pre- and post Covid-19 samples No (main sample); Yes (sub sample) Baseline: 2019/05; Endline: various samples 01/02/03 2020 Dictator Game; Ultimatum Game; Trust Game; Prisoner’s Dilemma Game; Stag Hunt Game; Risk attitudes (Holt and Laury, 2002); Ambiguity attitudes Yes ($) Main analysis: repeated cross-sectional data (pre-post analysis); Robustness: panel data on sub-sample, N=92 Yes: Prisoner Dilemma [cooperation] (+); Stag Hunt [risky action] (-); Risk aversion in gains (-); Risk tolerance in losses (-); Ambiguity aversion (+)
Bu et al. (2020) Students from Wuhan University N=257 Yes (retention 88%) Baseline: 2019/10; Endline: 2020/02 - early 2020/03 Hypothetical allocation to a risky investment; Stated risk aversion (risk attitudes) No Main analysis: heterogenous exposure (Wuhan, Hubai Province or rest of China); Robustness: panel DiD framework Yes: Risk investment (-); Risk aversion (+)
Li et al. (2021) Chinese general population N= 1872 across pre- and post Covid-19 samples No (pre: 696; post: 1176) Baseline: 2019/9鼂ǣ2019/12; Endline: early 2020/3 Trust game; Risk attitudes (Holt and Laury, 2002); Time preferences Yes ($) Main analysis: repeated cross-sectional data (pre-post analysis) Yes: Trust [-]; Trustworthy [+]; Risk aversion [+]; Impatience [+]
Our paper Students from different Beijing universities N=793 Yes (Retention 68%) Baseline: 2019/10 2019/12; Endline: early 2020/03 Joy of Destruction; Take Game; Dictator Game with Third-Party Punishment; Trust Game (hypothetical); Public Good Game (hypothetical); Lottery Choice Task; Investment Game (hypothetical); Time preferences Yes ($), majority of the games Main analysis: heterogenous exposure + panel DiD framework Yes: Joy of destruction (+); Take Game (+)
Our paper also links to research on the connection between economic and social preferences and health behaviours, including the willingness to take protective action and the demand for vaccines (Böhm, Betsch, Korn, 2016, Chapman, Coups, 1999, Galizzi, Miraldo, 2017, Sutter, Kocher, Daniela, Trautmann, 2013). For example, recent research with respect to the spread of COVID-19 finds that pro-social preferences and patience positively correlate with personal protective behaviour related to COVID-19, while risk tolerance negatively impacts the willingness to engage in such behaviour (Campos-Mercade, Meier, Schneider, Wengström, 2021, Müller, Rau, 2021).5 However, the direction of these effects would become unclear if exposure to an acute public health crisis itself could trigger behaviour and preferences to change in different directions for significant segments of the population. On the one hand, evidence from economics and psychology suggests that people exposed to a major crisis event may more likely display selfish and reckless behaviour (Fisman, Jakiela, Kariv, 2015, Fritsche, Jugert, 2017). Anecdotal evidence from panic buying and increased racial discrimination, xenophobia, and riots in response to the coronavirus outbreak is indicative of such behaviour. On the other hand, research also indicates that disaster and crisis lead individuals to engage in widespread altruism and acts of solidarity (Bauer, Blattman, Henrich, Miguel, Mitts, 2016, Solnit, 2010). With respect to the COVID-19 outbreak, the public’s willingness to engage in cooperative behaviour including social distancing as well as the formation of neighbourhood networks to assist vulnerable groups speaks to this strand of literature.
The research described in this paper contributes to the aforementioned literatures in several important ways. First, it adds to the body of empirical work testing the theoretical assumption of stable preferences over time. Our study explores the acute effect of a public health crisis on temporal stability of fundamental preferences predictive of economic and social behaviour, including risk aversion, patience, trust, cooperation, altruism, norm enforcement and anti-social behaviour. More importantly, it also explores potential mechanisms behind any changes in preferences and behaviour.
Second, unlike a number of cross-sectional studies, it applies a dose-response’ difference-in-difference framework to panel data, tracking the same individuals before and after the virus outbreak. Our identification strategy exploits within-individual variation in economic decision-making and exogenous variation in exposure to the virus across 183 cities to assess causal impacts of the crisis. Importantly, our design resembles a type of natural experiment, whereby the individuals’ locations (and thus exposure to the virus) are pre-determined by factors unrelated to the virus outbreak. Compared with between-individual identification, it yields more precise estimates by explicitly controlling for individually heterogeneous confounders (fixed effects) to preferential changes.
Third, it combines data from multiple sources and disciplines. To ascertain incentive compatible economic decision-making, we employ well-established experimental protocols as opposed to responses to purely hypothetical behavioural questions. Together with a range of survey variables from economics and psychology, we can capture both behavioural and trait-like characteristics. In order to comprehensively reflect what COVID-19 means for individuals, we go beyond simple epidemiological measures of virus prevalence and exploit information from big-data extracted from Chinese social media to construct two additional measures of virus exposure capturing social concern and sentiment: (1) an innovative index reflecting public concern/anxiety based on internet search volume sourced from China’s largest search engine (Baidu Inc.) and (2) a novel index of expressed negative sentiment based on linguistic text analysis of 523,222 tweets posted on the main microblogging platform (Sina Weibo).
Finally, to better purge non-random components of the exposure to the virus in identification as well as to minimise omitted variable problems in regressions, we collected data from various sources including population mobility based on mobile phone check-ins at Baidu Inc. and official air quality information from 1,436 air monitoring stations across China. We also hand-collected and coded city-level lockdown policies on various aspects of life, work, and education from government sources.
We show a substantial and statistically significant increase in anti-social behaviour for those individuals more intensely exposed to the virus outbreak. In contrast, our measures of pro-social behaviour and economic preferences are largely unaffected by the Covid-19 shock. Moreover, our analysis of potential mechanisms suggests that increases in depression and negative affect are likely driving the observed relationship for anti-social behaviour. The indication that mental well-being is likely responsible for the increase in anti-social behaviour can inform better targeted policies and relief programs, including increased attention to mental health issues at the onset of a public health emergency and in turn greater investment into mental health services (Liu, Yang, Zhang, Xiang, Liu, Hu, Zhang, 2020, Dong, Bouey, 2020).
Our paper is structured as follows. Section 2 describes the design of study, detailing our outcome, control and mediation variables. Section 3 presents our identification strategy and how we address potential endogeneity concerns. Section 4 describes our empirical strategy, presents sample statistics and outlines how we address attrition. Section 5 presents our results, the sensitivity analysis undertaken, as well as the potential mechanisms explored. Section 6 concludes with a discussion of our main findings and how these relate to the relevant literature.
2 Study Design
The experiment was conducted on a sample drawn from the general student population of universities in Beijing (with the majority of students enrolled at Renmin University) in October 2019.6 We informed participants about the longitudinal nature of the study and asked them to consent to participate in multiple experimental survey waves.7 Students were offered a 10 Yuan (1.50 USD) flat-fee payment for participation in the panel study and the opportunity to obtain bonus payments based on their decisions in the experiments. Note that we follow standards in experimental economics to conduct an incentive-based experiment in which participants obtain a monetary reward based on the results of their decisions.8
Experimental protocols and surveys were administered online using a survey tool integrated into WeChat, a popular mobile messaging application in China. The average payment per participant was approximately 32 Yuan (5 USD), including a 10 Yuan show-up fee for each wave). Average completion time per wave varied between 15-20 minutes.
Data was collected in three waves. Wave 1 (N=793) was conducted in October 2019 and designed as a baseline survey including questions on participants’ socio-demographics which were not repeated in later waves. Wave 2 (N=650) was conducted in December 2019 and Wave 3 (N=539) in March 2020 which comprised elements of both proceeding surveys as well as questions specific to the COVID-19 crisis. Importantly, Waves 1 and 2 were conducted before the outbreak of COVID-19 in China, while Wave 3 at a point when the epidemic in China had significantly slowed and new cases were close to zero. Figure 1 displays a detailed timeline of events and highlights the spread of the epidemic, indicating daily new confirmed cases of COVID-19 in China.Fig. 1 Timeline of Data Collection and Virus Outbreak Confirmed cases of COVID-19 were obtained from official sources (State Council, provincial governments, and the Chinese CDC)
Fig. 1
The experimental modules which were employed across the three waves of the survey consist of well-established experimental games. To measure anti-social behaviour as well as economic preferences on risk and time/discounting (our main outcome variables) we use the following incentivized decision tasks: a joy of destruction game; a take game with and without deterrence; a third-party punishment game; a lottery choice task; an investment game and a convex time budget task. In addition, we use a hypothetical trust game and one-shot public good game to capture other aspects of social preferences (results presented in the Appendix).
The survey waves also included standardized survey modules to obtained relevant socio-economic control variables, but also measures of participant’s cognitive functioning and well-being. The latter two sets of measures would serve as potential mechanisms explaining the effects of Covid exposure on our outcome variables. In particular, to measure cognitive functioning, we use a set of Raven’s matrices and a five-item self-completion questionnaire to assess participants’ momentary level of ego-depletion. For psychological and physiological well-being, we measure self-reported subjective well-being, depressive symptoms, positive and negative affect, sleep quality and general health status of all participants.
Table 1 provides an overview of each survey module. Table A2 in the Appendix provides more detail on the experimental modules and how the outcome and mediating variables were defined. Note that Wave 3 consisted of all experimental modules, while Waves 1 and 2 were made up of sub-sets of these.
To incentivise truthfulness and effort, the majority of tasks were incentivised so that payoff depended on the participant’s choices. The incentivized tasks were presented in separate questionnaire parts to participants.9 In Part I of the questionnaire, participants were presented with the Joy of Destruction Game, the Take Game and the Third-Party Punishment game and subjects were paid on the basis of one randomly selected task from Part I.10 . The average endowment for each task was approximately 20 Yuan (3 USD). In Part II, participants made a total of 25 decisions across a Lottery Choice Task and a Convex Time Budget Task with significantly increased stakes (payoff between 56 鼂ǣ 140 Yuan, equivalent to 8.60 鼂ǣ 21.50 USD). Participants were informed that 30 students would be selected at random to receive payment for one of their decisions (selected at random) from Part II. In Part III, participants were incentivized to complete the Raven Matrices test, in which we paid participants for each correct answer (out of 9). Note that the trust game and the one-shot public good game were not incentivized in any of the waves.11 . At the end of each wave, the decision tasks that were used for payment were randomly selected and respondents received their respective payments to their WeChat Wallet on the following day. Note that the time preferences payments were delivered according to the time schedule indicated in the selected decision task (details provided below). All instructions were provided in Chinese and all choices were framed in terms of Chinese Yuan (CNY). The English translation of the instructions is included in Appendix C. In the following subsection we describe the survey modules and key variables used in our analysis in more detail.
2.1 Outcome variables
2.1.1 Anti-social behaviour
The anti-social behaviour module consists of two separate incentivized games to elicit different dimensions of people’ willingness to engage in anti-social behaviour. The binary Joy of Destruction (JOD) game provides a measure of nasty behaviour (Abbink and Herrmann, 2011). In this two-player game, participants were anonymously matched in pairs (each with an initial endowment of 20 Yuan) and then faced the binary decision whether to destroy their assigned partner’s endowment by half at a cost of 2 Yuan or maintain the status quo. Participants were further informed that, with a one third probability, the other player’s endowment will be reduced to 10 Yuan, regardless of their decision. The design of JOD game removes all conventional motivations for anti-social behaviour and further allows destructive behaviour to be partially hidden behind a component of random destruction. The primary outcome variable from this task is a binary indicator identifying individuals that chose to destroy their counterpart’s endowment. The Take Game provides a measure of covert anti-social behaviour in the form of stealing or theft (Schildberg-Hörisch and Strassmair, 2012). In this two-player game, participants were anonymously matched and provided unequal endowment (of 10 Yuan or 18 Yuan). The participants then had to decide whether to take from the other player’s initial endowment in two different scenarios. In the first scenario, the player could take any amount (between 0 and 18 Yuan) without facing any consequences. In the second scenario, the player could take any amount but faced a 60% probability of being detected, effectively reducing their payoff to 6 Yuan due to a penalty. Note that the game was constructed as such that no losses or negative payments were possible. From this task we obtain two primary outcome variables for our analysis: (1) a continuous measure of taking without and (2) with a risk of being detected.12
2.1.2 Risk and time preferences
Risk preferences are obtained using a standard incentivised Lottery Choice Task Eckel and Grossman (2002). In this task, participants had to decide between six lotteries each with a 50% chance of paying a lower or higher amount. Lotteries were increasing in variance, total pay-off and riskiness. Find instructions in the Appendix C4, Part 4.2. Based on the chosen lottery, we obtained the participant’s constant relative risk aversion (CRRA) parameter interval. For our analysis, we calculate the CRRA interval midpoint for each participant in a given survey wave, with a higher value indicating greater risk aversion.13 In an additional task, we obtain a simple measure of risk aversion with the help of a non-incentivized Investment Game based on Gneezy and Potters (1997). Participants could invest part of their hypothetical 20,000 Yuan endowment into a lottery with a winning probability of 50%. The higher the investment, the higher the risk participants are willing to take.
Time preferences are elicited using Convex Time Budgets (CTB) following Andreoni et al. (2015). Participants made 24 consecutive decisions between sooner or later payments, across four different timeframes, with six budget lines for each timeframe. Participants thus faced decisions over payment ‘today and 5 weeks from today’, ‘today and 9 weeks from today’, ‘5 weeks from today and 10 weeks from today’ and ‘5 weeks from today and 14 weeks from today’. The 24 budget lines and instructions are displayed in Appendix C4, Part 4.3. Prior to our main analysis, we estimated the individual-level parameters beta and delta parameters via non-linear least squares following Andreoni et al. (2015). For our main analysis, we utilize the individual-level delta parameter as a measure of patience and construct a binary measure of present bias equal to one if a participant’s individual-level beta parameter is smaller than 1.
2.2 Control and Mediation Variables
We collect extensive socio-demographic control variables relevant to the Chinese context including, participants urban or rural origin (or ‘Hukou’ status) and whether participants have siblings (‘only child’ due to family planning). In addition, we use a set of survey questions to assess cognitive functioning and well-being, which may serve as potential mechanisms for changes in economic decision-making.
To measure cognitive functioning, we used a subset of Raven’s Standard Progressive Matrices (Bilker et al., 2012) and pay subjects for each correct answer. Cognitive performance was indexed by the sum of correctly solved matrices (range 0-9). In addition, we assessed participants’ momentary and self-reported state of ego-depletion, which reflects an individual’s self-control capacity at a given moment, according to ego-depletion theory (Baumeister et al., 1998).14 This measure was obtained from a modified 5-item Depletion Scale adapted from Twenge et al. (2004) where a higher score indicates higher levels of depletion.15
The well-being module consists of a selection of survey questions to capture different dimensions of well-being. We use the Center for Epidemiologic Studies Depression Scale (CESD) 10-item scale as a validated self-reported instrument to measure the prevalence of depressive symptoms (Andresen et al., 1994). Respondents are asked to report the frequency at which they experienced a given mood or symptom during the past week on a four-point scale, ranging from zero (“none of the time”) to three (‘most of the time’). A depression score is obtained by totalling responses to each of the 10 items (range 0 – 30). Moreover, we construct a binary measure indicating the presence of depressive symptoms for subjects with a depression score of 10 or higher (Andresen et al., 1994). To measure short-term mood on the day of the survey, we use the international short form of the Positive and Negative Affect Schedule (PANAS-ISF) consisting of a 10-item self-reported questionnaire (Thompson, 2007). Using the respective negative and positive affect items (five each), we construct scores for positive and negative affect, where higher scores indicate greater presence of positive or negative mood on the day of the survey (range 5-25). To measure subjective well-being, we focus on three dimensions including life satisfaction, happiness, and meaningfulness of life, where higher scores indicate higher levels of subjective well-being in the respective categories. We also check the general health status of our participants, using responses to a question on their general health condition ranging from 1 to 5, indicating very poor to very good health status on the day of the survey. See Appendix C4-C5, for instructions.
Finally, we also assess participant’s pro-social behaviour with some simple hypothetical tasks: A standard one-shot Public Good Game was used to obtain a measure of cooperation (see Appendix 2, Part C2, for instructions. In this game, participants could invest part of their hypothetical endowment (10,000 Yuan) into the production of a public good with a return of 1.6. We also used a Trust Game to obtain a measure of trust in an investment setting (Berg et al., 1995). Participants chose how much of their hypothetical endowment (100 Yuan) to invest into a partner who doubles the investment and decides how much to return. Finally, we used an incentivized Third-Party Punishment Game (Fehr and Fischbacher, 2004) to measure both prosocial behaviour and third-party sanctioning behaviour for violations of a distribution norm (Fehr and Fischbacher, 2004). As in a classic dictator game, players first decided whether to transfer between 0 and 10 Yuan of their 20 Yuan endowment to an anonymously matched recipient. They then took the role of a third party observing another player’s transfer decision, with the option to enact costly punishment for each possible transfer amount sent by the observed dictator. In our setting, the third-party observer had an endowment of 10 Yuan and could use any of this amount to punish the dictator by reducing their endowment by a factor of three (e.g., 2 Yuan would reduce the dictator’s endowment by 6 Yuan). As players faced multiple decisions, they were informed that one of their choices would be randomly selected for payment. From this game we construct three primary outcomes for our analysis: (1) an incentivised measure of (observed) giving from the dictator game, as a measure of pro-social behaviour or altruism, (2) the amount spent to punish if the observed dictator transfers zero and (3) a binary indicator identifying subjects that were willing to pay any amount to punish a dictator that gave zero.16 Fig. A1 Norm-enforcement preferences in pre (December 2019) and post-outbreak waves (March 2020).
Fig. A1
2.3 Summary Statistics
Table 2 presents summary statistics for all outcome variables employed in the analysis, as well as the socio-demographic characteristics of the full sample pooling responses from all waves (if N=1566 the variable was collected in all three waves, if N=1044 the variable was collected in only two of three waves).17 Most notably, with respect to our main outcome variables related to anti-social behaviour we observe that 16% of participants decided to destroy their counterpart’s endowment, and 9.48 (10.23) Yuan were taken, on average, in the Take Game with (and without) deterrence. Both risk measures suggest that the sample was slightly risk averse, and 67% of participants were classified as present biased.Table 2 Summary Statistics
Table 2 Mean SD Min Max N
Anti-social Behaviour
Joy of Destruction (Destroy = 1) 0.16 0.37 0.00 1.00 1044
Taking (¥) 10.23 6.30 0.00 18.00 1044
Taking with Deterrence (¥) 9.48 6.73 0.00 18.00 1044
Risk & Time Preferences
Risk Aversion (CRRA midpoint - EG) 2.99 2.78 -0.50 6.73 1566
Risk Taking (GP) 7156.81 4086.02 0.00 20000.00 1044
Present Bias (Yes = 1) 0.67 0.47 0.00 1.00 1026
Patience (δ parameter) 0.98 0.12 0.00 1.00 1026
Pro-social Behaviour & Norm-enforcement
Cooperation (¥invested in PGG) 4138.33 3370.25 0.00 10000.00 1044
Trust (¥invested) 43.55 25.29 0.00 100.00 1044
Dictator Giving (¥) 3.91 3.44 0.00 10.00 1044
Punishment (¥) 0.59 0.49 0.00 1.00 1044
Punish (Punish = 1) 2.08 2.29 0.00 10.00 1044
Cognition and Health
Cognitive Ability (correct puzzles) 6.70 1.39 1.00 9.00 1044
Depletion (score) 1.68 3.54 -7.00 11.00 1044
Depression (score) 10.60 5.67 0.00 29.00 1566
Depressive Symptomns (Yes = 1) 0.53 0.50 0.00 1.00 1566
Negative Affect (score) 9.81 4.21 5.00 25.00 1044
Positive Affect (score) 12.90 3.41 5.00 21.00 1044
General Health (scale) 3.81 0.80 1.00 5.00 1566
Socio-demographic Characteristics
Age 19.85 1.53 17.00 29.00 522
Female (%) 0.82 0.39 0.00 1.00 522
Rural Hukou (%) 0.21 0.41 0.00 1.00 522
Only Child (%) 0.64 0.48 0.00 1.00 522
Economics/Finance Major (%) 0.44 0.50 0.00 1.00 522
Year of Study 2.56 1.16 1.00 6.00 522
Table displays the summary statistics for the full sample by pooling data from all three waves (where applicable).
The ‘Cognition & Health’ section includes potential mechanism influencing decision-making including (i) cognitive ability and depletion, (ii) emotional affect and depressive symptoms and (iii) general health. We also obtained respondents ‘Socio-demographic Characteristics’ from the baseline demographic survey (N=522) which was conducted in October 2019.
3 Identification
We exploit geographical variation in virus prevalence to estimate the causal effect of virus exposure on economic decision-making (similar to Bu et al. (2020)). Although initial recruitment (prior to the COIVD-19 crisis) took place at Beijing universities in October 2019, students were geographically (and exogenously) dispersed across the country by the time of the 3rd Wave of data collection (14th 鼂ǣ 17th March). We also collected students’ travel history from the end of their academic term to our 3rd survey wave date. Section 3.2 below provide an in-depth discussion on possible threats to our identification strategy and how these were addressed.
At the time of Wave 3 data collection, 73.4% of participants had travelled outside Beijing and returned to their respective hometowns or family homes to celebrate the Spring Festival (25th January), the most important national holiday in China. For generations, it has been a very strongly and widely adhered tradition to celebrate Chinese New Year with one’s family. Note that the locations where students originate from are geographically diverse due to the college admission rule that has been implemented since 1978. The Ministry of Education and provincial governments jointly set up regional admission quotas according to not only provincial socioeconomic and demographic characteristics but also universities’ classifications, for the purpose of equal access to higher education across regions and ethnic groups. After the national college entrance exam in every June, the colleges/universities will announce their subject- and province-specific admission quotas according to the general guidelines of the Ministry and the provincial governments. Students submit their applications to colleges/universities according to these quotas and their predicted exam performance during June and August. The academic year starts in early September. Thus, the dispersion of our participants’ hometowns has been pre-determined by factors unrelated to those accounting for the distribution of Covid-19 prevalence.18 Shortly after the Spring Festival, nationwide travel restrictions were imposed, and the university spring term was postponed indefinitely. Effectively, the Ministry of Education restrained all students at the cities and towns they were located in late January 2020. This means, participants in our sample were located in 183 cities across China when the endline survey took place, with varying degrees of virus prevalence when we fielded our 3rd survey Wave.
Importantly (and what uniquely benefits our identification) is that participants’ geographic dispersion throughout the virus outbreak was totally unrelated to the COVID-19 crisis nor to different levels of COVID-19 exposure. Hence, our data has characteristics of a natural experiment in that treatment assignment (or in our case students’ exposure to different degrees of COVID-19) has been largely determined by exogenous distribution of their geographic locations as a result of the pre-determined universities’ admission across regions coupled with the government imposed domestic travel ban. Figure 2 provides a graphical illustration of the locations of our participants and corresponding city-level virus prevalence at the time of the third survey.Fig. 2 Survey Participants’ Locations during Survey Wave 3 and Virus Prevalence
Fig. 2
3.1 Measures of Virus Exposure
For robustness, we use three key measures of virus exposure.19 See 3 for a summary. First, we use a standard epidemiological measure of disease prevalence: the logged number of confirmed cases per million inhabitants at the city-level, which we obtained from a variety of official sources including central and provincial governments and the Chinese Centre for Disease Control and Prevention (CDC). We then match cumulative case statistics on the date of the survey in March 2020 with participants’ location. Cumulative case prevalence per million inhabitants in the 183 cities where our participants reside during the March survey fall between 0 and 5658. In our analysis, we use the log-transformed COVID-19 counts.20 Table 3 Exposure Variables
Table 3 N Mean SD Min Max
City-level Cases 183 47 419 0 5658
City-level Cases (logged) 183 2 1 0 9
Baidu Search Index 183 80443 78138 5669 647294
Baidu Search Index (logged) 183 11 1 9 13
Negative Sentiment Index 179 2 0 1 3
COVID-19 cases are population adjusted at the city-level (per 1 million inhabitants). Baidu Search Index is the city-level sum of search volumes for 20 Keywords related to COVID-19 between 23rd January and 17th March (see Table A3 for individual keywords). Negative Sentiment Index is the city-level average share of negative emotions expressed across all Sina-Microblog posts discussing COVID-19, shared between 7th and 14th March Data Sources: (1) Authors’ compilation of official data from the State Council, provincial governments, and the Chinese CDC. (2) & (3) Authors’ compilation of Baidu search data and Sina Weibo data.
Second, we construct a novel measure of city-level concern about the virus outbreak based on internet search data from Baidu, the most popular online search engine in China. The Baidu database provides daily population weighted search volume indices for commonly searched (coronavirus related) keywords at the city level. A high value of the Baidu concern index’ for a certain keyword indicates that many people searched for information on the relevant keyword and cared about the relevant topic. The index has been widely applied in public health research for disease monitoring and prediction (He, Chen, Chen, Wang, Shen, Liu, Suolang, Zhang, Ju, Zhang, Du, Jiang, Pan, Min, 2018, Li, Liu, Zhu, Lin, Zhang, He, Deng, Peng, Xiao, Rutherford, Xie, Zeng, Li, Ma, 2017, Yuan, Nsoesie, Lv, Peng, Chunara, Brownstein, 2013), the measurement of health-related public concern and awareness (e.g. Dong et al., 2019) and more recently also to the COVID-19 outbreak in China (Xiong et al., 2020). We extracted search volume indices for 20 keywords related to general interest searches about COVID-19 (e.g. novel coronavirus) and more specific to symptoms (e.g. dry cough) and personal protective measures (e.g. N95 masks) indexed at the city level (see Appendix Table A3 for a list of all keywords used). To capture overall city-level concern during the virus outbreak, we calculated the sum of all search term indices during the peak of the COVID-19 outbreak, between Wuhan Lockdown (23rd of January) and the date of the survey. We again use the log-transformed Baidu concern index for our analysis. Figure 3 displays the search volume indices between January and April for three popular keywords, as well as our 20-Keyword index.Fig. 3 Time Series Baidu Index The dashed lines indicate the dates on which the CDC announced the highest emergency response level (January 15th), the lockdown of Wuhan (23rd January) and the date of the third Survey was released (14th March)
Fig. 3
Third, we construct a novel city-level index of expressed (negative) sentiment related to COVID-19 from social media, as online sharing of emotional content specific to COVID-19 has the potential to bring about long-run societal change via emotional contagion (Steinert, 2020). For this, we extracted microblog posts (or tweets) from Sina Weibo, the Chinese equivalent to Twitter and one of the most popular social media platforms in China.21 First, we extracted 523,222 geotagged microblog posts with the keyword novel coronavirus (‘xin guan’) which were posted online during the week prior to the third survey wave (from 0:00 am on 7th March to 5:00pm on 14th March). Posts were recorded in 179 of the 183 cities in our sample. Second, we utilized the Linguistic Inquiry Word Count (LIWC) method, an automated text analysis method widely applied in psychology, which measures psychological and linguistic dimensions of written expression (Pennebaker and King, 1999). We employ the simplified Chinese version of the LIWC adapted by Gao et al. (2013). The LIWC text-processing programme uses a set of dictionaries to calculate the percentage of words that express positive and negative emotions for each microblog post. We construct our measure of expressed negative sentiment in a given city by calculating the average share of negative emotions expressed across all posts discussing COVID-19 in the week before the third survey was disseminated. The average score is recoded so that higher values represent greater negative mood (see Table 3 for details).
Both the Baidu search index and the negative sentiment index correlate positively to the infection rate, with the correlation coefficients being r=0.6 and r=0.2, respectively. The distributions across cities of the two indices do not deviate from that of the infection rate. We believe that the two indices provide valid measures of social sentiment, reflecting the intensity of exposure to the virus.
3.2 Threats to Identification
Our identifying assumption relies on virus exposure being randomly assigned across participants. There are two possible sources of endogeneity that could undermine our identification 鼂ǣ students’ geographic dispersion and the spread of the virus. We discuss below how both concerns do not apply in our case.
3.2.1 Participants’ Location Sorting
As discussed above, the pre-determined university admissions rule benefits our identification strategy by exogenously dispersing our participants across locations, which rules out potential bias from residential sorting. Moreover, the timing of student mobility in January 2020 was pre-determined exogenously by their term dates relative to the Chinese New Year.22 However, one may be concerned that individuals’ adaptive behaviour prior to the event undermines the estimated impact.23 Specifically, students’ travel decisions with respect to timing and destination may be related to how the unfolding disease situation was unfolding. To explore if this is the case, we first look at the descriptive statistics with respect to student movements. We observe that only 33 students (6% of the sample) whose registered Hukou (hometown) was not Beijing actually stayed in Beijing after the academic term had ended in December 2019 and none of these were from Hubei Province, the region most affected by the virus outbreak. During the holidays a small percentage of students normally remains in Beijing for various reasons (e.g., visiting family, internships, selection of civil servants, additional academic commitments). At the time of the 3rd survey wave, only 5 of these students (<1% of the total sample) had remained on the campuses that we surveyed. Hence, the raw data itself suggests that we do not observe any discernible patterns of adaptive behaviour that could undermine our identification strategy. To further investigate this concern, we explore using regression analysis whether students’ travel decisions are independent of virus prevalence. First, we regress students’ departure dates from Beijing on their initial (baseline) preferences, socio-demographic characteristics, their host university and their destination city. We do not find any significant estimates. Second, we regress a dummy variable equal to one if a student travelled to an alternative destination (i.e. not their hometown) or stayed in Beijing on future virus prevalence in their respective hometowns and a set of province dummies in which their hometown is located. Results show that whether students returned to their hometowns or not is unrelated to future virus prevalence. Moreover, only 28 students ever moved between neighbouring cities after January 23rd when Wuhan was locked down. In all cases, this was reported as visits to relatives, which is also part of the traditional celebration of the Chinese New Year. Overall, these findings clearly indicate that students did not behave adaptively in terms of mobility in response to the possible outbreak.
Finally, students’ mobility after the initial lockdown of January 2020 was strictly forbidden, and this was retained when the spring term started in late February. The Ministry of Education required all levels of schools to deliver online courses, and all students to stay home. College students were not allowed to return to their colleges.24 The timing of leaving Beijing and the subsequent restriction on student mobility make their cumulative exposure to the virus situation in their current cities less likely to be individually selected. That said, individual fixed effects in our panel model mitigate any remaining concerns regarding endogenous adaptation.
3.2.2 Dispersion of the Virus
Whilst the initial outbreak in Wuhan can be deemed an unanticipated event, the further dispersion of the virus across China is unlikely to have followed an entirely random pattern. There are two possible confounding factors. First, according to the Chinese Emergency Law, there are four levels of emergency (from 1 (high) to 4 (low)) and from the second to the fourth level, the provincial governments are responsible for designing and implementing policies to control and prevent the infectious diseases. The State Council announced the highest level on 23rd January and adjusted it to Level 2 on 23rd February. Given our sample dates in March, it is likely that provincial policies and implementation affect individuals’ most recent exposure (in the time domain) to the disease. Second, conditional on provincial environment, socioeconomic development (e.g., health facilities, population density) and geographic location of the city are plausible factors affecting individuals’ exposure to local outbreaks (in the spatial domain). There is evidence which suggests that the virus spread was largely determined by population flows from Wuhan to other cities in China in the days before strict travel restrictions from and to Wuhan were enacted (Kraemer et al., 2020). If confounding factors exist, we need to control for these in our main specification.
To determine which city-level factors might confound our results, we regress our three measures of city-level virus exposure on a set of city-level variables, which have been found to affect the dispersion of COVID-19, most importantly the rate of migration between Wuhan and other cities in China. To calculate population mobility we extracted data on inter-city population flows from the Baidu Migration Database (https://qianxi.baidu.com/) tracking individuals’ check-in locations in all Baidu applications (e.g., Baidu map, search, takeaway, and social media ‘tieba’) through their mobile devices. We use the average population inflow from Wuhan as a share of total immigration to each of our sample cities between 20th and 23rd January. Higher values indicate that a larger proportion of the inflowing population originated from Wuhan, which reflects a greater connectedness between Wuhan and the respective city.
Following recent research (e.g. Becchetti, Conzo, Conzo, Salustri, 2020, Pluchino, Inturri, Rapisarda, Biondo, Moli, Zappala’, Giuffrida, Russo, Latora), we further control for city-level population density, the number of hospitals and doctors per million inhabitants, the amount of city-level health expenditure as a share of total fiscal expenditure, GDP per capita and annual average Air Quality Index (AQI) based on daily records of 1,436 air monitoring stations since 2015.25 The stringency and duration of lockdown may also significantly affect the development of city-level virus outbreaks. We manually collected data of official re-opening dates for shops, restaurants, indoor and outdoor activities, respectively, for each city from 183 municipal governments’ official websites and news. We constructed a lockdown duration index as the standardised sum of days all city-level lockdown measures were in place. Finally, given that the provincial governments are responsible for designing and implementing local policy for COVID-19, the dispersion of the virus is likely to be determined by numerous province-level factors, including social and geographic proximity to Wuhan, long-run policies effecting socio-spatial vulnerability of communities, virus-preparedness, and the ability to respond (e.g. province-level measures to mitigate the virus outbreak). Hence, we include province-level fixed effects into the model.
The results of our regressions are shown in Appendix Table A4 . We find that for all three city-level exposure variables (LnCases, Baidu Concern Index and Sentiment Index) a large part of the variation is explained by province fixed effects and the share of immigration from Wuhan during the days prior to the lockdown of Wuhan and the imposition of travel restrictions. With respect to additional city-level factors, population density and GDP per capita are positively, and health expenditure negatively correlated with the Baidu Search Index, long-run air quality and the number of hospitals per capita are both positively associated with the Negative Sentiment Index. Based on this analysis, we include immigration rate, population density, GDP per capita, the number of hospitals, health expenditure and annual average AQI as city-level controls as well as province fixed effects into our main empirical specification, which we discuss next.Table A4 Threats to Identification - Formal Assessment
Table A4 LnCases Baidu Index Sentiment Index
(1) (2) (3) (4) (5) (6)
Immigration Rate (Wuhan) 0.912*** 0.844*** 0.450*** 0.343*** 0.173* 0.196**
(0.116) (0.121) (0.091) (0.089) (0.098) (0.097)
Population Density 0.088 0.142* -0.036
(0.108) (0.080) (0.087)
Number of Hospitals 0.017 -0.024 0.174**
(0.065) (0.044) (0.076)
Lockdown Duration Index -0.088 -0.045 -0.074
(0.066) (0.060) (0.081)
GDP per Capita 0.128 0.179** -0.068
(0.120) (0.075) (0.122)
Health Expenditure Share -0.055 -0.074* -0.023
(0.052) (0.038) (0.057)
Annual Average AQI -0.067 -0.007 0.224**
(0.068) (0.072) (0.096)
Constant 3.378*** 3.200*** 13.316*** 13.012*** 0.304*** 0.312**
(0.017) (0.112) (0.013) (0.084) (0.014) (0.140)
R2 0.711 0.734 0.443 0.515 0.420 0.473
Province Fixed Effects Yes Yes Yes Yes Yes Yes
Observations 183 183 183 183 179 179
Table shows results from simple OLS regressions to assess city-level determinants of virus exposure. Dependent variables are LnCases, Baidu Index and Negative Sentiment Index. LnCases is the logged number of cumulative confirmed cases at the city-level per million inhabitants officially reported on the date of the third survey. Baidu Index is an index of city-level COVID-19 concern based on Baidu search volume indices for 20 virus-related keywords. Sentiment Index is the city-level average share of negative expressed emotions via social media. All explanatory variables are z-scored and all regressions include province fixed effects. Robust standard errors in parentheses.
4 Empirical Strategy and Attrition
To estimate the effect of virus exposure on social behaviour and economic preferences, we use a generalised Difference-in-Differences Model (DID). It differs from a classic DID model in the sense that the treatment variables in our case are continuous, rather than binary (Wing et al., 2018). Importantly, the panel structure of our data allows us to control for individual unobserved fixed effects and isolate the effects of the exogenous treatment, by comparing the differences before and after the virus outbreak across participants who experienced different levels of exposure to COVID-19. We estimate the following main specification:(1) Ykijt=δExposurej+β3Xjt+ηi+λtdp+εijt
where Yijtk is primary outcome k from the experimental modules discussed above for individual i living in city j at time t.Xjt is a vector of city-level controls ; ηi represents unobservable time-invariant individual fixed effects; λtdp represent a province-specific time trend, given that provincial governments’ design and implementation of policies provide sources of variation in city-level exposure to the virus; Exposurej is a continuous variable of being exposed to COVID-19 (City-level cases, Baidu Concern Index, and Sentiment Index) at the time of survey Wave 3 and εijt is the random error term. In this specification, the parameter of interest is the difference-in-differences estimator δ, reflecting the impact on Ykijt from variations in the intensity of treatment in the post-outbreak period (Post). We accommodate for potential serial correlation by estimating clustered standard errors at the individual level.
A key assumption underlying the DID identification strategy is the common trends in outcomes between treatment and control groups in absence of a treatment. Whilst this assumption is not directly testable, we are able to test parallel trends before the virus outbreak for outcome variables which were collected in both the October and December 2019 surveys, including an incentivised measure of risk preferences and two measures of well-being (i.e. depression and general health of participants). This is shown graphically in Appendix Figure A3 . We further estimate the difference-in-differences model above using the October and December data on the same three outcome variables as if the outbreak had taken place before the December survey (see Table A5 in the Appendix). Both the visual and formal assessments lead to the conclusion that trends in risk preferences, depression and general health did not differ between treatment and control groups in the months prior to the virus outbreak.Fig. A3 Pre-trend Visual Assessment on Survey Outcomes Plots show change in Risk aversion measured via the CRRA interval midpoints from a lottery choice task, Depression measured using the Centre for Epidemiological Studies Depression Scale Short-form (CESD-10) and General health assessed via self-reported health condition between wave 1 and wave 2 of the panel survey. Both surveys took place prior to the outbreak of COVID-19.
Fig. A3
Table A5 Difference-in-difference Analysis: Parallel Survey Trends October December 2019
Table A5 (1) (2) (3)
Risk Aversion Depression General Health
December 2019 0.011 0.624*** -0.140
(0.105) (0.111) (0.146)
December 2019 ×LnCases -0.010 -0.039 0.036
(0.035) (0.039) (0.051)
Number of Individuals 522 522 522
Waves 2 2 2
Observations 1044 1044 1044
Difference in Difference Analysis using fixed effects OLS regressions to test for pre-outbreak parallel trends between October and December 2019. Dependent variables are standardized (see details of measures in Table A2). LnCases is the logged number of cumulative confirmed cases at the city-level per million inhabitants officially reported on the date of the third survey. December 2019 is a dummy referring to the second survey wave (prior to the virus outbreak). Standard errors in parentheses
For the remaining outcomes that only appear in either the October or December survey, we repeat the same regressions described above using survey data from each corresponding month. The results indicate that pre-outbreak preferences are uncorrelated with future virus-exposure (see Table A6 ). We conclude from this exercise that the common trends assumption likely holds in the context of our data.Table A6 Pre-Outbreak Exposure Analysis
Table A6 (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11)
Co-op Trust Altruism Punish
(Binary) Punish
(Extent) Destruction Taking Taking
(Det.) Risk
Taking Present
Bias Discounting
LnCases -0.037 -0.022 -0.049 -0.033 -0.058 -0.049 0.026 0.025 0.059 0.067** 0.062*
(0.050) (0.037) (0.039) (0.055) (0.045) (0.030) (0.029) (0.027) (0.036) (0.034) (0.035)
R2 0.002 0.001 0.003 0.001 0.005 0.003 0.001 0.001 0.005 0.006 0.008
Observations 522 522 522 522 522 522 522 522 522 513 513
OLS analysis of pre-outbreak exposure. Standard errors clustered at the city level in parenthesis. LnCases is the logged number of cumulative confirmed cases at the city-level per million inhabitants officially reported on the date of the third survey.
We are also able to ascertain that individuals did not differ in their socio-demographic characteristics with respect to the degree of virus exposure. Based on the epidemiological measure of exposure (i.e. the number of cumulative confirmed cases at the city-level on the day of the survey adjusted by population), we report summary statistics of basic characteristics of survey participants between those that were severely exposed (the top tercile of virus prevalence), moderately exposed (the middle tercile) and those that were only mildly exposed (the bottom tercile). See Table A7 in the Appendix. We find broad balance across basic demographics including age, gender, year of study, being the only child (significant at the 5% level, chi2-test) and Hukou registration indicating rural or urban origin of participants.Table A7 Basic Characteristics of Participants by Exposure Tercile
Table A7 Full Sample Mildly Exposed Moderately Exposed Highly Exposed P-val
Gender 0.82 0.79 0.86 0.81 0.22
Age 19.85 19.73 19.78 20.03 0.23
Year of Study 2.56 2.47 2.58 2.61 0.82
Hukou 0.21 0.24 0.20 0.18 0.35
Only Child 0.64 0.58 0.63 0.73 0.01
Chronic Illness 0.09 0.08 0.09 0.10 0.81
General Health 3.76 3.75 3.75 3.78 0.77
Observations 522.00 179.00 169.00 174.00 .
Mild, moderate and high exposure categories are based upon terciles of the number of cumulative confirmed cases at the city-level per million population officially reported on the date of the third survey. Mildly exposed (0-7 Cases per million population), Moderately exposed (8-30 Cases per million population), Highly exposed (>30 Cases per million population). P-val refers to the p-value obtained from tests of equality of means across all three categories of exposure using Anova and proportions using chi2-test.
A further concern relates to the potential of differential attrition, which may bias our estimates. Table B1 in Appendix B shows that attrition rates across the three waves in our data as 16% between Waves 1 and 2, 19% between Waves 2 and 3. These rates are comparable to previous research conducted via WeChat surveys (e.g. Chen and Yang, 2019). In Appendix B, we also explore in more detail the patterns of attrition in our data and conduct standard attrition tests. We attempt to address differential attrition in our analysis by applying inverse probability weights (IPW) following Wooldridge (2002). First, we predict the probability (pi) of being observed in all three survey waves by regressing a dummy variable equal to one if an individual did not attrite, on (1) a constant term, (2) the primary treatment variable (LnCases) and (3) a rich set of co-variates measured at baseline for all initially recruited participants. Each individual then receives a weight equal to 1/pi in all regressions in the proceeding analysis.Table A13 Wave 3 Survey Data Analysis
Table A13 (1) (2) (3) (4) (5) (6)
Wash Hands Social Distancing Stay Home Use Face Mask Avoid Touch Virus Knowledge
Index
Pro-sociality 0.158** 0.015 0.052 0.043 0.077 0.030
(0.069) (0.046) (0.043) (0.036) (0.096) (0.193)
Anti-sociality -0.017 0.070 0.034 0.044 -0.007 -0.099
(0.067) (0.043) (0.045) (0.032) (0.103) (0.210)
Norm-enforcement 0.103 -0.073 -0.093 -0.050 0.035 0.050
(0.065) (0.059) (0.062) (0.056) (0.084) (0.157)
Observations 522 522 522 522 522 522
This table is based on 18 OLS regressions (all coefficient estimates presented in this table come from individual regressions). Dependent variables are based on individual survey responses to questions on frequency of protective behaviours collected in the third survey and an index of virus-related knowledge. Each OLS regressions includes additional controls for age, gender, a dummy for being an only child, hukou registration, general health status, depression score, risk aversion, a categorical variable for political membership, an index for perceived virus-risk and city fixed effects.
Table B1 Attrition Share across Survey Waves
Table B1Wave Participants Attrition Attrition Share
1 771
2 646 125 16.21%
3 522 124 19.20%
Finally, we address the threat of multiple hypothesis testing and the possibility of false positives by estimating sharpened q-values using the false discovery rate (FDR) procedure (Anderson, 2008, Benjamini, Krieger, Yekutieli, 2006). We calculate FDR adjusted q-values for three sets of p-values across all k-outcomes (including three indices) for each of our three treatment variables. We report both conventional p-values and FDR adjusted q-values in all regression output tables.
5 Results
5.1 Short-term effects
We present our main treatment effects based on official COVID-19 infection data. Figure 4 shows the average treatment effect on the treated estimated following equation (1) and corresponding confidence intervals for our incentivised primary outcomes for anti-social behaviour and economic preferences.26 Prior to estimation, all outcomes were standardized (z-scored) on the mean to allow for a comparison of treatment effects in units of standard deviations across different outcomes.Fig. 4 Treatment Effects - Official COVID-19 Infection Data X-axis plots the estimated coefficient for a 1-unit increase in the Log of Cases per million Inhabitants. Significance stars *** p<0.01, ** p<0.05, * p<0.1 based on p-values estimated using cluster-robust standard errors, clustered at the individual level. All models are estimated with IPW to account for differential attrition. Number of observations N=1044.
Fig. 4
Table A11 Difference-in-difference Analysis: Norm Enforcement Behaviour
Table A11 (1) (2) (3)
Punishment (Binary) Punishment (Extent) Norm-enforcement Index
Panel A
Post×LnCases 0.070 0.038 0.076
(0.105) (0.099) (0.084)
[0.680] [0.947] [0.577]
Panel B
Post× Baidu Index -0.018 -0.088 -0.041
(0.104) (0.127) (0.104)
[1.000] [1.000] [1.000]
Panel C
Post× Sentiment Index -0.034 -0.026 0.001
(0.096) (0.092) (0.076)
[1.000] [1.000] [1.000]
Number of Individuals 522 522 522
Observations 1,044 1,044 1,044
Difference in differences analysis using fixed effects OLS regressions accounting for attrition using Inverse Probability Weighting (IPW). Standard errors clustered at the individual level in parenthesis. Multiple testing adjusted False Discovery Rate (FDR) q-values in square brackets. Post×LnCases is the interaction of logged number of cumulative confirmed cases at the city-level per million inhabitants officially reported on the date of the third survey with a post-outbreak indicator. Post× Baidu is the interaction of Baidu Search Index with a post-outbreak indicator. Post× Sentiment is the interaction of the Negative Sentiment Index with a post-outbreak indicator. All regressions include individual fixed effects, time-varying city-level controls for average immigration rate from Wuhan (20-23 Jan), number of hospitals per million inhabitants, health expenditure as a share of total expenditure, population density, GDP per capita and province-specific time trends. The dependent variable in column (3) is an index for norm enforcement based on the average of the z-scores of three punishment decisions (punishment extent if the dictator gives 0, 2 or 4 Yuan).
Fig. A5 Treatment effects - Social Media Data X-axis plots the estimated coefficient for a 1-unit increase in the log of the Baidu Index measuring concern about COVID-19 (Panel B) and a 1-unit increase in the Negative Sentiment Index (Sina Weibo) (Panel C). Significance stars *** p<0.01, ** p<0.05, * p<0.1 based on p-values estimated using cluster-robust standard errors, clustered at the individual level. All models are estimated with IPW to account for differential attrition. Number of observations Panel B: N=1044, Panel C: N=1036.
Fig. A5
Table A8 Difference-in-difference Analysis: Anti-social Behaviour
Table A8 (1) (2) (3) (4)
Joy of Destruction Take Game Take Game (Det.) Anti-sociality Index
Panel A
Post×LnCases 0.237*** 0.222*** 0.179* 0.212***
(0.076) (0.081) (0.101) (0.058)
[0.014] [0.028] [0.311] [0.005]
Panel B
Post× Baidu Index 0.301** 0.017 0.067 0.128*
(0.124) (0.083) (0.114) (0.072)
[0.123] [1.000] [1.000] [0.299]
Panel C
Post× Sentiment Index 0.178** 0.047 0.039 0.088
(0.084) (0.070) (0.089) (0.057)
[0.887] [1.000] [1.000] [0.887]
Number of Individuals 522 522 522 522
Observations 1,044 1,044 1,044 1,044
Difference in differences analysis using fixed effects OLS regressions accounting for attrition using Inverse Probability Weighting (IPW). Standard errors clustered at the individual level in parenthesis. Multiple testing adjusted False Discovery Rate (FDR) q-values in square brackets. Post×LnCases is the interaction of logged number of cumulative confirmed cases at the city-level per million inhabitants officially reported on the date of the third survey with a post-outbreak indicator. Post× Baidu is the interaction of Baidu Search Index with a post-outbreak indicator. Post× Sentiment is the interaction of the Negative Sentiment Index with a post-outbreak indicator. All regressions include individual fixed effects, time-varying city-level controls for average immigration rate from Wuhan (20-23 Jan), number of hospitals per million inhabitants, health expenditure as a share of total expenditure, population density, GDP per capita and province-specific time trends. The dependent variable in column (4) is an index for anti-sociality based on the average of the z-scores of all three anti-social outcome variables.
Fig. A4 Treatment Effects - Official COVID-19 Infection Data X-axis plots the estimated coefficient for a 1-unit increase in the Log of Cases per million Inhabitants. Significance stars *** p<0.01, ** p<0.05, * p<0.1 based on p-values estimated using cluster-robust standard errors, clustered at the individual level. All models are estimated with IPW to account for differential attrition. Number of observations N=1044.
Fig. A4
Figure 4 shows the estimated treatment effect of a one-unit increase in the log of city-level cases per million inhabitants. We find that people more exposed to virus appear to become more antisocial. Estimates for pro-social, norm enforcement, risk and time preferences are close to zero and show no statistically detectable difference. However, people more exposed to the virus outbreak appear to become more antisocial.
Table 4 provides corresponding difference-in-difference estimates for anti-social behaviour, the only dimension of decision-making which appears to be significantly affected by virus exposure. We observe that the coefficient of interest (post × LnCases) shows a significant relationship between the intensity of the outbreak and all outcomes. Specifically, we find that individuals destroy more of their paired player’s endowment in the Joy of Destruction Game (column 1) and take more in the Take Game without deterrence (column 2). The 0.24 standard deviation increase in destructive behaviour corresponds to an increase of approximately 9 percentage points, which is statistically significant at the 1% significance level. Similarly, we find that more exposed individuals take on average around 7% more of the other player’s endowment (0.22 s.d.). Both results are statistically significant at the 1% significance level and remain significant at the 5% level after adjusting for multiple hypothesis testing. In column (3), we find a slightly smaller effect of virus exposure on taking when there is a risk of being detected (0.18 s.d.). which is statistically significant at the 10% level using conventional p-values, but does not survive multiple hypothesis testing corrections.Table 4 Difference-in-difference analysis: Anti-social behaviour
Table 4 (1) (2) (3) (4)
Joy of Destruction Take Game Take Game (Det.) Anti-sociality Index
Panel A
Post×LnCases 0.237*** 0.222*** 0.179* 0.212***
(0.076) (0.081) (0.101) (0.058)
[0.014] [0.028] [0.311] [0.005]
R2-Within 0.018 0.038 0.036 0.053
Number of Individuals 522 522 522 522
Observations 1,044 1,044 1,044 1,044
Difference in differences analysis using fixed effects OLS regressions accounting for attrition using Inverse Probability Weighting (IPW). Standard errors clustered at the individual level in parenthesis. Multiple testing adjusted False Discovery Rate (FDR) q-values in square brackets. Post×LnCases is the interaction of logged number of cumulative confirmed cases at the city-level per million inhabitants officially reported on the date of the third survey with a post-outbreak indicator. All regressions include individual fixed effects, time-varying city-level controls for average immigration rate from Wuhan (20-23 Jan), number of hospitals per million inhabitants, health expenditure as a share of total expenditure, population density, GDP per capita and province-specific time trends. The dependent variable in column (4) is an index for anti-sociality based on the average of the z-scores of all three anti-social outcome variables.
Finally, we also construct a simple index for anti-social behaviour compromising the choices made in all three games of the anti-social behaviour module.27 Column (4) reports the effects of a unit increase in exposure on the anti-social behaviour index, which confirms our earlier results and show that participants exposed more heavily to the virus significantly increase anti-social behaviours (0.21 s.d.).
5.2 Results based on Social Media Data
The following section presents the results of our alternative measures of COVID-19 exposure based on social media data. Panel B in Figure 5 shows the estimated treatment effect of a one-unit increase in the log of the Baidu Index, which captures city-level concern around COVID-19. Panel C shows the estimated treatment effect of a one standard-deviation unit increase in the Negative Sentiment Index. The latter index, constructed using text-analysis of Sina Micro-blog posts discussing COVID-19, provides a measure of city-level (negative) sentiment. Regression results presenting detailed estimations can be found in the Appendix Tables A8-A9 .Fig. 5 Treatment effects - Social Media Data X-axis plots the estimated coefficient for a 1-unit increase in the log of the Baidu Index measuring concern about COVID-19 (Panel B) and a 1-unit increase in the Negative Sentiment Index (Sina Weibo) (Panel C). Significance stars *** p<0.01, ** p<0.05, * p<0.1 based on p-values estimated using cluster-robust standard errors, clustered at the individual level. All models are estimated with IPW to account for differential attrition. Number of observations Panel B: N=1044, Panel C: N=1036.
Fig. 5
Table A9 Difference-in-difference Analysis: Risk & Time Preferences
Table A9 (1) (2) (3) (4)
Risk Aversion Risk Taking Present Bias Discounting
Panel A
Post×LnCases 0.074 -0.144 -0.174 -0.082
(0.080) (0.125) (0.124) (0.124)
[0.577] [0.549] [0.423] [0.680]
Panel B
Post× Baidu Index 0.180** 0.066 -0.088 0.054
(0.090) (0.117) (0.141) (0.144)
[0.249] [1.000] [1.000] [1.000]
Panel C
Post× Sentiment Index 0.064 -0.065 0.026 0.221
(0.078) (0.090) (0.124) (0.141)
[1.000] [1.000] [1.000] [0.887]
Number of Individuals 522 522 522 522
Observations 1,044 1,044 1,044 1,044
Difference-in-difference analysis using fixed effects OLS regressions accounting for attrition using Inverse Probability Weighting (IPW). Standard errors clustered at the individual level in parenthesis. Multiple testing adjusted False Discovery Rate (FDR) q-values in square brackets. Post×LnCases is the interaction of logged number of cumulative confirmed cases at the city-level per million inhabitants officially reported on the date of the third survey with a post-outbreak indicator. Post× Baidu is the interaction of Baidu Search Index with a post-outbreak indicator. Post× Sentiment is the interaction of the Negative Sentiment Index with a post-outbreak indicator. All regressions include individual fixed effects, time-varying city-level controls for average immigration rate from Wuhan (20-23 Jan), number of hospitals per million inhabitants, health expenditure as a share of total expenditure, population density, GDP per capita and province-specific time trends.
With respect to anti-social behaviour, we observe again a similar yet less pronounced pattern as in the previous section. In Panel B, an increase in city-level concern is associated with a general increase in destructive behaviour (0.28 s.d.), significant at the 5% level. In Panel C, higher levels of negative sentiment led to a general increase in destructive behaviour (0.21 s.d.), significant at the 5% level. However, after adjusting for multiple hypothesis testing, the observed increases in destructive behaviour are no-longer statistically different from zero.
The exposure variables based on social media data reveal additional treatment effects, not found when using infection data. First, we find that higher levels of city-level concern (Panel B) are associated with a significant increase (0.21 s.d.) in risk-aversion (at the 5% level, measured using Eckel & Grossmann’s lottery choice task (Risk Aversion – EG). However, FDR adjustments render this finding insignificant. Second, we observe that city-level concern (Panel B) is also associated with a decrease in altruism, which is highly statistically significant at 1% level and remains statistically significant at the 10% level after FDR adjustments.
5.3 Sensitivity Analysis
We perform additional sensitivity analysis to ensure robustness of the results presented in this section. First, we exclude participants located in Hubei Province (N=10) from the analysis to mitigate the influence of potential outliers. Wuhan, the epicentre of the outbreak and surrounding cities in Hubei province were most severely affected by the virus and reported disproportionally high numbers of cases compared to the rest of China. We find that our results are largely unaffected (see Appendix Figure A6 ).Fig. A6 Sensitivity Analysis Panel A: Treatment effects when Hubei Province participants (10 individuals) are excluded from the analysis (Number of Individuals N = 512). Panel B: Treatment effects when city-level Mortality is entered as a control (Number of Individuals N = 522). X axis plots the estimated coefficient for a 1-unit increase in the Log of Cases per million population. Significance stars (*** p<0.01, ** p<0.05, * p<0.1) based on p-values estimated using cluster-robust standard errors, clustered at the individual level. Individual regression result tables are available upon request
Fig. A6
Second, another indicator of the COVID-19 epidemic which is usually reported is mortality and thus we control for reported mortality at the city-level. In China, COVID-19 related mortality was largely concentrated in Hubei Province, with 50% of the cities in our dataset reporting zero deaths by the date of the survey. Hence, we believe that mortality does not serve as a good indicator for virus exposure per se. Nonetheless, we add mortality (i.e. the cumulated confirmed cases reported on the date of the third survey at the city level) as a control to our baseline specification. Again, we find that our main results are robust to this specification (see Appendix Figure A6).
Finally, as our study sets itself apart from a number of rapidly emerging COVID-19 papers, relying on post-outbreak data between-subject designs, we test whether our results would be affected by how the impact of COVID-19 is identified. We focus on the following comparison: We use the data collected in March 2020 only and re-estimate equation (1) thereby reflecting a between-subject design relying entirely on post-outbreak data and exploiting variations in individual exposure to the virus. This identification has been widely utilised by existing studies reviewed in the Introduction. Although differences are subtle, the results show that we would underestimate the effect of virus exposure on anti-social behaviour, if ignoring individuals’ heterogeneous initial preferences and other time-invariant unobservables (see Appendix Figure A7 ).Fig. A7 Comparing Estimates from simple OLS (Post-outbreak data only) and the preferred DID model in equation (1)
Fig. A7
5.4 Potential Pathways
The analysis so far has found consistent evidence that COVID-19 exposure leads to an increase in anti-social behaviour. In this section, we explore a range of potential pathways through which exposure to COVID-19 may be associated with anti-social behaviour. We are especially interested in cognitive and psychological well-being, which have found to be important determinants of anti-social behaviour. We utilise variables measured both before and after the outbreak, capturing components of cognitive ability, psychological and physiological well-being. In addition, we construct a measure of virus-specific subjective risk perception using a set of variables elicited in the post-outbreak survey.28 Empirically, we use a triple-difference approach to assess potential pathways by estimating separate regressions for each variable using a fully interacted variant of our main equation (1):(2) antisocialit=δ(LnCasesj)+β2(postt×Zit)+θ(postt×LnCasesj×Zit)+Zit+Xijt+ηi+εijt
where antisocialit is an index of anti-social behaviour29 ; Zit captures the change in cognitive ability, psychological, physiological well-being or virus risk perception measured only in Wave 3. Xjit now represents a vector of all time-varying control variables and time-fixed effects contained in equation (1) as well as their interaction with Zit. In this regression, a positive significant estimate for the triple-difference coefficient θ would suggest that there is a statistically significant difference between individuals who experienced an increase in Zit and those who did not. Table 4 provides an overview of all estimation results from equation (2).
First, we explore whether effects of COVID-19 exposure vary by subjective virus-risk perception. This is particularly relevant, as the perceived threat of the virus may differ largely between individuals, even if they are exposed to the same number of cases at the city-level. Hence, one might hypothesise that only those individuals with higher subjective risk perception change their behaviour in response to increased objective virus exposure. The triple-difference estimate in Table 5 , column (2) suggests that this may be the case. There is a statistically significant positive difference between individuals with higher subjective risk perception, which points to the importance of how the virus is perceived. However, this difference is only significant at the 5% level and the estimate of δ remains positive and highly statistically significant, which suggests that differences are not fully explained by subjective risk perception.Table 5 Heterogeneous Impact of Virus Exposure by Potential Mechanism
Table 5 Anti-sociality Index
(1) (2) (3) (4) (5) (6) (7)
Post×LnCases 0.215*** 0.213*** -0.008 0.192*** 0.098 -0.153 0.273
(0.058) (0.059) (0.352) (0.066) (0.072) (0.152) (0.382)
Post× Virus Risk ×LnCases 0.137**
(0.069)
Post× Cognitive Ability ×LnCases -0.034
(0.053)
Post× Depletion ×LnCases 0.030*
(0.016)
Post× Depressive Symptoms ×LnCases 0.460***
(0.125)
Post× Negative Affect ×LnCases 0.042***
(0.015)
Post× General Health ×LnCases -0.013
(0.094)
R2 0.115 0.204 0.208 0.235 0.208 0.194 0.201
Number of Individuals 522 522 522 522 522 522 522
Observations 1044 1044 1044 1044 1044 1044 1044
Table reports OLS estimates of equation (2) where the dependent variable is an index of anti-social behaviour. LnCases is the logged number of confirmed cases at the city-level per million inhabitants reported on the date of the third survey. All triple interaction terms provide estimates for potential heterogeneous effects. Virus-risk Factor is a continuous score of virus-risk perception obtained from a factor analysis of post-outbreak survey responses (score ranges between approximately -2 and 2). All remaining variables were measured both pre and post outbreak: Raven score captures the number of correctly completed puzzles (Score: 0-9, recoded so that a higher score represents less completed puzzles). Depletion is a continuous score for state self-control capacity (Score between -7 and 11: higher score indicating more depletion). Depression is a binary variable that takes the value 1 if an individual has depressive symptoms. Negative affect is a continuous score measuring negative affect (Score: 0-30, higher score indicating higher negative affect); General health is a continuous measure of general health (Likert scale: 1-5, higher score indicating better health). For details on how variables were measured and constructed, see Table A2.
A large literature in behavioural economics suggests that cognitive capacity and self-control can affect economic and social decision-making (e.g. Carvalho, Meier, Wang, 2016, Friehe, Schildberg-Hörisch, 2017, Mani, Mullainathan, Shafir, Zhao, 2013). We hypothesise that changes in cognitive capacity may interact with higher virus-prevalence. For example, it has been shown that individuals with low self-regulatory resources (i.e. in a state of ego-depletion), feel less guilt and subsequently show less pro-social behaviour (Xu et al., 2012). In columns (3) and (4) we explore two measures of cognitive capacity. We find no statistically significant difference for individuals who perform worse in a set of Raven’s Progressive Matrices (a measure of cognitive ability). We find suggestive evidence of higher anti-social behaviour, significant at the 10% level, for individuals who report higher levels of momentary ego-depletion (evaluated at the time the survey was taken) and hence may have lower self-control capacity.
Next, we explore whether mental health may be driving the observed relationship. Emerging research in psychology shows that COVID-19 is likely to have serious consequences on mental health, resulting in increased levels of depression and other mental disorders (Huang, Zhao, 2020, Pfefferbaum, North, 2020, Raker, Zacher, Lowe, 2020, Thombs, Bonardi, Rice, Boruff, Azar, He, Markham, Sun, Wu, Krishnan, Thombs-Vite, Benedetti, 2020). In turn, research in behavioural economics and cognitive science find that depression and negative emotions and mood are able to impair decision-making in more general terms (Gotlib, Joormann, 2010, Haushofer, Cornelisse, Seinstra, Fehr, Joëls, Kalenscher, 2013, De Quidt, Haushofer, Roth, 2018). Based on such previous evidence, we hypothesise that once an individual’s mental health is compromised, he or she may be less likely to care for others and act in a more anti-social manner. In columns (5) and (6) we provide evidence that this might be the case. We find a statistically significant increase in anti-social behaviour for individuals who were subject to greater virus exposure and experienced an increase in depressive symptoms (as measured by the 10-item CESD depression scale) and negative affect (or mood) (measured by the PANAS scale).30 Table A12 Mechanism: Improvement in Mental Health
Table A12 Anti-sociality Index
(1) (2) (3) (4) (5)
Post=1 ×LnCases 0.215*** 0.618 0.024 0.386 -0.157
(0.058) (0.403) (0.430) (0.457) (0.354)
Post=1 × Positive Affect ×LnCases -0.028
(0.029)
Post=1 × Life Satisfaction ×LnCases 0.054
(0.113)
Post=1 × Happiness ×LnCases -0.049
(0.122)
Post=1 × Meaningfulness ×LnCases 0.077
(0.089)
R2 0.115 0.207 0.185 0.194 0.202
Number of Individuals 522 522 522 522 522
Observations 1044 1044 1044 1044 1044
This table reports OLS estimates of equation (2) where the dependent variable is an index of anti-social behaviour. LnCases is the logged number of confirmed cases at the city-level per million inhabitants reported on the date of the third survey. All triple interaction terms provide estimates for potential mechanisms
Finally, besides psychological well-being, we also check for the effects of physiological well-being using self-reported health status as an indicator (column 7). We find no statistically significant difference, which leads us to conclude that changes in anti-social behaviour are likely to be driven by a deterioration in mental health. In the following section, we discuss interesting directions for the design of public health interventions to mitigate compromising social behaviour and mental health.
5.5 Limitations
The following clarifies important limitations of our sample with respect to attrition and generalizability. In addition, we also address the fact that our study’s time frame is limited to only the pre- and immediate post-outbreak and first lockdown period in China. Therefore, we are only able to provide estimates on the short-term impact of Covid-19 and our results are unable to speak to literature addressing long-term impacts and the effect of multiple lockdowns.
One of the major problems with longitudinal studies is attrition by introducing possible bias when participants who drop out of a study are systematically different from those who remain in it. We have taken various steps to deal with this potential concern in our dataset (all additional analysis can be found in Appendix B). Amongst others, we formally test for non-random attrition and find that attrition is unrelated to our treatment variable “city-level Covid-19 cases” yet is related to certain participant characteristics measured at baseline. We address attrition by implementing a separate BGWL test and by applying inverse probability weights to all our regressions. We acknowledge, however, that inverse probability weighting is limited in that it can only address attrition based on observable characteristics, and some attrition might still be non-random.
Another caveat is that our study was conducted with a convenience sample of university students from Beijing which is not representative of a more general population sample and therefore our results and suggestions for certain policy interventions should be interpreted considering this specific group. Nonetheless, although university students differ from the general population in certain characteristics (e.g., our sample is significantly younger and better educated and females are overrepresented), other research indicates that student populations exhibit very similar behavioural patterns with respect to social preferences, where university student samples usually provide lower bound estimates of pro-sociality (i.e., they are less altruistic) (Snowberg, Yariv, 2021, Falk, Meier, Zehnder, 2013).
Finally, our study focuses on the immediate impact of the Covid-19 outbreak, leveraging data from just before the outbreak of COVID-19 and immediately after the first wave was overcome. We are therefore not able to investigate preferences, perceptions and attitudes over longer periods of time or capture the effects of experiencing multiple lockdowns as other studies are able to (e.g. Harrison, Hofmeyr, Kincaid, Monroe, Ross, Schneider, Swarthout, 2022, Aragon, Bernal, Bosch, Molina, et al.). Noteworthy in the Chinese context is that China has maintained a Zero-Covid’ strategy, which has resulted in multiple large-scale lockdowns since the initial lockdown which we study. Another notable difference to the initial lockdown is that those later, larger and longer lockdowns have also sparked social unrest among residents and university students living under strict lockdown conditions. Some literature focusing on Covid-19 and social unrest highlights an association between increased emotional stress, anxiety and aggression and the incidence of social unrest (Lackner et al., 2021). This also speaks to our results, as we already observe an increase of negative affect and anti-social behaviour after the first lockdown period in China. Finally, we acknowledge, that our results must be interpreted as short term effects, as we are confined to data from before and immediately after the first lock-down. Our findings thus complement research which utilises longitudinal data and multiple surveys over longer time periods after the first lockdown.
6 Discussion and Conclusion
In this paper, we test whether exposure to the COVID-19 pandemic alters social behaviour and economic preferences of individuals. We exploit a unique experimental panel dataset that enables us to track changes in social behaviour and economic decision-making of the same individuals before and after the COVID-19 outbreak. In order to capture multidimensional responses to the virus outbreak, we construct city-level measures of societal concern and sentiment specific to COVID-19 in addition to standard epidemiological measures of virus exposure (cases per million inhabitants). The novelty of our approach pertains to our within-subject design which controls for unobserved individual characteristics, rich variation in individual exposure to multiple measures of the virus outbreak and the ability to provide insights into the channels transmitting the influence on individual preferences.
Our main finding is that greater exposure to COVID-19 causes an increase in anti-social behaviour. This finding contributes to a growing body of literature exploring how preferences respond to traumatic exogenous shocks and stressful situations such as war, conflict and public health crises. We are able to extend this earlier work by considering the acute effect on decision-making during an unfolding crisis and testing potential pathways through which such an event may influence behaviour, in particular mental health. Bauer et al. (2016) note that negative shocks are likely to have a positive legacy on pro-social behaviour in the long-term in terms of cooperation, altruistic giving and civic participation. This is in line with findings from Grimalda et al. (2021) showing that exposure to COVID-19 is associated with increased altruism measured months after the outbreak. In contrast, our findings show that, in the short-term, anti-social behaviour increases. In addition, we show that anxiety reflected by online search behaviour at the onset of the crisis and negative sentiments further undermine altruism. Our findings of increased antisociality and largely stable prosociality contribute to the literature on social preferences and exogenous shocks, which has largely produced mixed evidence. For instance, Branas-Garza et al. (2022) and Buso et al. (2020) find that prosociality decreased during periods of the first Covid-lockdowns. Others, such as Bokern et al. (2021) using data of multiple waves up to one year after the start of the first lockdown, note some short-term fluctuations yet show by large stability of social preferences measured with the help of a solidarity game. Shachat et al. (2021) provides mixed findings with respect to social preferences, showing greater levels of cooperation and lower levels of trust in their sample.31
We also contribute to the literature that examines the stability of risk and time preferences over the course of the Covid-19 outbreak. We find no significant changes in either risk or time preferences caused by exposure to the virus outbreak. Our findings are in line with a number of other studies providing evidence on the intertemporal stability of risk and time preferences (Angrisani, Cipriani, Guarino, Kendall, Ortiz de Zarate, 2020, Harrison, Hofmeyr, Kincaid, Monroe, Ross, Schneider, Swarthout, 2022, Drichoutis, Nayga, 2021, Guenther, Galizzi, Sanders, 2021). Two studies focusing on samples from Wuhan, China provide mixed evidence. Shachat et al. (2021) find increased risk tolerance, while Bu et al. (2020) find decreased risk tolerance in their post-outbreak survey, the latter effect potentially explained by rising pessimistic beliefs rather than changes in general risk preferences. Exploiting within-student changes in preferences, and variation in exposure to the outbreak, Bu et al. (2020) also show that risk taking is irresponsive to the level of virus exposure, which aligns with the findings from our within-subject analysis.
In addition to methodological innovations, our research is further able to elucidate the potential mechanisms driving the relationship between COVID-19 exposure and changes in anti-social behaviour. We find that the effect of virus-exposure on anti-social behaviour is most pronounced for those individuals who experienced an increase in depression or in their negative mood, whereas changes in cognitive ability and ego-depletion do not seem to interact with virus exposure. Our results are related to Belot et al. (2020) providing survey evidence from the early phase of the pandemic in China, documenting that younger people are significantly more likely to report negative effects on mental health. That said, our results from a student sample suggest that the effect on anti-social behaviour is likely to be smaller in a general population sample. Nonetheless, we are not able to rule out that alternative mechanisms exist, which are not explored in this paper. For example, economic stressors are often named as a cause of antisocial behaviour (e.g. Schneider et al., 2016). Due to a lack of specific data on individual economic conditions, we are unable to ascertain whether economic uncertainty or financial insecurity interact with increased virus exposure. Nonetheless, we believe economic stressors to be closely related to the emotional well-being pathway, for which we find robust evidence.
This finding has important and practical implications for policies designed to tackle major public health crisis events. While most government resources usually focus on mitigating the virus outbreak per se, such as in the form of expanding medical treatment for infected people, our results suggest that interventions to provide psychological support are critical in response to such pandemics. In the context of COVID-19 or similar events, investments should therefore also focus on expanding the supply of consultation with mental health professionals in the form of online and smartphone-based psychological support avenues that can reach a wider audience of potentially affected people. Our evidence suggests that such psychological interventions that aim to promote mental well-being should be initiated from the starting point of a major health crises and not follow much later (Duan and Zhu, 2020).32 In addition to counselling, research from behavioural economics and psychology point out promising light-touch interventions to reduce acute stress and depression and foster pro-social behaviour including the application of mindfulness mediation and mindfulness-based cognitive therapy (Iwamoto, Alexander, Torres, Irwin, Christakis, Nishi, 2020, Kang, Gray, Dovidio, 2014, Leiberg, Klimecki, Singer, 2011, Sun, Yao, Wei, Yu, 2015).33
Promoting and galvanizing socially responsible behaviour has been at the core of many governments’ COVID-19 response and research shows that pro-sociality predicts health behaviours and compliance with public health guidelines (Campos-Mercade et al., 2021).34 Our findings suggest that addressing poor mental health, early on during the crisis, may play an important role in avoiding increases in anti-social behaviour and ensuring wide-scale adherence to public health guidelines.
Declaration of Competing Interest
none
Appendix A
Tables
Table A10 Difference-in-difference Analysis: Pro-social Behaviour
Table A10 (1) (2) (3) (4)
Cooperation Trust Altruism Pro-sociality Index
Panel A
Post×LnCases -0.034 -0.155 0.003 -0.062
(0.112) (0.096) (0.109) (0.059)
[0.959] [0.353] [1.000] [0.577]
Panel B
Post× Baidu Index 0.139 -0.050 -0.283*** -0.065
(0.125) (0.117) (0.099) (0.068)
[1.000] [1.000] [0.075] [1.000]
Panel C
Post× Sentiment Index 0.140 -0.004 -0.002 0.045
(0.088) (0.083) (0.086) (0.051)
[0.887] [1.000] [1.000] [1.000]
Number of Individuals 522 522 522 522
Observations 1,044 1,044 1,044 1,044
Difference in differences analysis using fixed effects OLS regressions accounting for attrition using Inverse Probability Weighting (IPW). Standard errors clustered at the individual level in parenthesis. Multiple testing adjusted False Discovery Rate (FDR) q-values in square brackets. Post×LnCases is the interaction of logged number of cumulative confirmed cases at the city-level per million inhabitants officially reported on the date of the third survey with a post-outbreak indicator. Post× Baidu is the interaction of Baidu Search Index with a post-outbreak indicator. Post× Sentiment is the interaction of the Negative Sentiment Index with a post-outbreak indicator. All regressions include individual fixed effects, time-varying city-level controls for average immigration rate from Wuhan (20-23 Jan), number of hospitals per million inhabitants, health expenditure as a share of total expenditure, population density, GDP per capita and province-specific time trends. The dependent variable in column (4) is an index for pro-sociality based on the average of the z-scores of all three pro-social outcome variables.
Figures
Fig. A2 Frequency Distribution of Sample Exposure to COVID-19 Exposure measured as the logged number of cumulative confirmed city-level cases per million inhabitants on the date of the third survey (Panel A) and Baidu Search Index (Panel B) and Negative Sentiment Index (Panel C).
Fig. A2
Appendix B
Data Collection & Attrition
The experiment was initially designed as a two-wave experiment, with data collection taking place in October and December 2019. The short survey administered in October (Wave 1) was used to build an initial subject pool, with the objective to collect socio-demographic information and key preference measures relevant to our original research question. This information allowed us to implement a stratified randomisation procedure prior to Wave 2. In March 2020 we re-contacted all students from the original subject pool with a follow-up survey (Wave 3), designed around the new objective to assess the stability of preferences after COVID-19.
In all three waves, the entire data collection was conducted via the Chinese messaging app WeChat. Research Assistants were trained to contact students via WeChat, send survey links on pre-specified dates and administer payment directly to participants’ WeChat Wallets. Due to the lack of reliable and trustworthy online crowdsourcing platforms in China (such as Amazon MTurk or Prolific), using WeChat is a common procedure to maintain student subject pools for research purposes. However, one can expect high levels of attrition with this form of data collection (see e.g. Chen and Yang, 2019). To minimise attrition, the original study design included an additional prize-draw for ten 100Y bonus payments, for which participants were eligible only if they completed both initial survey waves (1 and 2). For Wave 3, no such incentive was possible.
From the initial sample (N=793) recruited in October 2019, we exclude 3 individuals for which no city location is available, 4 individuals who live in Hong Kong, Macau and Taiwan, and 15 individuals who completed Waves 1 and 3, but skipped Wave 2 (the main experimental survey in the pre-outbreak period). The remaining sample of 771 individuals serves as our starting point for the following attrition analysis. Table B1 shows the number of participants in each wave, the number of attrited individuals as well as the share of attrition for each survey wave. As attrition poses a potential threat to producing unbiased estimation results, the analysis below will carefully consider the potential impact of attrition.
Table B1 shows that attrition rates are high across the three waves in our data (16% between Wave 1 and 2, 19% between Wave 2 and 3), however, comparable to previous research conducted via WeChat surveys.
First, we explore the patterns of attrition in our data by comparing attritors vs. the non-attritors using a rich set of sociodemographic characteristics, heath indicators and economic preferences collected at baseline (Wave 1). We further explore city-level variables (representative of the respondents’ hometown) as well as city-level confirmed cumulative cases (log-transformed) reported in the respondents’ hometown on 14th March 2020, our primary treatment variable. Tables B2 and B3 present the results from this exercise for attrition between Waves 1 and 2 and 2 and 3, respectively. Columns (1) and (2) show the means of both attrition and non-attrition samples columns (3) and (4) report the difference in means and a p-value derived from a t-test for the equality of means. In Table B2 we first focus on attrition that occurred between Waves 1 and 2.Table B2 Difference between Attrited and Non-Attrited: Wave 1 to 2
Table B2 (1) (2) (3) (4)
Variable Non-Attritors Attritors Difference p-value
LnCases 2.607 2.633 0.026 (0.816)
Pay-off (Wave 1) 26.296 21.376 -4.920*** (0.003)
Cooperation 4,487.288 4,337.112 -150.176 (0.638)
Trust 48.260 47.728 -0.532 (0.831)
Risk Aversion 3.009 2.988 -0.021 (0.940)
Risk Taking 7,805.771 7,990.112 184.341 (0.670)
Age 19.920 20.488 0.568*** (0.001)
Female 0.774 0.704 -0.070* (0.092)
Rural Hukou 0.204 0.232 0.028 (0.487)
Only Child 0.655 0.664 0.009 (0.843)
General Health 3.771 3.632 -0.139* (0.097)
Depression Score 9.065 10.096 1.031** (0.047)
Economics Major 0.455 0.600 0.145*** (0.003)
Chronic Illness 0.091 0.104 0.013 (0.656)
Perseverance 2.532 2.552 0.020 (0.751)
Prosocial Trait 0.221 0.208 -0.013 (0.741)
Competitiveness 12.673 11.376 -1.297*** (0.001)
Immigration Rate (Wuhan) 0.497 0.568 0.071 (0.167)
Hospitals (City) 30.615 30.634 0.019 (0.991)
GDP per Capita (City) 90.283 84.338 -5.945 (0.181)
Health Expenditure Share (City) 0.077 0.081 0.004 (0.167)
Observations 646 125 771
Table B3 Difference between Attrited and Non-attrited: Wave 2 to 3
Table B3 (1) (2) (3) (4)
Variable Non-Attritors Attritors Difference p-value
LnCases 2.596 2.654 0.059 (0.590)
Pay-off (Wave 1) 26.205 26.677 0.472 (0.795)
Pay-off (Wave 2) 32.518 29.390 -3.127 (0.157)
Pay-off Difference (W1-W2) 6.313 2.713 -3.600 (0.215)
Cooperation 4,472.960 4,547.605 74.645 (0.817)
Trust 48.056 49.121 1.065 (0.675)
Risk Aversion 3.008 2.687 -0.321 (0.257)
Risk Taking 7,605.580 8,648.508 1,042.928** (0.015)
Altruism 3.939 3.774 -0.165 (0.632)
Punishment (Binary) 0.588 0.573 -0.016 (0.753)
Punishment (Extent) 2.103 2.081 -0.023 (0.923)
Destruction 0.157 0.145 -0.012 (0.742)
Taking 9.983 11.089 1.106* (0.079)
Taking (Deterrence) 9.362 10.500 1.138* (0.095)
Age 19.849 20.218 0.369** (0.017)
Female 0.818 0.589 -0.229*** (0.000)
Rural Hukou 0.207 0.194 -0.013 (0.741)
Only Child 0.644 0.702 0.058 (0.223)
General Health 3.699 3.653 -0.046 (0.575)
Depression Score 12.153 13.097 0.944* (0.088)
Economics Major 0.443 0.508 0.066 (0.188)
Chronic Illness 0.088 0.105 0.017 (0.562)
Perseverance 2.522 2.573 0.051 (0.438)
Prosocial Trait 0.230 0.185 -0.044 (0.285)
Competitiveness 12.795 12.161 -0.634 (0.125)
Raven Score 6.548 6.137 -0.411*** (0.006)
Sleep Quality 7.739 7.597 -0.143 (0.364)
Life Satisfaction 3.404 3.331 -0.074 (0.438)
Immigration Rate (Wuhan) 0.485 0.545 0.059 (0.224)
Hospitals (City) 30.530 30.975 0.446 (0.801)
GDP per Capita (City) 90.826 87.998 -2.828 (0.538)
Health Expenditure Share (City) 0.076 0.077 0.001 (0.768)
Observations 522 124 646
Statistically significant differences in means of attritors and non-attritors show that there are systematic attrition patterns between the first two survey waves. With respect to sociodemographic characteristics, we observe that individuals who are older, identify as male, major in economics, revealed a lower willingness to compete and earned less in the baseline survey are all more likely to leave the sample at Wave 2. With respect to health variables, individuals with a higher depression scores and a lower general health score are significantly more likely to attrite.
In Table B3 we focus on attrition that occurred between Waves 2 and 3. In addition to the individual sociodemographic characteristics, health variables and city-level variables observed at baseline, we further include variables measured in Wave 2. These variables include our main outcome measures of anti-social and norm-enforcement behaviour as well as additional subjective well-being and health indicators. Here we see that older participants and men are significantly more likely to be in the attrition sample. Attritors are less risk-averse and show slightly more anti-social behaviour in the Take-Game. Individuals with higher depression scores and lower cognitive ability are more likely to attrite.
Following Fitzgerald et al. (1998) we formally test for non-random attrition in the data. Specifically, we explore whether the observable individual- and city-level characteristics are associated with a greater probability of leaving the sample. To do so, we regress an attrition indicator, equal to 1 for attrited individuals and zero otherwise, on the full set of variables measured in the initial survey waves shown in Tables B2 and B3. If attrition is random, the estimated parameters will not be statistically different from zero. Results are shown in Table B4 . The dependent variable in column (1) captures attrition at either Wave 2 or 3. The results indicate that our primary treatment variable (city-level COVID-19 cases) is unrelated to attrition, which shows that attrition is exogenous to treatment (i.e., exposure). However, the analysis confirms that attrition is significantly associated with certain baseline characteristics, which suggests that attrition is non-random and warrants further investigation into potential selection bias.Table B4 Attrition Probit
Table B4 (1)
Attrition any Wave
LnCases 0.040
(0.079)
Pay-off (Wave 1) -0.005
(0.003)
Cooperation -0.000
(0.000)
Trust -0.001
(0.002)
Risk Aversion -0.004
(0.017)
Risk Taking 0.000
(0.000)
Age 0.102***
(0.028)
Female -0.537***
(0.112)
Rural Hukou 0.013
(0.141)
Only Child 0.177
(0.123)
General Health -0.001
(0.063)
Depression Score 0.012
(0.010)
Economics Major 0.281***
(0.099)
Chronic Illness 0.094
(0.176)
Perseverance 0.100
(0.077)
Prosocial Trait -0.122
(0.121)
Competitiveness -0.030**
(0.013)
Immigration Rate (Wuhan) 0.067
(0.144)
Hospitals (City) 0.002
(0.003)
GDP per Capita (City) -0.002
(0.002)
Health Expenditure Share (City) 0.933
(1.760)
Constant -2.361***
(0.788)
Observations 771
In the presence of non-random attrition, a second standard procedure is to assess whether attrition is ignorable. To do so, we implement the BGLW (Becketti, Gould, Lilliard, & Welch, 1988) test which assesses whether attrition is statistically associated with our main dependent variables. The BGLW test involves regressing an outcome variable from the initial wave on a set of explanatory variables, an attrition dummy (capturing future attrition), and the attrition dummy interacted with the other explanatory variables. An F-test of the joint significance of the attrition dummy and the interaction variables can help to determine whether the explanatory variables differ systematically between non-attrited and attrited households. We implement the BGLW test for outcomes measured in both Waves 1 and 2, using the attrition dummy from the previous attrition test and its interaction with individual characteristics and city-level variables as the predictors. We reject the null hypothesis of no difference between attrited and non-attrited for only two of 12 outcomes, namely the Trust Game (Wave 1) and our measure of Altruism (Wave 2). Although we find no pervasive evidence that attrition is non-ignorable, differential attrition may still pose a threat to statistical inference from our analysis.
In an attempt to adjust for differential attrition, we use the inverse probability weighting (IPW) technique, following the procedure outlined in Wooldridge, 2002, Wooldridge, 2007. The key assumption of IPW methods is that by conditioning on a set of observed covariates, the complete-population density of an outcome of interest can be derived by weighting the conditional density by the inverse selection probabilities (Fitzgerald et al., 1998). We use the full set of individual and city-level characteristics observable at baseline (Wave 1), shown in column (3) of Table B4, to predict the probability (pi) that an individual will be observed in all three survey waves. Each individual receives a weight equal to 1/pi, giving more weight to participants who are similar on baseline observables to those individuals who did not stay in the sample at Waves 2 or 3. We apply the IPW to all model estimates throughout the analysis.
Appendix C
Experimental Protocol & Questionnaire
Appendix C is hosted online at https://drive.google.com/file/d/1-JDd4r19m91zOsISqWJFPiEfJWVaKL51/view?usp=sharing
Supplementary material
Supplementary material associated with this article can be found, in the online version, at 10.1016/j.jebo.2022.12.007
Appendix D Supplementary materials
Supplementary Data S1
Supplementary Raw Research Data. This is open data under the CC BY license http://creativecommons.org/licenses/by/4.0/
Supplementary Data S1
Data Availability
Data will be made available on request.
1 The authors are not making an assertion as to the global origin of the specific virus, but simply that within China, Wuhan municipal Center for Disease Control and Prevention (CDC) released the first epidemiological alert of 27 cases on 31 December 2019.
2 See, for instance, Andrabi and Das (2017); Becchetti et al. (2014); Brown et al. (2019); Callen (2015); Cassar, Grosjean, Whitt, 2013, Cassar, Grosjean, Whitt, 2014, Cassar, Healy, von Kessler, 2017; Cohn et al. (2015); Falco and Vieider (2018); Filipski et al. (2019); Fleming et al. (2014); Grosjean (2014); Hanaoka et al. (2018); Page et al. (2014); Said et al. (2015); Voors et al. (2012).
3 See, for instance, Aksoy and Palma (2019); Cahlíková and Cingl (2017); Cahlikova et al. (2019); Cettolin et al. (2019); Delaney et al. (2014); Fehr et al. (2019); Haushofer et al. (2013); Kettlewell (2019); Koppel et al. (2017); Prediger et al. (2014).
4 We acknowledge that the majority of Covid cases were concentrated in Wuhan during the first Wave of the pandemic in China. Our findings thus complement those of Shachat et al. (2021) and Bu et al. (2020) by exploiting the wider geographic dispersion in our data. Moreover, comparing only the extremely high prevalence rate in Wuhan against zero otherwise could potentially exacerbate the variance of the ”intervention” and, thus, the estimated ”treatment” effect of Covid-19. The wider geographic coverage of our sample is able to reduce this upward bias. This point, that empirical regularities in the far tails of the distribution tend to disappear, has been re-illustrated recently by (Hamermesh and Leigh, 2022).
5 Notably, many governments have designed their response to COVID-19 around the premise that people are able and willing to engage in pro-social behaviour. The UK’s slogan ‘Stay Home, Protect the NHS, Save Lives’ (and other similar informational campaigns in other countries) directly conveys an underlying appeal to pro-social behaviour. In contrast, the Chinese government has largely drawn on wartime rhetoric to enforce strict containment and lockdown policies.
6 We acknowledge that it is often criticised that student samples do not accurately represent the overall population. However, there is increasing evidence that student samples are appropriate for studying human social behaviour (Exadaktylos, Espín, Brañas Garza, 2013, Falk, Meier, Zehnder, 2013). In addition, we argue that in the case of COVID-19 response, this is a particularly important demographic. Students are subject to a lower risk of suffering severe medical consequences of infection, however, mitigating the spread of the virus relies heavily on low-risk demographics to follow public health guidelines and engage in social distancing. Hence, we believe that studying students’ behaviour is highly relevant in the context of COVID-19.
7 Note that Waves 1 and 2 of the experiment were initially designed and collected as part of a pre-registered experiment on economic decision-making and air pollution. Details at: https://doi.org/10.1257/rct.4856-1.0
8 While incentivization is the norm for preference elicitation in experimental economics in order to reduce hypothetical bias, we would like to highlight recent results by Hackethal et al. (2022) which suggest that hypothetical bias is rather limited when eliciting risk preferences in online experiments 鼂ǣ a setting very similar to ours. Nonetheless, previous literature provides no clear indication if the results of Hackethal et al. (2022) can be extended to social preference elicitation (Engel, 2011, Gillis, Hettler, 2007, Camerer, Mobbs, 2017).
9 Note that participants at no point were provided feedback about the (payoff) outcomes of the different experimental tasks they completed. By doing so, we can exclude learning effects or strategic behaviour of participants, which could potentially bias our results.
10 We acknowledge that if a task was chosen in which participants were assigned to multiple roles, we applied a Pay One’ payment procedure, i.e., we randomly draw one role of that task for payment. Such a procedure has been shown to eliminate hedging opportunities and also wealth effects (e.g. Bardsley et al., 2009)
11 Previous literature indicates that even hypothetical incentives in economic experiments can give accurate results (e.g. Gillis and Hettler, 2007)
12 For more details find the English translation of the instructions in Appendix C.
13 To calculate the mid-points, we first replaced the infinity value for the lower bound with -1 and for the upper bound with 10.
14 While the theory of ego-depletion is very prevalent in the psychology literature, more recently, it has also attracted attention in economics and there is a growing number of studies which have assessed the impact of self-control depletion on economic preferences (Achtziger, Alós-Ferrer, Wagner, 2016, Achtziger, Alós-Ferrer, Wagner, 2018, Gerhardt, Schildberg-Hörisch, Willrodt, 2017).
15 The following five items were used: “I feel drained”, “I feel calm and rational”, “I feel lazy”, “I feel sharp and focused” and “I feel like my willpower is gone”. Responses were given on a 5-point Likert scale ranging from 1 “not true” to 5 “very true”.
16 For our analysis, we selected to explore sanctioning behaviour for the most unequal distribution (i.e., dictator giving nothing to the recipient). We also observe punishment decisions for each of the alternative transfer amounts (2, 4, 6, 8 and 10 Yuan) and now provide a descriptive overview Appendix Figure A1. For robustness, we additionally explore sanctioning behaviour to enforce a 50/50 distribution norm based on the amount participants were willing to punish if the dictator transferred half of their endowment (i.e., 10 Yuan). Our results are robust to this analysis.
17 We acknowledge that a greater proportion of participants in our sample are female (80%). This is due to the fact that around 70% of our sample come from liberal arts colleges/universities where the share of female students constitutes on average more than 60% with the highest share being at 98%. However, related research on preferences and the Covid-19 pandemic in China does not suggest a significant heterogeneity in results by gender Bu et al. (2020). The gender bias of our sample should therefore not preclude a valid interpretation of the presented findings.
18 Lu et al. (2018) have utilised this exogenously determined admission rule to study the impact of students’ experiences in competitive college admissions on their risk preferences.
19 Admittedly, there are different measures of exposure that one can consider. We primarily use the number of confirmed infections or cases to measure exposure, which is heavily used in the epidemiological literature to model epidemic spread (e.g. Zhao and Chen, 2020) and well-accepted in the economics literature to investigate the effects of epidemics and pandemics on economic outcomes (Aksoy, Eichengreen, Saka, 2020, Flückiger, Ludwig, Önder, 2019, Gonzalez-Torres, Esposito, 2020). An alternative measure is mortality and number of deaths. While mortality has been used as a measure of severity in papers assessing the long-term effects of a pandemic such as the Spanish flu (Aassve, Alfani, Gandolfi, Moglie, 2020, Adda, 2016, Karlsson, Nilsson, Pichler, 2014), it is not practical for assessing short-term effects due to its little variability at the onset of a pandemic. Epidemiological measures may however not fully capture the extent of exposure to the virus nor the general social concern’ or sentiment’ about the epidemic at the time. For robustness purposes we, thus, also use two alternative measures of exposure that capture these dimensions based on internet and social media data.
20 We use a log-transformation of COVID-19 confirmed cases to deal with skewed data due to the over proportionally large amount of cases reported in Wuhan City and Hubei province where some of our participants were located.
21 A popular view is that an authoritarian regime censors social media. We believe that Chinese social media data provides a particularly interesting and valid source of expressed opinion in China. First, social media is not necessarily censored in an authoritarian regime, as the government can also use it as propaganda or surveillance tools (Qin et al., 2017). Second, the COVID-19 outbreak is a public health crisis and is less sensitive than a political event for the purpose of censorship of public opinions. Third, Sina microblog has been widely used as a reliable tool to analyse and track sentiment dynamics, psychological well-being, public knowledge and opinions, as well as a range of other attitudes towards public issues (e.g. air pollution in Zheng et al. (2019) and COVID-19 (Han, Lam, Li, Guo, Zhang, Li, Chen, Chen, Zhang, Pang, Chen, 2020, Li).
22 There are typically two terms in Chinese education system 鼂ǣ autumn and spring terms. The former consists of 17-20 weeks starting from early September till the Chinese New Year. The term dates are pre-determined and released before each academic year in September. The Term dates were not altered on account of the pandemic.
23 For example, people would migrate out of cities in response to rising risk of adverse events (Brown et al., 2019).
24 For example, some of our sample universities also required students to report their locations and health information on a daily basis. Mobility out of their current city has been forbidden.
25 The city-level factors are the 2018 data compiled from provincial statistical yearbooks. The AQI is an index of air quality consisting of six key pollutants from 1,436 air monitoring stations across 338 cities, having been set up by the Ministry of Ecology and Environment since 2012. We calculate the annual average AQI for each city based on daily AQI readings between 2015-2019.
26 All regressions are estimated using all participants who took part in all 3 survey waves (N=522). Note that 15 individuals were excluded from the original sample (N=539), who had not completed all three surveys. Additionally, one individual from Macau and one individual from Hong Kong were removed from the sampled due to unavailability of data for control variables. Individual beta parameters could not be estimated for 9 individuals. This resulted in models for present bias to be estimated with 513 individuals and all other models estimated with 522 individuals. The full results of each regression can be found in Appendix Tables A8 鼂ǣ A11. A visualisation of treatment effects for all outcome variables is provided in Figures A4 and A5.
27 The Anti-sociality index is an average of z-scores of Destruction, Taking and Taking with deterrence. The index construction follows Kling et al. (2007).
28 Specifically, we asked respondents to indicate, on a 10-point Likert Scale, the perceived level of risk/threat posed by the virus to (1) themselves, (2) their family and (3) society as a whole. This provides a measure of emotional risk perception. We further asked respondents how they perceived the level of infections at their current location and whether any of their friends or family had been infected with the virus, which captures cognitive risk perception. As all five variables are highly correlated, we conduct a factor analysis to predict an underlying ‘Virus-Risk Factor’ for each individual.
29 The index is constructed by calculating the average of z-scores of the three tasks of the anti-social behaviour module following Kling et al. (2007).
30 We also assess whether changes in other dimensions of psychological well-being including happiness and positive mood interact with virus-prevalence. We find no statistically significant difference in anti-social behaviour for individuals with increased positive affect (on the date of the survey), self-assessed happiness, meaningfulness of life and life satisfaction (see table A12 in the Appendix).
31 We acknowledge that our experimental approach holds many similarities to Shachat et al. (2021), but there are also some notable differences with respect to research design and identification strategy, including the use of a within- instead of between-subject design, additional survey data to study potential mechanisms and a more nuanced analysis with respect to exposure to the virus outbreak through ample geographical variation in virus prevalence. Note that the main sample difference to Shachat et al. (2021) and Bu et al. (2020) is that both studies heavily draw on students located in Hubei province where the majority of Covid-19 cases were reported, while our study relies on geographical variation in student’s location with only few students having been located in Hubei.
32 The advantage of online consulting is that it can be efficiently scaled at low cost and at the same time there is evidence of the effectiveness of digitally provided psychotherapy when compared to face-to-face therapy, in particular when treating acute symptoms of stress and depression (Andersson, Cuijpers, Carlbring, Riper, Hedman, 2014, Barak, Hen, Boniel-Nissim, Shapira, 2008, Carlbring, Andersson, Cuijpers, Riper, Hedman-Lagerlöf, 2018).
33 Again, this intervention has been shown to be effective when delivered online (Spijkerman et al., 2016) and thus lends itself for large-scale application during COVID-19 or similar events.
34 We also assess whether social behaviour correlates with self-reported compliance with protective behaviour and knowledge related to the virus. Exact wording of the questions can be found in Appendix C. We find little to no correlation between our indices of pro-sociality, anti-sociality and norm-enforcement and protective behaviour as well as virus knowledge. This, however, is likely caused by a lack of variation in compliance with protective behaviour, with overall compliance being overwhelmingly high amongst our sample population. Regression results are presented in Table A13 in the Appendix.
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| 0 | PMC9744689 | NO-CC CODE | 2022-12-15 00:01:53 | no | J Econ Behav Organ. 2022 Dec 13; doi: 10.1016/j.jebo.2022.12.007 | utf-8 | J Econ Behav Organ | 2,022 | 10.1016/j.jebo.2022.12.007 | oa_other |
==== Front
Chaos Solitons Fractals
Chaos Solitons Fractals
Chaos, Solitons, and Fractals
0960-0779
0960-0779
Elsevier Ltd.
S0960-0779(22)01163-8
10.1016/j.chaos.2022.112984
112984
Article
COVID-19 spread control policies based early dynamics forecasting using deep learning algorithm☆
Ali Furqan a
Ullah Farman b
Khan Junaid Iqbal a
Khan Jebran ac
Sardar Abdul Wasay a
Lee Sungchang a⁎
a School of Electronics and Information Engineering, Korea Aerospace University, Deogyang-gu, Goyang-si 412-791, Gyeonggi-do, South Korea
b Department of Electrical and Computer Engineering, COMSATS University Islamabad, Attock Campus, Punjab 43600, Pakistan
c Department of Artificial Intelligence, AJOU University, South Korea
⁎ Corresponding author.
13 12 2022
13 12 2022
11298424 1 2022
14 10 2022
1 12 2022
© 2022 Elsevier Ltd. All rights reserved.
2022
Elsevier Ltd
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Many severe epidemics and pandemics have hit human civilizations throughout history. The recent Sever Actuate Respiratory disease SARS-CoV-2 known as COVID-19 became a global disease and is still growing around the globe. It has severely affected the world’s economy and ways of life. It necessitates predicting the spread in advance and considering various control policies to avoid the country’s complete closure. In this paper, we propose deep learning-based stacked Bi-directional long short-term memory (Stacked Bi-LSTM) network that forecasts COVID-19 more accurately for the country of South Korea. The paper’s main objectives are to present a lightweight, accurate, and optimized model to predict the spread considering restriction policies such as school closure, workspace closing, and the canceling of public events. Based on the fourteen parameters (including control policies), we predict and forecast the future value of the number of positive, dead, recovered, and quarantined cases. In this paper, we use the dataset of South Korea comprised of several control policies implemented for minimizing the spread of COVID-19. We compare the performance of the stacked Bi-LSTM with the traditional time-series models and LSTM model using the performance metrics mean absolute error (MAE), mean absolute percentage error (MAPE), and root mean square error (RMSE). Moreover, we study the impact of control policies on forecasting accuracy. We further study the impact of changing the Bi-LSTM default activation functions Tanh with ReLU on forecasting accuracy. The research provides insight to policymakers to optimize the pooling of resources more optimally on the correct date and time prior to the event and to control the spread by employing various strategies in the meantime.
Keywords
COVID-19
Forecasting
Deep Learning
Stacked Bi-LSTM
Long short-term memory
Pandemic
Time series
==== Body
pmc1 Introduction
Mortality is an inescapable reality of the human experience, but the unavoidable nature of epidemics is debatable. Humanity has been suffering from epidemic diseases throughout history. However, once epidemics become foreseeable, it is possible to make preparations and fight back. COVID-19 is a novel corona virus infectious disease that transmits from person to person through airborne particles [1]. Major symptoms include shortness of breath and sometimes loss of taste buds and smell. While the virus mortality rate is relatively low, COVID-19 has proven to be quite adept at spreading quickly to large numbers of people. The impact of this virus on the country of South Korea can be seen in Fig. 1.
In January 2020, COVID-19 and the relevant precautionary guidelines were publicly announced by the World Health Organization (WHO) [3]. Many countries around the globe enforced curfews in their cities and adopted a complete state of lockdown. Health authorities stated that the disease had a more significant impact on older demographic groups. Thus far, the virus has killed more than five million people worldwide. Official figures are based on data accumulated by researchers, keeping in mind that such calculations are always prone to errors or bias. Some advanced studies have also shown that forecasting this disease in the future with minimal error is also possible, particularly with deep learning modeling.Fig. 1 Number of COVID-19 cases in South Korea as of October 14, 2021 [2].
Previous studies have highlighted that pandemics do not follow a linear pattern in their spread [4], [5]. Accordingly, the challenge is to not only control the pandemic with strategies like contact tracing and social distancing [6], but also develop a model that can forecast the future given nonlinear and unpatterned data, allowing the policy makers to make proper action to deal with future state of the pandemic. This problem persists due to data scarcity and prediction uncertainty. The decay in uncertainty is directly proportional to how well the model performs over the nonlinear patterns of historical data. Researchers have proposed various techniques to resolve nonlinear pattern forecasting with lower error rates and higher levels of accuracy [7]. Deep learning is an effective tool employed to address these issues, eliciting promising results. Previous approaches attempted to fit a curve using one feature plotted against time. Multi-parametric approaches have made this obsolete, which consider multiple features plotted against time and fit the curve upon the relevant pattern. In deep learning, the selection of essential and relevant parameters is critical [8]. Therefore, multiple parameters are tested in a given scenario to fit the best curve against time and arrive at the model with the lowest validation error.
The government must pool resources optimally at the correct locations and times to combat the pandemic. In this paper, we propose a deep learning-based stacked Bi-directional long short-term memory (Bi-LSTM) network that can forecast four different parameters in time, i.e., COVID-19 confirmed patients, recovered, dead, and quarantined cases. Bi-LSTM is an advanced variant of recurrent neural networks (RNNs) [9]. RNNs are prone to the vanishing gradient problem [10], whereas Bi-LSTM models mitigate the vanishing effect. Different parameters comprised of control policies are input to the model. In order to evaluate the error, we employ the mean absolute error (MAE), root mean squared error (RMSE), and mean absolute percentage error (MAPE). The proposed model is efficient and computationally less expensive than previous hybrid approaches, which generally require significant computational power. The proposed approach is unique from previous approaches as it utilizes control policies data. However, in the literature the deep learning models are just trained on forecasting parameters such as positive rate, death rate etc. Our proposed approach uses control policies along with forecasting parameters to yield better and accurate results.
In the light of above description, following are our main contributions.
1. Design an accurate, simple, stacked bidirectional LSTM model that can forecast COVID-19 for the next three days.
2. Utilizing novel features set from the existing COVID-19 data such as user mobility policies.
3. Analyzing the mobility policies that are most helpful in increasing model precision.
4. Forecasting the positive rate, death rate, recovered rate, and quarantined rate considering the ten different policies employed by Govt such as school closure, movement between cities, and international travel.
The rest of the paper is divided as follow: Section 2 briefly describe the related works and background about the time series forecasting and modeling in context of COVID-19 and AI. The proposed methodology for forecasting COVID-19 using novel features is explained in Section 3. Section 4 shows the results and discussion on it, and finally we conclude the paper findings in Section 5.
2 Literature review
Many studies exist that show the current spread of COVID-19 and its effect on human health, psychology, and daily routines. There are also studies on detection, diagnosis, and the current transmission rate.
Many mathematical models have been derived to forecast the outspread of COVID-19 and came up with diagnostics. An early Monte Carlo simulation model was applied to show the transmission rate of COVID-19 with the help of a daily mean reproduction number (Rt), taking different parameters into account, such as the number of daily cases and the number of confirmed cases versus deaths [11]. A recent study has been carried out on COVID- 19 diagnostics using radiological images. Systematic reviews were collected from three different databases, PubMed, Scopus, and Web of Science, providing insights into which model provided the best accuracy in terms of sensitivity and specificity values [12]. Another study compared the federated machine learning model versus the traditional machine learning model and derived the best parameters for the early detection of COVID-19 using chest X-ray images. It was observed that the activation function (softmax) and a model optimizer (SGD) played a crucial role in improving model accuracy [13].
Time-series analysis is forecasting the future of a particular phenomenon by utilizing previous data. It is categorized into three different classes [14]: statistical modeling, machine learning modeling, and deep learning modeling for time series analysis. The proposed research is concerned with developing a better model for forecasting COVID-19 cases with respect to time. It provides insight into the spread pattern of COVID-19 by visualizing its spread graph, it also helps policymakers to determine the best policies that are helpful in improving the accuracy of forecast and is meaningful for the control of COVID-19. To forecast the growth rate of COVID-19, researchers have used various approaches to obtain the best accuracy [15]. Amar et al. [16] used a machine learning regression model to forecast the COVID-19 spread rate in Egypt. They used seven different regression model variants and came up with the best approach with the minimum error value. The models forecasted COVID-19 for the next 15 days with a government-provided dataset. Table 1 shows the summary of approaches and datasets used for the COVID-19 future value forecasting.
Ardabili et al. [36] forecasted COVID- 19 spread for Italy, China, Iran, Germany, and the United States using the dataset of the World metro website [37]. They used multilayer perceptron (MLP) and adaptive neuro-fuzzy inference systems (ANFIS) to easily forecast COVID-19 infection rates with significantly less error. They proposed that to increase the accuracy of the MLP model, the integration of susceptible-exposed-infectious- removed (SEIR) showed promising results. Gupta et al. [38] predicted three different parameters: active rate, death rate, and recovered rate using the data of [39]. Using three different machine learning models, the support vector machine (SVM) model, FB prophet, and linear regression model, the FB prophet achieved the highest accuracy. US COVID-19 cases using ML and statistical models are studied in [40]. The study showed that the random forest model best found the cumulative growth of COVID-19 in the US. They also concluded that the rise of COVID-19 was significantly affected by the implementation of shelter-in-place (SIP) orders, which caused a reduction in COVID-19 cases and set an example many countries followed.Table 1 Literature review and related works for forecasting COVID-19 cases.
Ref No. Proposed Model Key Assertion Dataset
[17] The author aims to predict the future conditions of novel Coronavirus to recede its impact. Stacked LSTM, Bi-directional LSTM, ConvLSTM COVID-19 cases were forecasted for one month. Convolution LSTM outperforms the other two models. [18], [19]
[20] The goal is to forecast time series at large intervals. Transformers A self-attention-based transformer network with exceptional capability in time series forecasting is demonstrated. Real-world TSF datasets
[21] It demonstrates that COVID-19 spreads at varying rates and scales in distinct geographic regions. Attention crossing time series model Author created a new forecasting model called ACTS that produces predictions by analyzing patterns across several time - series data. Johns Hopkins University
[22] A worldwide forecasting tool that forecasts COVID-19 confirmed cases for the next seven days around the world. ANN, LSTM, ARIMA A comparative analysis between 4 different models is conducted i.e. ANN, LSTM, ARIMA and CNN. John Hopkins University
[23] The aim is to forecast COVID-19 infection rate of 60 days for 4 different nations. Fb-Prophet Demonstrated a nonlinear association between total registered cases and confirmed cases, as well as a linear relationship between confirmed cases and deaths. John Hopkins University
[24] The aim is to forecast COVID-19 for the selected states of India using different models. Encoder-Decoder LSTM and bidirectional LSTM Authors compares the infections spread of different states with those regions where the infections spread have reached its peak. [25]
[26] Forecasting, predictive modeling, and creating a heat map representation of policy measures across countries. ARIMA, LSTM, MLP LSTM outperformed the other models in terms of forecast accuracy and fewer error rate. Johns Hopkins University
[27] Nine countries COVID-19 data Forecasting using Deep Learning. M-LSTM, MLP, Random Forest The author utilized multiple models, compared their performances and effective features in forecasting. John Hopkins University
[28] Predicting the future cases of infection, based on the study of data mined from the internet search terms of people in the affected region. GWO-LSTM (Grey Wolf Optimizer) The author automated the process of hyperparameter-tuning using a meta-heuristic search algorithm namely, Grey Wolf Optimization (GWO). Johns Hopkins University
[29] Three hybrid approaches for forecasting COVID-19 using time series data, based on combining three deep learning models is proposed. Multi-head attention, CNN, LSTM The author used deep learning and Bayesian optimization methodologies for hyperparameter-tuning. Johns Hopkins University
[30] A DL-based approach is used to forecast the rate of new cases and new deaths cases for the three and seven days ahead. LSTM, Convolutional LSTM, and GRU Results show that forecasting for a longer horizon is harder than forecasting for a shorter horizon and Bi-directional models have lower error than other models. [31]
[32] The author proposed an ANN based online incremental learning technique to analyze the temporal dynamics of the disease spread. ANN The model is able to intelligently adapt to new ground realities in real-time eliminating the need to retrain the model from scratch. [33]
[34] In order to estimate COVID-19 (SARS-CoV-2) evolution in Spain, a semi-parametric technique was proposed. The Bayesian optimization with LSTM. It combines new Deep Learning (DL) techniques for analyzing sequences with the traditional Bayesian Poisson-Gamma model. [35]
Saba and Elsheikh et al. [41] used two different approaches, nonlinear autoregressive artificial neural networks (NARANN) and autoregressive integrated moving average (ARIMA), to forecast the growth of COVID-19 in Egypt. RMSE, MAE, the deviation ratio, and the coefficient of residual mass are used as performance metrics, and NARANN outperformed ARIMA. Neeraj et al. [42] proposed a new attention-based model named AttentionLSTM, which used the architecture of the LSTM model. However, an additional attention layer was added to the model to store information in the context vector with respect to time. Instead of using the hidden state vector itself, the authors used the phenomena of fine-grained attention, i.e. attention on hidden state dimensions. The author additionally added an embedding layer that converted time into vector representations. This layer is known as Time2Vec. They employed the dataset obtained from Johns Hopkins University, and they forecasted the data of five different countries Canada, North America, Italy, Spain, and France.
Stefano Cabras et al. [43] proposed a semi-parametric approach to forecast COVID-19 for the next 14 days using an LSTM deep learning model along with the Bayesian Poisson-Gamma model using data from [44]. The data had not been recorded properly, so they used cumulative incidences over 14 days, which resulted in more reliable information about the pandemic. LSTM deep learning model [45] forecasted the COVID-19 and its possible endpoint in Canada using the Johns Hopkins University and the Canadian Health Authority. They also found out that the recovery rate played a vital role in forecasting COVID-19 more accurately. They applied a wavelet transformation to preserve the time-frequency component to minimize random noise in the dataset. They concluded that their model performed exceptionally well as compared to existing models.
Arora et al. [46] forecasted COVID-19 using three different deep learning models, stacked LSTM, bidirectional LSTM, and convolutional LSTM. The data was collected from the Ministry of Health and Family Welfare. The bidirectional LSTM provided better results than the other two models. The dataset was used to forecast weekly and daily cases for all Indian states using historical data from March 2020 to May 2020. Devaraj et al. [47] forecasted the outbreak of COVID-19 using different machine learning and deep learning models, namely ARIMA, LSTM, stacked LSTM, and the FB prophet model. They forecasted the cumulative confirmed positive patients, dead, and recovered cases for different cities in India. The correlation between different input parameters was computed as it was a multivariate time series approach. Features like rainfall, cumulative infected cases, total population, area, temperature, and population density were used. The stacked LSTM performed better than the other models, with an error reduction of two percent. Tomar and Gupta et al. [48] proposed a simple and effective LSTM-based approach to forecast COVID-19 for the next 30 days in India using the Johns Hopkins University dataset. They used this data to forecast total confirmed cases, daily confirmed cases, total recovered cases, and total deaths. They found that recoveries were as high as the total number of infections, but the time needed for recovery was higher than the time needed for viral transmission. Hence, recovery time needed to be improved by utilizing resources more effectively to achieve a healthier balance. The LSTM-based approach delivered 90 percent accuracy in predicting COVID cases.Fig. 2 Proposed architecture for COVID-19 spread control policies based early dynamics forecasting using deep learning algorithm.
Huang et al. [49] presented an analysis of COVID-19 diagnosis and isolation procedures that effectively slowed the spread of the virus, as well as a reduction in casualties during a period of the rapid increase in diagnosed cases in Wuhan, China. In the early phases of a pandemic, the authors urged governments to implement forceful public health actions quickly. However, such strategies have not been as effective in other nations with similar populations, such as India, even though they would have helped curb COVID-19’s spread in the US and Brazil.
3 The proposed COVID-19 spread control policies forecasting using deep learning algorithm
In this section, we have covered the pipeline of our deep learning model to forecast COVID-19 cases. We employed a stacked Bi-LSTM-based approach using the COVID-19 control policies to forecast confirmed cases, recovered cases, death cases, and people quarantined. We introduce restriction policy data and use this data to plot curves. Bi-LSTM is a type of RNN that combines the LSTM layers in the forward and backward directions. It avoids long-term dependencies and is best for processing and predicting time-series problems. First, the LSTM is applied in a forward direction over the input sequence data and then in the reverse direction (i.e., backward layer). Applying both the forward and backward LSTM twice improves the long-term dependencies and accuracy of the model. Before applying the model, we clean and normalize it as preprocessing steps. The missing data are imputed using the forward and backward imputation methods. We apply feature extraction techniques to determine the dependent and independent variables from the data. A windowing technique is applied to the multivariate data to forecast one and three days’ future value by considering data for the past three and seven days. Moreover, we split the data into training and testing sets. We use the Bi-directional LSTM layers along with ReLU and Tanh activation functions. We fit the model on the training data and validate it with the testing data. Single dense layers are connected at the end to produce the final prediction and a dropout layer to avoid overfitting the model. We calculated Model loss is calculated using RMSE and MAE. We analyze three different curves under three different conditions, i.e., the curve before the COVID-19 peak, the curve during the COVID-19 peak (when prevention policies are implemented), and the forecast of the curve after restrictions are lifted to observe the number of cases in all three periods.
Fig. 2 shows the overall architecture of the proposed COVID-19 Spread Control Policies Forecasting using Deep Learning Algorithm. We also provide a comparative analysis of Bi-LSTM and LSTM model with different policies. Among all approaches, the deep learning model stacked Bi-LSTM offers the best forecasting performance [50] with three restriction policies i.e. school closing, workspace closing, and facial covering. The overall methodology is composed of:
• Dataset description
• Preprocessing and feature extraction
• LSTM architecture for forecasting the future value of COVID-19 parameters.
• Stacked Bi-LSTM
• Performance metric
3.1 Dataset description
The dataset is obtained from different resources, one of the most renowned of which is SNU ARIC website [51] Novel Coronavirus (COVID-19) Cases, made available by SNU ARIC. The dataset consists of several various parameters. We apply pre-processing technique to select data only for the country of Korea and drop all those parameters which are not relevant.Fig. 3 Pictorial overview of the dataset parameters.
In Fig. 3, the x-axis represents days and y-axis represent policy applied by the Govt, as described below.Fig. 4 Dataset target variables.
1. OVAR1 (It represents data from the school shutdown period. 0 - there are no measurements/1 - suggest closure/2 - mandate closure (but only for certain levels or categories, such as high school or public schools)/3 - all levels must be closed/No data - “blank”)
2. OVAR3 (It represents the closing of the workplaces time period. 0 - no measures/1 - recommend closing (or recommend work from home)/2 - require closing (or work from home) for some sectors or categories of workers/3 - require closing (or work from home) for all-but-essential workplaces (e.g. grocery stores, doctors)/Blank - no data)
3. OVAR5 (It denotes the postponement of public events. 0 indicates no measurements; 1 indicates that cancellation is recommended; 2 indicates that cancellation is required, and Blank indicates that no data is available.)
4. OVAR7 (0 - restrictions on very large gatherings (the limit is above 1000 people)/1 - restrictions on gatherings between 101–1000 people/2 - restrictions on gatherings between 11–100 people/3 - restrictions on gatherings of 10 people or less/Blank - no data)
5. OVAR9 (It represents the closing of the public transport time period. 0 - no measures/1 - recommend closing (or significantly reduce volume/route/means of transport available)/2 - require closing (or prohibit most citizens from using it)/Blank - no data. Since we had no data regarding this parameter therefore we dropped it.)
6. OVAR11 (It represents the time period of confining in the home or workplace. 0 - recommend not leaving house/1 - require not leaving the house with exceptions for daily exercise, grocery shopping, and ‘essential’ trips/2 - require not leaving the house with minimal exceptions (e.g. allowed to leave once a week, or only one person can leave at a time, etc.)/Blank - no data.)
7. OVAR13 (It represents the record of restrictions on internal movement between cities/regions. 0 - no measures/1 - recommend not to travel between regions/cities/2 - internal movement restrictions in place/Blank - no data)
8. OVAR15 (It represents the record of restrictions on international travel/Note: this records policy for foreign travelers, not citizens. 0 - no restrictions/1 - screening arrivals/1 - quarantine arrivals from some or all regions/2 - ban arrivals from some regions.)
9. OVAR21 (It represents public information campaign data but since we don’t have many records therefore we dropped this variable.)
10. OVAR24 (It represents Contact-tracing data. 0 - no contact tracing/1 - limited contact tracing; not done for all cases/2 - comprehensive contact tracing; done for all identified cases.)
11. OVAR40 (It represents the restriction on the Facial-Covering time period. 0 - Recommended/1 - Required in some specified shared/public spaces outside the home with other people present, or some situations when social distancing is not possible/2 - Required in all shared/public spaces outside the home with other people present or all situations when social distancing not possible /3 - Required outside the home at all times regardless of location or presence of other people.)
12. MVAR1 (It represents the total number of confirmed patients on y-axis and number of days on x-axis)
13. MVAR2 (It represents the total number Covid death patients on y-axis and the number of days on x-axis)
14. MVAR3 (It represents the total number of recovered patients record on y-axis and number of days on x-axis)
15. MVAR4 (It represents the total number of people quarantined on y-axis and the number of days on x-axis)
These parameters are input into the deep learning model, and four parameters are forecasted as output as shown in Fig. 4, which are:
1. MVAR1 (It represents the total number positive/confirmed patients on y-axis and number of days on x-axis)
2. MVAR2 (It represents the total number Covid death patients on y-axis and number of days on x-axis)
3. MVAR3 (It represents the total number of recovered patients record on y-axis and number of days on x-axis)
4. MVAR4 (It represents the total number of people quarantined on y-axis and number of days on x-axis)
The dataset consists of a total of 536 days of samples; the data were collected from 23 January 2020 to 12 July 2021, so the total number of days is 536. We analyze it under three different conditions. (1) COVID-19 curve before the implications of restriction policies, (2) COVID-19 curve during the implication of restriction policies, and (3) COVID-19 forecasting curve after the restrictions have been lifted. With the help of this information, the obtained forecasting curves showed the importance and benefits of these policies in controlling COVID-19. The collected dataset is from 23 January 2020 to 12 July 2021 [51]. The real-world data has missing values. The missing data points between the time frame were replaced using forward and backward imputation. Forward imputation replaces the corresponding missing value with the previous value, and backward imputation fills the missing value using the following data point. The outliers in the data are removed using the box plot technique. Furthermore, the data is split into a train and test set, such as 480 sample days for training and 56 sample days for testing and validation. Finally, the data is scaled between 0 and 1 using the min–max scaler technique.
3.2 Preprocessing and feature extraction
The data is preprocessed using various techniques. First of all, the dates are parsed into years, months and days. Secondly, if the whole row data contains more than 5 NaN values out of 14 columns, the whole row is removed. Otherwise, if a few columns (2–3) have NaN values, then the missing data are imputed using forward and backward imputations in the respective feature column. In forwarding imputation, the data is filled with the previous raw value, and in backward imputation, the data is filled with the next available row value. For example, in our dataset, the data in the positive cases (MVAR1) column from Jan 27, 2020, till Jan 30, 2020, is missing, so it got replaced with the previous available value of Jan 26, 2020, which was ‘3’. The data in the quarantined cases (MVAR4) column is missing for the day, Feb 5, 2020, so it was replaced with the next row value (23) of the date Feb 6, 2020. Similarly, the same approach is applied to fill in the remaining missing values, and after that, the data is normalized between 0 and 1 using min–max scaling. The formula is described in Eq. (1). (1) xscaled=x−xminxmax−xmin
Once the data is normalized, windowing technique is applied on the dataset. A window takes previous 3 days data and predicts the next day data point.
3.3 LSTM architecture
Deep learning methods are a kind of recurrent neural network (RNN) that have proven to be effective predictive models [52] due to the automatic extraction of relevant features from the training samples. It feeds the activation function from the previous time step as input for the current time step and network self-connections. RNNs are good at processing data and exhibit great potential in time-series prediction [53] by storing large historical information in its internal state. However, it has a drawback concerning vanishing and gradient exploding problems, which lead to large training time expenditures or outright training failures. To address these shortcomings, [54] designed the LSTM RNN structure in 1997 to deal with a long-term dependency on the multiplicative gates that regulate the information flow and memory cells in the recurrent hidden layer. LSTM structure consists of four gates: the input gate, forget gate, control gate, and output gate, which are shown in Fig. 5 [55].
The input gate is defined by Eq. (2) as: (2) it=σ(Wi×[ht−1,xt]+bi)
Fig. 5 LSTM cell working.
The gate decides which information can be transferred to the cell. The information from the input of the previous memory that should be neglected is decided by the forget gate and is defined by Eq. (3) as: (3) ft=σ(Wf×[ht−1,xt]+bf)
The update of the cell is controlled by the control gate and is given by Eqs. (4), (5). (4) CIt=tanh(Wc×[ht−1,xt]+bc)
(5) Ct=tanh(ft×Ct−1+it×CIt)
where control gate is represented by CIt. The hidden layer (ht−1) is updated by output layer which is also responsible for updating the output as is given by Eqs. (6), (7). (6) Ot=σ(Wo×[ht−1,xt]+bo)
(7) ht=Ot×tanh(Ct)
In the above equations, tanh is used to scale the values into range −1 to 1, σ is the activation function which is taken as sigmoid and W is the corresponding weight matrices.
3.4 Stacked bidirectional LSTM
The proposed model uses stacked bidirectional LSTM architecture. It consists of two bidirectional LSTM layers with multiple units in each layer, as shown in Fig. 6. The Bi-LSTM network is used to forecast the time series data over the given interval of time followed by the previous time step data fed in as an input. To elicit deeper insights from the data and to study the varying trends, multiple Bi-directional LSTM layers are stacked together to construct an accurate model with high-level deeper representation [47]. The previous layer representations are learned by the subsequent layer for better optimization.
Conventionally, LSTM techniques can process the data in one direction. In other words, if something important in the future has a link with the future as well as the past simultaneously, then that information would have a chance of being missed. To overcome this issue, the bidirectional LSTM concept was introduced. A bidirectional LSTM can process data in both directions, i.e. in the forward and in the backward directions simultaneously. This helps Bi-LSTM memorize the contextual information in the past. The combination of two bidirectional LSTM layers yields a multi-stack Bi-directional LSTM model. The previous layer receives input and passes the information on to the next layer for further processing and the extraction of meaningful insights from the data.
The mathematical explanation of Bi-LSTM can be derived from the mathematical explanation of LSTM. The corresponding formulation of this architecture as Eqs. (8), (9), (10), (11), (12). (8) it=σ(Wixt+Uiht−1+bi)
(9) ft=σ(Wfxt+Ufht−1+bf)
(10) Ot=σ(Woxt+Uoht−1+bo)
(11) c˜=ft×Ct−1
(12) ht=Ot×tanh(Ct)
where Xt, σ, and Ct represent the input sample at time t, the sigmoid activation function, and the memory unit, respectively. (bf,bi,bo) and (Wf,Wi,Wo) stands for the bias and weight matrix for each gate, respectively.
To improve the learning capabilities of the classical LSTM model, the temporal structure considers the two-way relationship of the input data. In other words, Bi-LSTM processes the information forward and backward simultaneously. This results in obtaining a better understanding of contextual information in the data. Each Bi-LSTM block consists of the forward and backward layer. The output of the forward and backward layer are computed using Eqs. (13), (14). (13) ht=βhtf+γhtb
(14) yt=tanh(ht)
where β and tanh are the numerical factors respecting the equality β + γ = 1
This proposed model has been developed using the tensorflow 2.5 deep learning python framework.
Fig. 6 Stacked bidirectional LSTM.
3.5 Performance metric
The performance of The Stacked Bi-directional LSTM model is calculated using RMSE (Root mean square error), MAE (Mean absolute error) and MAPE (Mean absolute percentage error). The best model gave the overall RMSE value of 214.50, MAPE value of 0.0143 and MAE value of 99.251 respectively. The RMSE values are calculated by Eq. (15). (15) RMSE=∑i=1n(yiˆ−yi)2n
Similarly, the MAE value is obtained using formula described in Eq. (16) as. (16) MAE=∑i=1n|yi−λ(xi)|n
Finally, the MAPE value is obtained using formula shown in Eq. (17). (17) MAPE=1n∑t=1n|At−FtAt|
Fig. 7 Training and validation loss. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 8 Stacked Bi-LSTM architecture.
Table 2 Network Architecture and parameters.
Network No of layers No of units per layer Loss Learning rate Activation function Optimizer No of epochs No of variables fed as input
LSTM 02 184, 164 MAE ReduceLROnPlateau Tanh Adam 800 5,6,7,14
LSTM 02 184, 164 MAE ReduceLROnPlateau ReLU Adam 800 7
Stacked Bi-LSTM 02 184, 164 MAE ReduceLROnPlateau Tanh Adam 800 5,6,7,14
Stacked Bi-LSTM 02 184, 164 MAE ReduceLROnPlateau ReLU Adam 800 7
Fig. 9 Forecasting curve (school closing policy). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 10 Forecasting curve (closing of workplaces). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 11 Forecasting curve (cancelling of public event). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 12 Forecasting curve (restrictions on large gathering). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 13 Forecasting curve (stay at home restriction). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 14 Forecasting curve (internal movement between cities restriction). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 15 Forecasting curve (restriction on international travel). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 16 Forecasting curve (public information campaigns). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 17 Forecasting curve (contact tracing policy). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 18 Forecasting curve (facial covering policy). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 19 Forecasting curve (school closing & cancelling of public events).
Fig. 20 Forecasting curve (cancelling of public event & public information campaign).
Fig. 21 Forecasting curve (facial covering & restriction on large gathering policy).
Fig. 22 Forecasting curve (school closing & workspace closing policy).
Fig. 23 Forecasting curve (school closing, workspace closing policy & public event cancellation).
Fig. 24 Forecasting curve (school closing, facial covering & public event cancellation).
Fig. 25 Forecasting curve (school closing, facial covering & restriction on large gathering).
Fig. 26 Forecasting curve using 10 control policies.
4 Results and discussions
In this section, we discuss the results of the stacked Bi-LSTM forecasting. The results revolve around two major methods of forecasting COVID-19. The first uses the simple 2-layer LSTM model and the second uses the stacked Bi-LSTM model. Both the networks have a similar configuration and both are trained over a combination of different policies to figuring out the best policy which aids in improving the forecasting accuracy.
4.1 Features representation
The South Korean COVID-19 dataset includes the positive rate, death rate, recovered rate, quarantine rate, and ten other mobility policies. The policies are introduced in the dataset to observe the effects of restriction levels on the forecasting curve and accuracy. The stacked Bi-LSTM model is trained on different feature sets to determine which policy has a larger effect on modeling the correct prediction. The dataset features and target values are visualized in Fig. 3, Fig. 4.
4.2 Training LSTM and stacked Bi-LSTM models
ARIMA, SARIMA, VAR, LSTM, and proposed stacked Bi-LSTMS techniques are employed to forecast COVID-19 with high precision. Most of the comparison is made between LSTM and bi-LSTM. The LSTM network consists of two LSTM layers, with 184 units in the first layer and 164 units in the second layer, followed by a single dense layer with no activation function. Contrary to this approach, the present study uses the stacked Bi-LSTM technique, which consists of two Bi-LSTM layers with the same network configuration as LSTM. Table 2 shows the units and layers details used in the stacked Bi-LSTM model.
Stacked Bi-LSTM network graph architecture is shown in Fig. 8.
We achieved the highest accuracy with two stacked bidirectional LSTM layers compared to LSTM [50] with the same network configuration. It also surpasses the accuracy of traditional forecasting models ARIMA, SARIMA, and VAR. Accuracy comparison is shown in Table 14, Table 15. When increasing the number of layers or units, the model loses the point of global minima, resulting in a bad model. The parameters presented in the Table 2 are obtained after several iterations. We train the model using the ‘Tanh’ and ‘ReLU’ activation functions. The default activation function in the Bi-LSTM layer is ‘Tanh,’ but it is replaced with ReLU to observe the change in accuracy. We used only the best forecasting model obtained using seven feature sets (three policies and four target parameters) shown in Table 2. However, the accuracy with Tanh is higher compared to the ReLU. Hence, the default activation function outperforms ReLU. The forecasting accuracy results with ReLU and Tanh are shown in the Table 10, Table 11. This study uses a normalization method that scales the data between 0 and 1. Adam is used as an optimizer for the model. We observed that the model does not perform well when optimizers other than Adam are used, such as SGD, RMSprop, and Adadelta. An early stopping callback is also used with a patience value of 100, and the mode of monitoring validation loss is minimum. The learning rate decreases by a factor of 0.3 with a patience value of 80, and the mode of monitoring is validation loss. Fig. 7 shows the learning curve of the best-performing stacked Bi-LSTM model (with seven parameters).
Table 3 Forecasting/Prediction accuracy with 6 parameters (two control policies and 4 target parameters) in forecasting of Positive (P), Death (D), Recovered (R) and Quarantined (Q) cases using Bi-LSTM.
Policy Mean absolute error (MAE) Mean absolute percentage error Root mean square error (RMSE)
P D R Q P D R Q P D R Q
School closing & Cancelling of public event 229.09 5.038 211.08 388.17 0.145 0.251 0.151 4.598 372.09 6.329 252.54 539.99
Facial covering & Large gathering restriction 318.45 1.650 206.91 364.47 0.0020 0.0008 0.0014 0.044 534.29 2.226 324.86 461.06
Public event cancellation & Public information campaign 320.81 8.314 479.84 316.65 0.0021 0.0041 0.0034 0.037 356.65 10.648 552.77 437.56
School & Workspace closing policy 220.85 6.919 132.25 316.97 0.141 0.346 0.093 3.737 317.09 7.726 167.43 449.36
Table 4 Forecasting/Prediction accuracy over 5 parameters (Single control policy and 4 target variables) in forecasting of Positive (P), Death (D), Recovered (R) and Quarantined (Q) cases using LSTM.
Policy Mean absolute error (MAE) Mean absolute percentage error Root mean square error (RMSE)
P D R Q P D R Q P D R Q
School closing 4402.3 90.68 7089.7 612.7 2.930 4.298 5.234 7.462 5846.1 97.94 7874.8 968.51
Workplace closing 1702.2 9.199 899.6 659.8 0.010 0.0045 0.0061 0.079 2350.1 12.78 1541.9 872.0
Public event cancellation 2432.8 13.98 3908.2 644.38 0.015 0.006 0.027 0.077 4631.1 24.24 4238.1 926.8
Large gathering restriction 1269.6 55.35 2470.1 548.25 0.0084 0.026 0.017 0.065 1550.4 70.68 2862.1 797.03
Stay at home restriction 1060.0 87.76 2706.2 735.31 0.0067 0.040 0.019 0.087 1577.0 119.90 3037.2 946.92
Internal movement restriction 1705.8 41.27 1461.3 897.7 1.121 1.933 1.045 11.89 2228.4 68.24 1640.9 1470.8
International travel restriction 3169.7 12.59 3453.9 695.35 0.020 0.006 0.024 0.083 4730.1 15.71 4561.8 964.4
Public information campaign 1824.1 120.3 2135.8 675.8 0.011 0.056 0.014 0.083 3071.4 130.27 2810.6 1104.8
Contact tracing policy 1836.9 112.04 2116.7 858.4 0.012 0.052 0.014 0.101 2606.3 125.44 2516.3 1078.6
Facial covering 4128.0 16.22 2699.3 863.9 0.027 0.0080 0.019 0.104 5968.1 16.86 3391.9 1235.9
Table 5 Forecasting/Prediction accuracy over 5 parameters (Single control policy and 4 target variables) in forecasting of Positive (P), Death (D), Recovered (R) and Quarantined (Q) cases using Bi-LSTM.
Policy Mean absolute error (MAE) Mean absolute percentage error Root mean square error (RMSE)
P D R Q P D R Q P D R Q
School closing 195.73 2.727 238.05 236.22 0.125 0.136 0.166 2.828 296.67 3.123 350.8 330.66
Workplace closing 174.17 5.014 265.26 288.56 0.0011 0.0024 0.0018 0.0390 222.08 9.447 337.10 373.21
Public event cancellation 145.70 8.062 352.14 312.16 0.0009 0.004 0.0024 0.037 188.19 9.356 446.16 420.59
Large gathering restriction 186.09 3.699 113.48 225.13 0.0012 0.0018 0.0008 0.026 226.11 4.611 149.07 314.37
Stay at home restriction 440.09 12.592 206.87 339.2 0.002 0.006 0.001 0.047 523.08 24.01 288.28 443.26
Internal movement restriction 580.17 6.724 190.01 539.27 0.365 0.329 0.131 6.664 1037.8 11.805 330.91 957.63
International travel restriction 313.66 8.592 230.76 383.32 0.002 0.0043 0.0016 0.045 484.39 9.076 275.63 576.78
Public information campaign 178.84 3.536 302.10 332.3 0.0011 0.0017 0.0021 0.039 220.72 4.185 376.02 459.9
Contact tracing policy 143.35 4.08 521.46 317.90 0.0009 0.002 0.003 0.039 181.09 5.592 651.73 425.56
Facial covering 228.74 5.354 165.78 269.27 0.0014 0.0026 0.0011 .032 346.72 6.058 218.90 326.52
Table 6 Forecasting/Prediction accuracy over 7 parameters (3 control policies and 4 target variables), 7 days prior data used in forecasting of Positive (P), Death (D), Recovered (R) and Quarantined (Q) cases.
Policy Mean absolute error (MAE) Mean absolute percentage error Root mean square error (RMSE)
P D R Q P D R Q P D R Q
School closing, Workspace closing & Public event cancellation (With Bi-LSTM) 1228.0 10.65 465.4 374.5 0.0079 0.0053 0.0034 0.045 1406.5 11.94 611.09 531.16
School closing, Workspace closing & Public event cancellation (With LSTM) 3658.2 23.43 2971.4 1180.2 0.024 0.011 0.021 0.137 4950.3 24.41 3661.4 1401.5
Table 7 Forecasting/Prediction accuracy over 6 parameters (2 control policies and 4 target variables) in forecasting of Positive (P), Death (D), Recovered (R) and Quarantined (Q) cases using LSTM.
Policy Mean absolute error (MAE) Mean absolute percentage error Root mean square error (RMSE)
P D R Q P D R Q P D R Q
School closing & Cancelling of public event 3002.0 51.68 5583.6 658.55 1.969 2.727 4.066 7.890 3900.9 62.18 6192.5 819.9
Facial covering & Large gathering restriction 2804.1 9.690 2467.0 811.20 0.018 0.004 0.017 0.102 4677.9 10.899 3377.3 1296.8
Public event cancellation & Public information campaign 3066.2 23.48 2342.3 650.7 0.0202 0.011 0.016 0.079 4121.3 29.21 3337.2 1047.2
School & Workspace closing policy 7670.7 67.30 8424.8 658.6 5.283 3.233 6.294 7.989 8748.3 72.25 9249.3 987.01
Table 8 Forecasting/Prediction accuracy over 14 parameters (10 control policies and 4 target variables) and with 4 parameters (no policy control), in forecasting of Positive (P), Death (D), Recovered (R) and Quarantined (Q) cases using Bi-LSTM.
Mean absolute error (MAE) Mean absolute percentage error Root mean square error (RMSE)
P D R Q P D R Q P D R Q
All 10 policies 787.63 21.238 422.66 344.34 0.0050 0.0103 0.0029 0.040 1042.3 29.120 559.05 524.42
3 best policies 186.55 6.809 179.21 322.13 0.0011 0.0034 0.0012 0.038 276.41 7.649 234.88 436.40
No policy 603.30 2.323 413.53 376.10 0.0039 0.0011 0.0029 0.044 711.61 2.767 471.49 569.38
Table 9 Forecasting/Prediction accuracy over 14 parameters (10 control policies and 4 target variables) and with 4 parameters (no policy control), in forecasting of Positive (P), Death (D), Recovered (R) and Quarantined (Q) cases using LSTM.
Mean absolute error (MAE) Mean absolute percentage error Root mean square error (RMSE)
P D R Q P D R Q P D R Q
All 10 policies 6667.1 24.06 11 493.5 1436.3 0.045 0.011 0.088 0.161 7990.0 36.90 12 399.8 1568.9
No policy 2532.6 70.17 1032.7 1012.2 0.016 0.033 0.0072 0.136 2809.5 84.04 1641.8 1301.6
Fig. 7 depicts that initially, the weights are initialized with very low values resulting in huge errors at the beginning of the training process. With training, the weights converge to a good value, causing the error approach to zero. During training, the validation loss started becoming more stable, causing the model to get stuck in local minima. It happens when the learning rate is very low, and the model gets stuck in local minima. We use a learning rate scheduler to change the learning rate adaptively to not stuck the model in local minima. Therefore, the validation loss tends to improve further with the number of increasing iterations in the graph. The blue line represents training loss, and the orange line represents validation loss. The y-axis represents loss values ranging between 0 and 1 because the data is normalized between 0 and 1. The X-axis represents the number of iterations. Since the data is normalized between 0 and 1, the loss reduces drastically at the beginning.Table 10 Forecasting/Prediction accuracy over 7 parameters (3 control policies and 4 target variables) in forecasting of Positive (P), Death (D), Recovered (R) and Quarantined (Q) cases using Bi-LSTM.
Policy Mean absolute error (MAE) Mean absolute percentage error Root mean square error (RMSE)
P D R Q P D R Q P D R Q
School closing, Workspace closing & Public event cancellation (with ReLU) 1572.8 59.79 2517.8 739.70 0.010 0.028 0.017 0.088 1863.5 74.60 2829.9 883.2
School closing, Public event cancellation & Facial covering 307.11 14.413 376.14 359.51 0.0020 0.0072 0.0026 0.042 448.32 15.10 427.80 532.09
School closing, large gathering restriction & Facial covering 294.01 6.440 150.03 379.61 0.0018 0.0032 0.0010 0.045 403.19 7.105 187.43 520.88
Table 11 Forecasting/Prediction accuracy over 7 parameters (3 control policies and 4 target variables) in forecasting of Positive (P), Death (D), Recovered (R) and Quarantined (Q) cases using LSTM.
Policy Mean absolute error (MAE) Mean absolute percentage error Root mean square error (RMSE)
P D R Q P D R Q P D R Q
School, Workspace closing & Public event cancellation 3401.8 27.70 3745.6 589.31 0.022 0.013 0.026 0.070 4198.5 39.47 4441.4 726.14
School, Workspace closing & Public event cancellation (with ReLU) 1082.7 70.84 1112.5 1332.6 0.007 0.033 0.007 0.148 1230.1 96.10 1417.8 1554.5
School closing, Public event cancellation & Facial covering 3615.6 152.5 2292.1 522.30 0.023 0.070 0.016 0.062 4417.6 161.30 2792.3 780.03
School closing, large gathering restriction & Facial covering 4865.0 19.165 6434.8 878.2 0.032 0.009 0.047 0.106 6584.2 19.480 7711.6 1251.5
Table 12 Forecasting/Prediction accuracy comparison between LSTM and Bi-LSTM in forecasting of Positive (P), Death (D), Recovered (R) and Quarantined (Q).
Policy Bi-LSTM (MAE) LSTM (MAE)
P D R Q P D R Q
School closing 195.73 2.727 238.05 236.22 4402.3 90.68 7089.7 612.7
Workplace closing 174.17 5.014 265.26 288.56 1702.2 9.199 899.6 659.8
Public event cancellation 145.70 8.062 352.14 312.16 2432.8 13.98 3908.2 644.38
Large gathering restriction 186.09 3.699 113.48 225.13 1269.6 55.35 2470.1 548.25
Stay at home restriction 440.09 12.592 206.87 339.2 1060.0 87.76 2706.2 735.31
Internal movement restriction 580.17 6.724 190.01 539.27 1705.8 41.27 1461.3 897.7
International travel restriction 313.66 8.592 230.76 383.32 3169.7 12.59 3453.9 695.35
Public information campaign 178.84 3.536 302.10 332.3 1824.1 120.3 2135.8 675.8
Contact tracing policy 143.35 4.08 521.46 317.90 1836.9 112.04 2116.7 858.4
Facial covering 228.74 5.354 165.78 269.27 4128.0 16.22 2699.3 863.9
School closing & Cancelling of public event 229.09 5.038 211.08 388.17 3002.0 51.68 5583.6 658.55
School & Workspace closing 220.85 6.919 132.25 316.97 7670.7 67.30 8424.8 658.6
All 10 policies 787.63 21.238 422.66 344.34 6667.1 24.06 11 493.5 1436.3
No Policy 603.30 2.323 413.53 376.10 2532.6 70.17 1032.7 1012.2
Table 13 Forecasting/Prediction accuracy in forecasting of Positive (P), Death (D), Recovered (R) and Quarantined (Q) cases using ARIMA and SARIMA (using 4 forecasting parameters).
Models Mean absolute error (MAE) Mean absolute percentage error Root mean square error (RMSE)
P D R Q P D R Q P D R Q
ARIMA 6338.5 24.05 2678.1 2005.5 0.044 0.012 0.019 0.237 7462.3 38.31 3217.9 2380.9
SARIMA 6075.39 168.56 5578.2 1156.8 0.042 0.085 0.041 0.133 7069.9 200.18 6787.3 1599.7
Table 14 Forecasting/Prediction accuracy comparison between VAR, LSTM and Bi-LSTM in forecasting of Positive (P), Death (D), Recovered (R) and Quarantined (Q) cases using 3 policy.
Policy MAE RMSE
P D R Q P D R Q
School closing, Workspace closing & Public event cancellation (VAR) 27 548 660.96 15 297.5 11 590 36 690 876.1 22 775 13 836
School, Workspace closing & Public event cancellation (LSTM) 3401.8 27.70 3745.6 589.31 4198.5 39.47 4441.4 726.14
Table 15 Forecasting/Prediction accuracy comparison between VAR, LSTM, Bi-LSTM, ARIMA and SARIMAX in forecasting of Positive (P), Death (D), Recovered (R) and Quarantined (Q) cases using all 10 policies.
Policy MAE RMSE
P D R Q P D R Q
All 10 policies (VAR) 8655.9 54.173 2275.23 6637.7 11 820 63.24 3414.8 8515.6
All 10 policies (LSTM) 6667.1 24.06 11 493.5 1436.3 7990.0 36.90 12 399.8 1568.9
ARIMA (No policy) 6338.5 24.05 2678.1 2005.5 7462.3 38.31 3217.9 2380.9
SARIMA (No policy) 6075.39 168.56 5578.2 1156.8 7069.9 200.18 6787.3 1599.7
4.3 Forecasting curve
The number of predicted positive cases, deaths, hospitalized, and quarantined cases in South Korea follows almost the same curve as the original curve. This study looks at the previous three days of data and forecasts the data for the next three days. We used 480 days of data for training and 56 days of data for testing. The total numbers of positive cases are around 170,000, death cases are 2200, recovered cases are 160,000, and quarantined cases are 185 000.
4.3.1 Forecasting using one policy with target variables data
First, we train the model only single policy with four target variables, so the input features are five and the output features are four. There are ten policies, and we used them one by one during training to observe which one performs better. The name of the policy used in the model can be found in the title of the figures. The forecasted parameters are the number of positive COVID patients, death cases, recovered cases and quarantined cases. The red line shows the forecasted curve and green line represents the original number of cases in Figs. 9, 10, 11, Fig. 12, Fig. 13, Fig. 14, Fig. 15, Fig. 16, Fig. 17, Fig. 18. These policies are trained using LSTM and stacked Bi-LSTM models. However, the stacked Bi-LSTM model gave better results than LSTM. The error rate comparison is shown in the Table 4, Table 5. The single policies that give a minimum error rate while forecasting target parameters can also be observed from these two tables. The policies with minimum error rates are noted and then further used as a combination of two with the forecasting models. The single policies that gave good results are School closing, workplace closing, public event cancellation, large gathering restriction, international travel, public information campaign, contact tracing, and facial covering.
4.3.2 Forecasting using 2 policies with target variables data
The best-performing single policy is grouped with another policy to input the pair of two policies along the four forecasting parameters into the model. The school closing and workspace closing policy are grouped, and similarly, the cancelation of public events and public information campaign policy are grouped. Figs. 19, 20, 21, and 22 shows the curve fit for the two grouped policies. It is observed that the Bi-LSTM model gives the best results when the following combinations are used:
1. Facial covering and large gathering restriction
2. School closing and workspace closing policy
3. School closing and cancelling of public events
Almost all the curves look similar to the figures, but their respective error rates can be visualized in the Table 3, Table 7. The accuracy table shows that the model trained using school closing and workspace closing policies has a slightly less error rate than those without these two policies. Combining these two policies can yield much better results when combined with any third policy that positively affects model accuracy.
4.3.3 Forecasting using 3 policies data with target variables data
After acquiring the best results with the combination of two policies, a combination of three policies is used to train the model to see if it improves the model’s accuracy. We form the combinations using those policies which gave minimum MAE rate while forecasting. The combination of three policies that we used as input are:
1. School, workspace closing and public event cancellation
2. School closing, public event cancellation & facial covering policy
3. School closing, large gathering restriction & facial covering policy
Their respective forecasting curves can be visualized in Fig. 23, Fig. 24, Fig. 25. Among these combinations, we found that the best policies aiding in improving the model’s accuracy are School closing, workspace closing, and public event cancellation policy. This combination gave the minimum MAE shown in the Table 10, Table 11. Table 10 shows the error rate of Bi-LSTM model whereas Table 11 shows the results of LSTM model. We show the comparison between both model accuracies. All the plotted figures from 12, 13, 14....26, only show the results of Bi-LSTM model.
We chose the best-performing model (trained over three policies). We changed the activation function in the Bi-LSTM layer keeping the final dense layer (with no activation function) constant. The default activation function is Tanh in the Bi-LSTM layer, but we replaced it with ReLU to further study its impact on model accuracy. We observe that changing the models’ activation function does not help improve the accuracy. The default Tanh performed better than ReLU. The difference between error rates with and without ReLU can be observed in the Table 10.
The model is also fed a week prior data to forecast one day’s future data, but the performance is not better compared to three days prior data. It can be assumed that too ‘old’ data points or more past days data points do not practically affect (correlate to) the most recent data points. The data points strongly correlated to the newer ones can be used for making the forecast, while the weakly correlated to the newer ones (or not correlated at all) should not be included in forecasting. The forecasting accuracy of the model is shown in Table 6.
4.3.4 Forecasting using 10 policies data
Finally the model is trained using all 10 policies and four target variables. The graph can be visualized in Fig. 26. The curve observed after the blue line represents the forecasting done on completely unseen data. 10 policies are used as an input along with four target variables to train both LSTM and Bi-LSTM model. The forecasting accuracy for both models can be observed in the Table 8, Table 9. It is inferred that adding more policies that are not useful distorted the curve and it increased the error rate. The models are also trained using 5 policies but the error rate kept increasing. Moreover, from Table 3 till Table 11. It can be observed that Bi-LSTM model performs better than LSTM model trained using COVID-19 control policies as Bi-LSTM model shows better forecasting accuracy than LSTM. Hence, it can be concluded as we found the best forecasting model trained using 3 control policies which are OVAR1 (School closing), OVAR3 (Closing of workplaces) and OVAR5 (Cancelling of public event). The model trained using these restriction policies showed the best forecasting results. It also performed better than the model trained over just four target variables i.e. Positive, death, recovered and quarantined cases without the involvement of control policies. The forecasting accuracy for this model is shown in the Table 8, Table 9 row 2, under the tag “No policy”. The combine results of best performing Bi-LSTM model in comparison with LSTM model are shown in the Table 12.
4.3.5 Forecasting using ARIMA, SARIMA and VAR (classical models)
We trained the classical models’ ARIMA, SARIMA, and VAR for positive, death, recovered, and quarantined cases. The VAR uses multiple parameters, which include all ten control policies. The results obtained using ARIMA and SARIMA are shown in Table 13. VAR is trained using three best-performing policies (which give good results and minimum error in Bi-LSTM), and finally, all ten policies are used. The difference between accuracy of VAR, Bi-LSTM and LSTM model is shown in Table 14, Table 15. Table 14 models are trained using three policies, and Table 15 models are trained using all ten policies alongside their comparison with ARIMA and SARIMA. We can observe that Bi-LSTM outperforms all the other models in forecasting positive, death, recovered, and quarantined cases.
5 Conclusion
This paper proposed the control policies-based COVID-19 parameters forecasting in South Korea using stacked Bi-LSTM architecture. We further presented the comparison between the accuracy of stacked Bi-LSTM with classical time-series models VAR, ARIMA, SARIMA, and LSTM. It is observed that Bi-LSTM performs better than traditional models and LSTM for forecasting COVID-19 cases, considering the past three days’ historical data. The models are also trained using seven days of historical data and changing the activation functions (ReLU and Tanh) in Bi-LSTM and LSTM layers. However, three days of historical data and default activation function Tanh in Bi-LSTM and LSTM layer outperformed seven days of historical data and ReLU. We examined ten policies, such as school closure, restrictions on international movement, restrictions on large gatherings, contact tracing, facial covering (face mask), internal travel (between cities), public event cancellation, stay-at-home restrictions, and vice versa, to forecast the future value of COVID-19 positive confirmed, recovered, death, and quarantine cases. The model is trained using a single policy, two pairs, and three pairs of policies, and finally, all the policies are taken as input altogether. The single policies that gave the best results are School closing, Workspace closing, public event cancellation, large gatherings, public information campaigns, and contact tracing policy. In the case of two-pair policies, the best results are given by School and workspace closing, secondly school closing and cancellation of public events. In case of three pair policies, the best forecasting results are yielded by School, workspace closing and public event cancellation with MAE of 186.55, 6.809, 179.21 and 322.13 for positive, death, recovered and deceased cases, respectively. We conclude that these three pairs of policies performed better than all other pairs. While originally, this study intended to deal with pandemic growth and its impact on South Korea. However, the proposed model can be developed to forecast COVID-19 cases and can be used on other pandemic time-series problems as well with further fine-tuning. Moreover, this study will also help the government bring out more effective policies to stop COVID-19 growth, and it will also help eliminate unusual restrictions that have no impact on stopping COVID-19.
In future work, we plan to incorporate vaccinated cases and vaccination policies to check the effect of the vaccination drive on COVID-19 cases. Furthermore, we will use attention models to see if there are more chances of getting better-optimized results.
CRediT authorship contribution statement
Furqan Ali: Conceptualization, Methodology, Software, Writing – original draft, Visualization, Formal analysis. Farman Ullah: Conceptualization, Supervision, Investigation, Validation, Final Review. Junaid Iqbal Khan: Writing – original draft, Visualization, Formal analysis. Jebran Khan: Data curation, Investigation. Abdul Wasay Sardar: Writing – original draft, Visualization. Sungchang Lee: Supervision, Investigation, Validation, Final Review, Fund acquisition.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data availability
Dataset link : https://sites.google.com/view/snuaric/data/covid-19-data/covid-19-data?authuser=0
☆ This research was supported by National Research Foundation of Korea (NRF) Grant funded by the Korean Government (Ministry of Science and ICT) NRF-2020K1A3A1A47110830.
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| 0 | PMC9744690 | NO-CC CODE | 2022-12-15 00:01:53 | no | Chaos Solitons Fractals. 2022 Dec 13;:112984 | utf-8 | Chaos Solitons Fractals | 2,022 | 10.1016/j.chaos.2022.112984 | oa_other |
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Resour Policy
Resour Policy
Resources Policy
0301-4207
1873-7641
Published by Elsevier Ltd.
S0301-4207(22)00625-0
10.1016/j.resourpol.2022.103182
103182
Article
Visualizing the sustainable development goals and natural resource utilization for green economic recovery after COVID-19 pandemic
Zhang Shikun ab∗
Anser Muhammad Khalid abc
Yao-Ping Peng Michael d
Chen Chunchun e
a College of Economics and Management, Shangqiu Normal University, Shangqiu, China
b Faculty of Business and Management Sciences, The Superior University, Pakistan
c School of Public Administration, Xi'an University of Architecture and Technology, China
d School of Economics and Trade, Fujian Jiangxia University, Fuzhou, China
e School of Management, Beijing Union University, Beijing, 100101, China
∗ Corresponding author. College of Economics and Management, Shangqiu Normal University, Shangqiu, China.
13 12 2022
13 12 2022
1031829 6 2022
23 11 2022
27 11 2022
© 2022 Published by Elsevier Ltd.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
After the COVID-19 outbreak, this study examines the influence of modifications in China's Sustainable Growth Goals (SDGs) and economic development goals on Chinese enterprises' energy conservation and emissions reduction behavior. Meanwhile, the COVID-19 epidemic has erupted, displacing the flimsy traditional techniques. As a result, the post-COVID-19 pandemic emphasizes the need for a long-term sustainable development method compatible with the local and regional environmental systems. The main objective of this study is used as a roadmap to steer the post-COVID-19 pandemic on a sustainable green path by emphasizing sustainable energy strategies to connect in SDG-related efforts. The investigation in this paper begins with examining significant impacts in the energy industry and their impact on progress toward sustainability. The empirical findings that the CO2 emissions reduction objectives in long-term development plans had a considerable impact on energy saving and emissions reduction, lowering energy consumption intensity by 3.33% and carbon emission intensity by 4.23% between 2010 and 2019. Besides, the results and long and short run techniques are built to describe the Sustainable Development Goals interface, with the result revealing that Sustainable Development Goals enhance the green economic recovery performance. Furthermore, this study recommends that the key natural resources and green economic recovery policies to overcome the climate change impacts by COVID-19 pandemic.
Keywords
Sustainable development goals
Energy conservation
Natural recourses
Post-COVID-19
Green economic recovery
==== Body
pmc1 Introduction
Authorities have implemented a wide range of green innovation strategies around the world in response to climate change and growing public concern about environmental issues(Shang et al., 2021), including policies to promote green brands, environmentally friendly innovations, and green finance such as green bonds(Xu et al., 2022). The increasing externality of environmental contamination necessitates green innovation in public administration(Qiu et al., 2022). Green innovation and green financing go hand in hand when it comes to protecting the environment, with the former providing funding for R&D into new clean energy technologies and ecologically friendly processes and goods(Li et al., 2021). Although governments' attitudes and attempts to safeguard the environment are reflected in green finance, green innovation reflects a more holistic approach to tackling environmental deterioration and innovation in the production and use of green energy. While conventional climate-related environmental quality solutions have received much attention, academia has mostly ignored one growing field: climate finance(Hu et al., 2021). To meet the Paris Agreement's net-zero carbon reduction targets and promote environmentally sound development, the term "climate finance" refers to capital flows for low-carbon and weather growth that have either direct or indirect effects on reducing GHG emissions or adapting to climate change(H. Gao et al., 2021). Nations provide beneficiary emerging economies with multipurpose assistance via climate financing, which funds low-emissions and environmental preservation programs and investments. It's possible to split climate financing into two classifications: adaptability and mitigation(Jin et al., 2022). Climate finance has been the subject of a growing number of studies. Fairness in climate change responses has been studied extensively(Liu et al., 2021), but climate financing has also been learned about recipient nations' adaptation ability to climate change. About climate finance and carbon dioxide emissions, little is known to date, and the connection between climate finance and emissions reductions is confusing at best.
Using assets and carbon-demanding development models has elevated green innovation and green financing to essential assessments in past years, and experts generally agree that they have a favorable impact on environmental quality. According to, earlier research(Qin et al., 2022) on green innovation focused mostly on financial assistance for clean energy R&D and environmental preservation expenditures. There is a dearth of research documenting environmental management-related green trademarks or patent requests, the ultimate barometer of green innovation. Few studies have also examined if ecological effectiveness, green finance, and green technology do not have unidirectional cointegration linkages, nor have they experimentally evaluated if environmental energy and green finance may affect green innovation (Han et al., 2022). have not been explored. There may be opportunities for green goods and procedures based on existing ecological quality effectiveness and green finance growth if the nexus between quality environmental efficiency, green finance, and innovation can be identified. These issues can be addressed by authorities to enhance environmental performance and financial growth by implementing strategies to stimulate green innovation and improve the distribution of financial resources, which can ultimately better encourage the whole world to advance in a sustainable, green, and environmentally friendly manner(Dong et al., 2021). Consequently, this research is attempting to reveal the link between these three factors and to determine how environmental performance, green financing, and green innovation all affect each other in the short- and long-term(Zhao et al., 2020a, Zhao et al., 2020b).
These studies examine the changes that have occurred throughout this time, from renewable energy transition and energy affordability to presenting holistic ideas and practical solutions for energy sustainability from the perspective of governments and policymakers. Nevertheless, the new study considers the Covid-19 pandemic, which could have a significant economic impact on green developments and increase the growth of the green investment.
2 Literature review
2.1 Nexus among economic performance and innovation
Long-term balance between environmental performance, green financing, and innovation in emerging nations. One of the most obvious benefits of green innovation is its ability to increase the use of renewable energy sources while simultaneously enhancing efficiency in energy use (Zhao et al., 2020a, Zhao et al., 2020b).For one thing, greater eco-innovation and the potential to produce more clean energy might attract more global financial assistance for clean energy R&D and renewable energy manufacturing, which in turn improves the environmental protection of green financing. Businesses are more likely to invest in green technology if there is more green innovation. This leads to greater global financial support and improved ecological effectiveness. In light of the above, we believe green innovation is essential to green finance and environmental efficiency(Lu et al., 2022).
The following illustrates the relationship between environmental effectiveness, green funding, and innovation. There are several ways in which higher environmental productivity might encourage people to live in more environmentally friendly surroundings. Second, according to(Ullah et al., 2020), higher environmental effectiveness is generally associated with the adoption of more environmentally friendly technology. This trend will likely continue as long as green innovation projects are designed to be long-term. Even more importantly, governments are spending more on clean and renewable energy manufacturing R&D due to increased financial support for green initiatives. We may deduce from this that ecological effectiveness and green funding have an impact on green innovation(Zhang et al., 2022). Through the selection of technical initiatives with high success possibilities, the financial sector discovers the finest possible technologies and accelerates technological innovation(Xiuzhen et al., 2022). Financial institutions help people save more money and use their money more effectively, resulting in greater efficiency in the use of resources and the development of new technologies. Banks and share prices harm economic development, but found that the financial sector has an overall positive impact, indicating that the financial industry is a growth engine regardless of the nation's bank or market structure.
2.2 Green finance and natural resources development
Investments in green technologies are essential for boosting green growth rates. Natural resources and capabilities mostly influence the effectiveness of green economic and social development via green technical advances. Since "innovation" and "introduction" are the primary means of technological advancement, we employ these two lenses to rationally examine the connection between endowed natural resources and green interest rates(Sun et al., 2019, Sun et al., 2019).
According to one school of thought, there is a "crowding out" impact of the endowment of natural resources on technical innovation in the renewable energy industry. The phenomenon of "crowding out" shows itself in four distinct ways. First, regions brimming with natural resources are more likely to have an economic structure predicated on extracting those resources, resulting in the extraction sectors "crowding out" industrialization(Sun et al., 2019). To some degree, the development rate of the green economy is stifled by the fact that the steel industry typically has a greater technical level and more frequent innovations and R&D actions than the renewable extractive industries sector. Second, there is a larger outflow of intellectual resources that might be used to innovate in the resource extraction industry from places that are wealthy in resources but fail to invest in talent acquisition. Economies in the area may be lacking in renewable technology creativity expertise since the natural resource industry's prevalence as the major product sector with low productivity and increased and the diversion of potentially inventive human capital to the core business sector(Iram et al., 2020).
Thirdly, technical innovations to increase resource and manufacturing efficiency are discouraged in mineral resource locations due to fewer resource restrictions and fewer opportunities for such gains in economic growth. Finally, the immediate advantages of exploiting natural resources are substantial, and these resources might be seen as "windfalls" in some sense. Because of this, areas wealthy in natural resources would likely prioritize the development of sectors based on these resources, even if these industries rely on a relatively low level of technical input for the growth of their economy(Abbas et al., 2022). Consequently, innovation and economic growth funding suffer in the long run. Recent research has revealed proof of the effects of Covid-19 pandemic on petroleum variability, adding to data from previous worldwide catastrophes. A recent study (Getis and Ord, 2010)examined this topic by comparing economic growth and asset price volatility before and after the Covid-19 pandemic. The research (Ikram et al., 2019)which used innovative wavelet parameters, found that during the Covid-19 outbreak in China, commodities prices for land and resources exhibited more volatility. Natural resources are claimed to have a medium-term, causal relationship with economic expansion, but only in one direction. Also, using this method, reveal that crude prices for natural assets were unstable before and after the development of the Covid-19 pandemic(Mohsin et al., 2019). The opposite conclusion was drawn from this research, which concluded that the cost of commodities derived from natural resources does not affect the economy's health.
The impact of Covid-19 on the variability of mineral wealth (oil prices in particular) has also been experimentally examined in research by(Xia et al., 2020). It has been shown through these analyses that Covid-19 spread significantly and favorably affects the liquidity of Earth's resources and oil stock prices. In addition, the demand for and supply of these resources have a substantial and beneficial impact on driving up natural resource prices, even in the face of the Covid-19 pandemic. Shocks to either the demand or supply in an area may significantly impact the market's volatility. Moreover, it has been shown (Jayanthakumaran et al., 2012) that a 4% decline in OPEC oil output dramatically raises oil prices in the gas nations, which may have a major influence on the fluctuation of natural resource prices in the oil-importing industries. Covid-19 active cases, its mortality ratio, and reports of negative oil prices all contribute to natural resource inflationary pressures, according to a study of the pandemic's propagation(Mohsin et al., 2021).Despite this, the studies all agreed on the significance of the link between various events and crises and the unpredictability of natural assets. Nonetheless, a significant part of the business prosperity of the nations and regions has been overlooked in these analyses.
A barrier for emerging nations is their degree of financial growth since this might limit their ability to benefit from technological transfers that would otherwise help them accelerate their economic progress(Rohr et al., 2022). Despite some conflicting views, the research has debated the role of finance in the economy over various time horizons and situations(Wang and Zhang, 2021). Green finance is predicted to influence long-term economic development because of its role in the financial system. In light of past research, this effect is achieved via various pathways. Sustainable economic growth may be completed by the use of renewable energy, according to several studies (Taghizadeh-Hesary and Taghizadeh-Hesary, 2020) points out that using nonrenewable energy leads to uncontrolled environmental deterioration and diminishes organic assets, making it impossible to maintain a system.(DILANCHIEV & TAKTAKISHVILI, 2021). Green bonds exclusively support low-carbon projects that affect climate change management or adaptability, natural resource and wildlife protection, and pollution avoidance. In terms of energy expenditures, fossil fuels take the lead. (Ahamd, 2019)(Chang et al., 2022). It is possible to indirectly participate in clean energy or green technology initiatives via bonds since the responsibility is dispersed across a wide range of investors. A secondary market gives investors liquidity and a means of exiting the company. Those with short-term investing views are likewise drawn to this trait. There are several reasons why green bonds should be promoted to increase investments in clean energy and environmentally friendly technologies(Saboori et al., 2017).
Furthermore, the impact of new technologies on achieving sustainability, along with their role in the electricity system, digitalisation, and economics, is examined. The Econometric technique is employed in Section four to examine and quantify the strengths, weaknesses, opportunities, and dangers of achieving energy sustainability. To be more pragmatic, one must examine these ideas from the perspective of political bodies and policies. As a result, a pre-COVID approach to energy sustainability from political China, Eurasia, Australasia, Africa, and Latin America is investigated. This interaction results from a careful examination of the Sustainable Development Goals (SDGs)' aims and selected indicators. In addition, the current study takes into account both the pre-and post-Covid-19 pandemic periods, which is one of the article's groundbreaking roles following the Covid-19 pandemic spread.
3 Econometric investigation
3.1 Theoretical background
(Perch-Nielsen et al., 2010)and(Gössling and Lund-Durlacher, 2021) identified increases in production and income as critical reasons for rising energy demand. According to the aforementioned theoretical framework, econmic development(GDP), investment in alternative energy(IRE),wind energy output and green finance were all presented as control variables by(Munir et al., 2020). Because of this, we may represent the relationship between green economic growth and natural resources development:(1) lnGERit=μi+α1lnNRRit+θ1lnPGDPit+β1lnIREit+β2lnINDit+β3lnGFit+β4lnEGLit+εit
Methodologically, this study employed a total of five variables derived from the theoretical assumption: economy (proxied by GDP) estimated in constant US$ 2010, investment in alternative energy (IRE), green economic recovery(GER) wind energy output (REL), and green finance (GF). The research of(Sovacool et al., 2021) inspired the present study, which focuses on the nexus between the volatility of crude oil prices for natural materials and economic effectiveness. As the economic impact of the Covid-19 pandemic continues to be felt most severely in China. This paper analyzes the impact of NRV on China's economic performance both before and after the COVID-19 pandemic, in part because of the current trend in China demonstrating policies targeting environmental protection. The effects of IRE, REL, and GF on China's economy during the COVD19 pandemic have also been analyzed. The above framework calculates the impact of rising income and living standards on energy use. How do natural resource and sustainable development goals contribute to green economic growth, and what are the processes behind this relationship? We use the dynamic threshold model further to understand the nature of their interplay (8). Through these two routes, finance may boost output: by encouraging the accumulation of capital and the development of innovative technologies and by facilitating the allocation of resources to projects with the potential for comparatively significant profits. That means that rising energy costs may be affected by economic prosperity via a multiplier effect on increased production. With this in mind, this research builds a dynamic panel threshold model with total natural resources development and sustainable development goals. It examines a rise in green economic growth in the context of varying levels of financial development.
3.2 Model development
This paper uses the novel Difference-in-Difference(DID) type method to estimate this paper's econometric models to see if low-energy-consuming enterprises' tax reduction policies can help them innovate and assess the dynamic impact of tax reduction policies. Our econometric models are presented as follows:(GPI)i,t=β0+β1×POSTCOVIDt+β2×β2NRTreati+β3×POSTCOVIDt×energyresourcesTreati+βi×Xi,t+ut+γi+εi,t
Where the dependent variable Greenprocessinnovationt(GPI)i,t is the innovation spending as a percentage of total assets. In terms of our independent variables, POSTCOVIDt is a dummy variable that is either 1 or 0 following the execution of the tax reduction strategy? energyresourcesTreati Showing the dummy variables, we set it to 1 if the company consumes little energy and to 0 otherwise. β3 Parameters are to figure out the primary variable.
3.3 Variable description
The main reason is that we are particularly interested in the nations that are still emerging. First and foremost, emerging economies in the early phases of modernization focus on climate strategy and ecological conservation regarding international justice(Sueyoshi and Goto, 2012). Second, developing nations have fewer financial and technological resources to deal with weather change and ecological damage than industrialized ones(Akpolat and Bakirtas, 2020). For the third time, emerging economies are the primary receivers of climate funding because of the trade-off between manufactured goods and environmental deterioration due to economic concentration(Hanssen et al., 2018).
Carbon dioxide emissions (metric tons per capita) are a key source of GHG and may be used to track environmental deterioration caused by human activities associated with economic development. Because it is one of the most significant factors in the climate-related environmental decline, such a measure has long been employed as a proxy for environmental quality(Zhu et al., 2018). If we are serious about reducing greenhouse gas emissions, we need to reduce the amount of CO2 we produce. This is a big factor in both global warming and the degradation of the environment. To quantify environmental sustainability, we focus on the World Development Indicators (WDI) generated carbon dioxide emissions.
Climate financing is quantified by comparing the GDP of the receiving nation to three kinds of global climate money: overall climate funds, international climate management funds, and climate adaptability funds. Annually, the OECD Development Aid Committee (DAC) compiles official growth advisory data, and other resource flows from regional and transnational growth collaboration sources(Scarpellini et al., 2019). To avert hazardous human interference with the climate system, mitigation funding primarily tries to stabilize GHG concentrations in the environment. Investing in renewable energy, such as solar photovoltaics and wind turbines is the most common form of mitigation funding. On the other hand, finance for climate change(Munda and Nardo, 2009) adaptability focuses on enhancing natural systems' capacity to withstand the present and future effects of climate change by boosting their adaptive capacity and raising their durability. This is a total of mitigation and adaptability banking, which refers to expenditure and funding operations that support additional money for climate change mitigation and low-carbon growth objectives.
A two-period averaging method is utilized to cope with climate money's dynamic impact, given that recipient nations require many years to complete projects. The planning process may be broken down into three stages(McCartney et al., 2021): It is possible to determine whether or not the same recipient got climate financing in the year (t) by utilizing a technique known as the variations; and if the recipient nation obtained climate finance in the year (t), the funds are shared evenly among years (t) and (t + 1). In other words, if climate funding is not received in a given year, it would not be included; (iii) we aggregate the total amount of climate finance flows, which provides for monies received in t and t-1 years. Other methods of smoothing out periods have the same effect.
Recipient nation population (POP), industrial value added (IVA), foreign direct investment (FDI), and energy intensity are all elements that might impact ecological sustainability at a country level (EI). It has long been recognized in the research that population has a significant impact on environmental quality(Ibn-Mohammed et al., 2021). However, some believe that a growing population harms environmental quality because it leads to higher levels of energy use and carbon emissions(H. W. Chen et al., 2010), while others believe the opposite, arguing that a growing population can help to reduce energy use and emissions by increasing the productivity of public services and fostering commercial coalescence(Vasylieva et al., 2019).
4 Data and descriptive statistics
4.1 Data source
This study uses the China energy Market & Accounting Research Database to obtain the from energy industrial firms Statistics data collected by regional confirmed Covid-19 cases instances in China from 2021 to 2022. The dataset includes detailed information about each firm's basic features and a diverse set of financial metrics from the cash flow energy markets, financial announcement, and financial equilibrium sheet, respectively. The post-COVID-19 world necessitates long-term growth, but the recovery period focuses on the economy. Because the benefits of energy sustainability are aligned with both economic and sustainable development, we are compelled to promote it. The elements influencing energy sustainability from post-COVID-19 situation perspectives are examined.
4.2 Descriptive statists
Table 1 Table 1 Descriptive results.
Table 1 (1) (2) (3) (4) (5) (6) (7) (8)
Variable Obs. Mean value Std.Dev. Minimum Maximum Control variable Treat Difference
R&D Dummy 44,344 0.533 0.530 1.000 0.000 0.533 0.560 −0.054***
R&D 44,344 0.030 0.035 0.000 0.456 0.021 0.019 −0.008***
Post-COVID 44,344 1.345 0.475 1.000 2.000 0.339 0.347 −0.008
Natural recourses 44,344 0.705 0.456 0.000 1.000 0.000 1.000 −1.000
KZ 15,470 5.533 2.051 5.030 7.091 4.766 3.350 0.089***
WW 13,612 2.273 0.120 0.677 1.540 1.210 1.233 0.022***
ROA 18,756 0.040 0.050 −0.240 0.290 0.030 0.023 0.007***
ROE 18,645 0.055 0.088 −0.520 0.450 0.063 0.065 0.009***
Economic growth 36,411 0.405 0.474 −0.754 2.685 0.522 0.625 −0.041***
Tobin's Q 21,541 2.365 3.114 0.621 52.441 3.652 3.254 −0.547***
Firm size 40,325 19.474 1.321 11.414 32.471 18.325 19.652 −0.085***
Firm age 25,478 3.411 0.747 0.000 4.254 3.254 3.254 0.254***
Note: ***, ** and * is for level of significance at 1%, 5% and 10%.
shows descriptive data for the paper's primary variables, including renewable energy development, green economic and natural resources policy-related variables, financial intermediation, and basic business characteristics. Regarding innovation measurement, the percentage of enterprises engaged in innovation is approximately 39.3 percent, and the mean clean energy investment in innovation is around 0.031. The difference between indicators is that low-energy-consumption businesses are more inventive. Furthermore, the program helped 70.5 percent of China's publicly traded companies. Furthermore, enterprises that have experienced financial limitations show substantial variability in both the KZ and SA indexes. .As evaluated by the firm, ROA and ROE are around 2.2 percent and 4.5 percent, respectively. These study areas still using renewable energy-consuming very low-level enterprises had higher financial status indicators, such as coverage energy and economic ratio, liquidity, and markets cash flow, with mean values of 3.433%, 0.766%, and 0.031%, respectively. Furthermore, the overall sales growth rate is 49.4 percent, and Tobin's Q is at 3.399. Lastly the firm size is approximately 30.455, and the age is approximately 3.344.
For Eq. (1), we estimate the influence of green-finance-system standards on greenwashing by adding fixed effects and firm- and industry-level control variables in Columns 1–3. No doubt, the findings in Column 3 are more accurate than those in Columns 1 and 2 since they include all the control variables and fixed effects. Post and Treat's combined effects on greenwash are positive and important, as shown in Table 1, with a correlation of 0.214 at the 1 percentage importance level, indicating that (Rempel and Gupta, 2021)a one-unit standard deviation in the pollution-control target causes a 21.3percentage increase in greenwashing for heavily polluting firms. Using the results to support our hypothesis, we may conclude that green financing standards enable greenwashing by polluting companies.
4.3 Main results
4.3.1 Renewable and sustainable energy transitions
Green efficiency, and green innovation are all negatively affected by green credit regulation due to financial limitations(Bai and Dahl, 2018). Firms make a variety of options in response to varying degrees of financial restriction. High liquidity helps provide regular operations and output for companies with fewer financial constraints, even though they may incur non-compliance expenses due to environmental control policy. As a result, enterprises in this category are less inclined to seek outside funding sources like green loans or engage in green washing practices to minimize the credit effect. Environmental control policies may significantly impact businesses that are already under financial pressure, but this can be alleviated by enterprises that are already under financial pressure and have a strong motivation to ease the impact of such limitations(Neralić and Kedžo, 2019). As a result, they may have a strong reason to green wash to fulfill strategy criteria and get easier access to green finance (see Table 4).
Financial restrictions have a major impact on green washing, according to Table 2 , which indicates how businesses' green washing actions are influenced by the green finance standards depending on the extent of financial limitations. In Table 2, Index both reveal that financial burdens have a positive and substantial influence on greenwashing. Financial limitations have a negligible effect of 0.4 percent (Gürlek and Tuna, 2018) on the WW and SA indices, according to columns 3–4, but the 2017 Guidelines dramatically increase the financial restrictions. When it comes to the second state, we examine the link between economic conditions and strategy shocks and greenwashing. Results are provided in Table 5 Panel B, and we discover that green financing standards greatly influence companies in groups with high financial restrictions but have no effect on those in groups with minimal financial limits(Kaakeh et al., 2021).Table 2 Results of probit test and OLS testing.
Table 2 Dependent variable: Real Investment Cost per Capita (in logs)
Variables Probit OLS Margins
R&D Dummy −0.0213 −0.0344∗∗ −0.0633∗
R&D (0.0194) (0.0115) (0.0301)
Post-COVID-19 −0.0367∗∗∗ −0.00748∗∗ −0.0242∗∗∗
Natural recourses (0.00822) (0.00359) (0.00714)
KZ −0.864∗∗∗ −0.268 −0.726
WW (0.334) (0.292) (0.466)
ROA −0.101 −0.164 −0.312
ROE (0.384) (0.233) (0.345)
Tobin's Q 0.00677 −0.000832 0.000678
Firm size (0.00522) (0.00367) (0.00543)
Firm age 0.785∗∗∗ 0.283 0.604∗∗
(0.280) (0.227) (0.342)
Intensity (logs) −2.067∗∗ −0.00237 −0.438
(0.537) (0.305) (0.462)
Constant −4.535∗ −2.708
(2.700) (2.222)
Observations 334 334 334
Log likelihood −87.282 −284.247
R-squared 0.445 0.277
Note: ***, ** and * is for level of significance at 1%, 5% and 10%.
Table 5 Results of GMM analysis for strengths factor.
Table 5Variable (1) (2) (3) (4) (5)
POLS RE FE Two-way GMM
R&D Dummy 0.8300 2.4547*** 2.7743⁎⁎⁎ 1.2573⁎⁎ 2.7252⁎⁎⁎
R&D (2.4346) (4.6543) (5.3653) (3.5583) (5.6032)
Post-COVID 3.7587⁎⁎⁎ 3.6774⁎⁎⁎ 0.8780⁎⁎⁎ 0.5099 0.9853⁎⁎⁎
Natural resources (25.8990) (30.8800) (5.0746) (0.8044) (5.388)
KZ 0.0026⁎⁎ 0.0033 −0.0077⁎⁎⁎ −0.0033⁎ −0.0054⁎⁎
WW (4.3734) (3.0659) (−5.4585) (−3.8777) (−3.5600)
ROA −0.0446⁎⁎⁎ −0.0347 0.0335 −0.0368 0.0072
ROE (−6.5599) (−3.5809) (0.8877) (−3.3854) (0.6682)
Tobin's Q −0.0114⁎ −0.0072 0.0454 0.0354 0.0313
Firm size (−2.7364) (−0.3998) (2.6054) (2.2586) (1.3192)
Firm age −0.0087⁎⁎⁎ −0.0097⁎⁎⁎ −0.0076*** −0.0077⁎⁎⁎ −0.0075⁎⁎⁎
(7.6366) (6.3785) (5.5776) (7.7232) (6.2249)
cons −7.7748⁎⁎⁎ −8.8627⁎⁎⁎ −3.0624 0.7657 –
(−22.7232) (−8.6738) (−2.6533) (0.2808) –
R2 0.7505 0.6558 0.5838 0.8565 0.6910
F/Wald 65.8855⁎⁎⁎ 563.223⁎⁎⁎ 87.86327⁎⁎⁎ 55.8826⁎⁎⁎ 71.5562
Obs. 480 480 480 480 470
Note: in parentheses ***p < 0.01, **p < 0.05, *p < 0.1.
When it comes to job prospects, an IRENA analysis shows that the jobs gained from the energy transition outnumber the jobs lost from fossil fuels globally (three times more job chances) [30]. The energy transition's employment potential is depicted in Figure 4. The level of employment varies depending on the technology. For both models, provide insignificant estimates. Furthermore, at the 1%, 5%, and 10% levels, the empirical estimates of EG-J and EG-J-Ba-Bo yield highly statistically significant estimates. The null hypothesis of no co integration relationship between the under-discussion variable is thus rejected. Furthermore, the altered energy sector demands improved market architecture that encourages short-term flexibility via appropriate pricing signals(Steffen et al., 2020). And cross-border electricity trade is a favoured upgrade for improving market stability.
Furthermore, the energy transition will ensure that the climate targets are met, and governments and energy policies will play a larger role in this process. Installing carbon capture devices would be capital demanding, and after COVID-19, it is nearly impossible to market quickly (Quitzow et al., 2021). However, by adopting an eco-friendly approach, it is feasible to RE recourses that produce clean and cheap energy for the country. In such circumstances, integrated modelling evaluation would be beneficial (Pappas, 2021). In light of Model-1's findings, all three FMOLS, Random effect, and CCR estimators show that total natural resources have a negative impact on world economic performance over the given time period. Alternative sustainable means of manufacturing renewable energy from natural gas from the trash can be studied in light of a lack of money and renewable resources (Raza et al., 2021).
Furthermore, the quickening of the transition would push the research scholar to use much more of the pre/post-COVID-19 pandemic period's short-run relationship between natural resource commodity price volatility and economic performance. In addition, the scientific community might make a significant contribution by estimating the geographical renewable energy potential. Studies for China and other regions, as well as challenges and policy requirement(Gumashta and Gumashta, 2021; Kenny and Mallon, 2021; Padhan and Prabheesh, 2021), Accelerating the review and approval of new projects, as well as the issue of licenses, At a 1% level, TNR considerably affects economic performance by 0.633 (FMOLS), 0.687 (DOLS), and 0.698 (CCR). The magnitude of influence fluctuates significantly, but the direction of influence remains constant. Furthermore, from a policy standpoint, we require creative policy mechanisms that promote sustainable growth while being cost-effective (Rivera-Ferre et al., 2021).
4.4 Global energy sustainability
Once the results were obtained, AMG and CCEMG estimation methods were tested for their resilience. Our findings are shown in Table 3 using the FMOLS method, which is a completely altered ordinary least squares (FMOLS).(Gumashta and Gumashta, 2021). According to FMOLS results, external variables' effects on economic growth are similar to those found by the AMG and CCEMG estimation method. On the other hand, a little shift in the amplitude of the correlation coefficients has been discovered. A rise of one percent in green finance, resources and energy expenditure, nation resource taxation, and technological innovation raises the economy's performance by 0.162, 1.545, 0.662, and 1.496%. The projected findings are statistically significant at all three stages (1%, 5%, and 10%)(Falagiarda et al., 2020; Melo-Oliveira et al., 2021; Rivera-Ferre et al., 2021).Table 3 Baseline estimations.
Table 3 (1) (2) (3) (4) (5) (6)
Tests Probit test Tobit test Fixed Effect Probit test Tobit test Fixed Effect
R&D Dummy −0.655*** 0.017*** −0.031*** 0.035 0.006*** −0.004
R&D (0.006) (0.001) (0.001) (0.018) (0.001) (0.002)
Post_COVID −0.099 −0.004*** 0.015*** 0.026** 0.011*** 0.012***
Natural recourses (0.110) (0.001) (0.002) (0.011) (0.002) (0.002)
KZ 0.088*** 0.009*** 0.003*** 0.017*** 0.004*** 0.004***
WW (0.023) (0.001) (0.001) (0.000) (0.001) (0.001)
ROA −0.002 −0.002*** 0.002**
ROE (0.059) (0.000) (0.001)
Tobin's Q −0.683*** −0.010*** −0.009***
(0.022) (0.000) (0.000)
Constant −1.093*** −0.003*** 0.244*** −3.334*** 0.183*** 0.115***
(0.408) (0.001) (0.006) (0.463) (0.006) (0.008)
Year Yes Yes Yes Yes Yes Yes
Industry Yes Yes Yes Yes Yes Yes
Observations 26,293 45,236 23,336 22,162 22,162 22,162
R-squared 0.169 0.214
Note: in parentheses ***p < 0.01, **p < 0.05, *p < 0.1.
Table 4 Results of model 1 to 9 testing.
Table 4Variables Model (1)lnGS Model (2) DFC Model (3) EDI Model (4) lnGS Model (5) DFC Model (6)lnDY Model (7) lnDY Model (8) EFC Model (9) lnIY
C −2.28 0.03 0.83 −0.76 0.02 −11.22∗∗∗ −12.65∗∗∗ 2.00∗∗∗ 6.67∗∗∗
R&D Dummy 3.60∗∗∗ 2.40 −0.03∗∗∗ 2.53
R&D 0.27∗∗∗ −68 × 20−4∗ 0.25∗ −6.56 × 20−5 0.03
Post COVID 0.83∗∗∗ 8.53 × 20−4 0.53∗∗ 0.88∗∗∗ 5.85 × 20−4 3.20∗∗∗ 2.89∗∗∗ −2.34 × 20−3 0.58∗∗∗
Natural recourses 3.05∗ 0.04∗∗∗ 3.44∗∗ 3.48∗∗ 0.04∗∗∗ −3.07 −3.65 0.05∗∗∗ 0.84∗∗
KZ −0.87 −4.26 × 20−3 −0.57 −0.82 −3.35 × 20−3 −0.33 −0.24 0.02∗∗ −0.06
WW 3.73∗∗∗ −0.02∗∗∗ 2.88∗∗ 4.23∗∗∗ −0.03∗∗∗ −2.02 −2.00 5.32 × 20−4 0.38
ROA −0.84∗ 0.02∗∗ −0.46 −2.02∗ 0.02∗∗ 2.88∗∗ 2.93∗∗∗ 3.33 × 2043 0.20
ROE 0.30 0.25 0.22 0.27 0.27 0.22 0.40 0.07 0.32
Note: in parentheses ***p < 0.01, **p < 0.05, *p < 0.1.
4.4.1 RE sources into the energy transition
It is necessary to mobilize green financial possessions to fully utilize renewable energy sources and achieve satisfactory energy efficiency. Simultaneously, associated financial and economic hurdles that cause the Group of the eight-nation energy sector to lag behind other regions must be overcome(S. Gao, 2020) are not important and are all near 0, inferring that there was no important variation in green technology innovation among the therapy group and that of the control group before that year. Since 2017, columns (1) and (2) show significant positive coefficients, indicating that following the policymaking, there were important variations among firms in the therapy and control groups, which meets the concept of parallel trends based on temporal trends. This is because the spread of current technologies and the creation of new ones take time. It is also important to note that the impact of communications architecture on green technology innovation is influenced by(Shahrestani and Rafei, 2020) factors such as regional factor flow, economic growth, and human capital.
Even though they were chosen at random in terms of geographic allocation and economic growth, the pilot towns are still being scrutinized because of concerns about other possible contradicting variables that may influence the results of SDG dynamics relations in Table 2. This research uses IV estimate as a robustness test to address the issue of strategic endogeneity. The two-stage least squares approach is used to assess the robustness of the benchmark findings based on the IV method, which (Hanif et al., 2019) adopted (2SLS).
4.5 Financial modelling
The findings are congruent with those of (Gumashta and Gumashta, 2021), who identified a favorable association between green money and renewable energy investment. Green bonds have little impact on renewable energy investments in the first year of COVID-19. Except for Model 7, the ADF test boosts renewable energy sources by 0.4356 and 0.4576. Green finance encourages investments in solar, wind, and hydro energy. The energy transition is a terrific approach to accelerate progress toward sustainability, but it can only be done by emphasising the affordability issue at the consumer level. The perception of energy affordability is frequently based on an individual's perspective rather than societal considerations (Melo-Oliveira et al., 2021). From the standpoint of energy production, affordability is defined as the prospective economic profitability in relation to the investments made. Governmental approaches and energy policies, on the other hand, can be effective in achieving cleaner energy goals but ineffective in promoting energy affordability due to the uncertainties involved. Overall, energy affordability is a complicated issue that necessitates multifaceted climate change problems facing both developing and non developing world, and RE sources must modify their perceptions of energy affordability. The rate of global electrification is also influenced by affordability. Electrification has numerous advantages for both producers and consumers(Aramburu and Pescador, 2019; Y. Chen et al., 2019; Diao et al., 2019; Turner and Schlecht, 2019). Consumer affordability is only attainable while the energy cost decreases with app effects. As a result, reducing poverty will aid in the resolution of these complex affordability concerns.
The standard deviation of each city's height is employed as an experimental variable in the first stage of the experiment. As a purely operational variable(Filippini and Greene, 2016), terrain relief meets the relevance requirement. When it comes to building telecommunications structures, higher terrain relief impacts both the cost and signal quality of such architecture, which in turn affects the effectiveness with which the system as a whole operates (Lang et al., 2021). The empirical findings of the study, on the other hand, support the use of effective techniques to increase RE. Lack of legislative reforms and poorly performed and implemented reforms targeted at boosting electrification.
The empirical data for the major indicator of post-COVID-19 and green economic variables in Table 3. We employ three alternative estimating methodologies depending on the dependent variables. In particular, the FMOLS findings show that a one percent increases in natural resource volatility affects economic performance by 0.255 percent. A 1% increase in improving sustainability, renewable power output, and green finance, on the other hand, improves economic performance by 0.544, 0.355, and 0.677 percent, respectively. At the 1%, 5%, and 10% levels, the results were highly statistically significant. Our findings highlight the importance of Using the probit and Tobit approach; this fills a vacuum in the literature addressing the pre and post Covid-19 conditions of China's natural resources, commodity pricing volatility and economic performance (Ulucak et al., 2020).
4.6 Pre-COVID pandemic testing
All UN member states endorsed the 2030 Agenda for Sustainable Development (2030 ASD) in 2015, including 17 SDGs. 'Clean and cheap energy (SDG 7) and 'climate change mitigation (SDG 13) were major global challenges. It reflect comparable conclusions to those previously mentioned. Nonetheless, varying magnitudes are recorded. In particular, a 1% increase in natural resource volatility reduces China's economic performance by 0.83 percent. A 1% rise in Model 1(DEF), Model 2, or Model 3 boosts economic performance by 0.657, 0.7687, and 0.8746 percent. At all levels of significance, i.e., 1%, 5%, and 10%, the estimated results are highly statistically significant. As a result, the Robust regression findings corroborate the empirical results obtained using FMOLS, DOLS, and CCR. Furthermore, the obtained results were consistent with previous empirical studies conducted in various regions of China.
The Breitung-Candelon (BC) spectral Granger causality test finds the causal link in all runs, including the long, medium, and short runs. On the other hand, the horizontal red line suggests a 5 percent level of a significant relationship between the variables that better understand dynamic situations and change directions in Table 5. The scenarios described in the next paragraphs are based on a qualitative approach and scenario analysis(Reilly, 2012), a foresight methodology. The ramifications of the pandemic for political stability are explored both at the domestic (intrastate) and international (global) levels in the scenarios presented here(Gielen et al., 2019).
4.7 Green financial results
We used financial constraints mechanism to build interaction terms between instrumental factors and time for 2SLS regression since using time-invariant instrumental variables in fixed-effects models is difficult(He and Guo, 2021). Using terrain relief as the instrumental variable, rows 1, 2, and 3 in Table 6 show the findings; rows 4, 5, and 6 in Table 6 show the results using fixed-line penetration as an instrumental variable. The impact of the Broadband China strategy on business green technology innovation is still considerable after accounting for exogenous variables via these parameters(Taghizadeh-Hesary et al., 2021). The first frame's instrumental variable's F-value is much over 10, suggesting that weak equipment is not a concern. This supports the hypothesis that improved telecommunications infrastructure encourages the development of environmentally friendly new technologies. To summarize, the Broadband China program supported green technology innovation in pilot regions of both high and poor quality. The policy had a stronger effect on encouraging low-quality green technology innovation than on encouraging high-quality green technology innovation. Because of China's lack of green technology, enterprises may be more difficult to achieve high-value levels in its green technology innovation(Kamyk et al., 2021).Table 6 Financial constraints mechanism investigation.
Table 6 (1) (2) (3) (4) (5) (6) (7) (8)
Probit Tobit Fixed Effect Probit Tobit Fixed Effect KZ WW
Financial constraint = KZ −0.045* −0.004*** −0.006***
Financial constraint = WW −0.298*** −0.044*** −0.051***
(0.088) (0.007) (0.008)
Post-Covid-19 0.048** −0.038**
(0.001) (0.001)
Treat −0.027 −0.017***
(0.003) (0.000)
DID Effect −0.044** −0.001***
(0.001) (0.000)
Financial growth −0.08 −0.002*** 0.08 0.009 −0.001*** 0.001 −0.073 −0.076
(0.081) (0.011) (0.008) (0.073) (0.056) (0.043) (0.075) (0.076)
Tobin's Q 0.084* 0.0052*** 0.007*** 0.059* 0.006*** 0.007*** −0.084 −0.003*
(0.074) (0.028) (0.084) (0.084) (0.002) (0.001) (0.018) (0.001)
Firm Size 0.230*** −0.002*** −0.005*** 0.062*** −0.008*** −0.007*** 0.625*** 0.007*
(0.025) (0.000) (0.000) (0.005) (0.000) (0.000) (0.000) (0.000)
Firm Age −0.744*** −0.008*** −0.008*** −0.525*** −0.005*** −0.004*** 0.004 0.004
(0.019) (0.002) (0.003) (0.002) (0.001) (0.001) (0.031) (0.003)
Constant −0.385*** 0.089*** 0.078*** −3.410*** 0.225*** 0.221*** −3.144*** 2.425***
(0.241) (0.009) (0.009) (0.155) (0.008) (0.009) (0.039) (0.003)
Year Yes Yes Yes Yes Yes Yes Yes Yes
Industry Yes Yes Yes Yes Yes Yes Yes Yes
Observations 12,524 12,524 12,524 12,524 12,524 12,524 12,524 12,524
R-squared 0.202 0.185 0.254
Note: in parentheses ***p < 0.01, **p < 0.05, *p < 0.1.
The negative and significant correlations for fiscal decentralization, renewable energy R&D, and institutional quality indicate that strengthening these characteristics lowered CO2 emissions in the sample countries. Three alternative models are estimated in this investigation. The impact of Tobin's Q, Financial constraint = WW, Financial constraint = KZ, and RE on CO2 emissions is estimated in the first model. Natural resource rent and income (GDP), on the other hand, have a positive relationship with CO2 emissions. Long-run elasticities for fiscal decentralization, GDP, natural resource rent, institutional quality, and renewable energy R&D are 0.026, 0.801, 0.129, 0.142, and 0.043, respectively, in Model 1.
FDI is also regarded as capturing possible technological spillover effects from other sources of expenditure since emerging nations cannot finance expensive abatement programs aimed at reducing emissions, combating climate change, and protecting the ecosystem without foreign help. Last but not least, we take into consideration EI since nations with intensive energy sources generally depend on fossil fuels to maintain their economic growth, making climate financing renewable energy investment more difficult to undertake(Yoshino et al., 2021).
4.8 COVID-19 related cases check
The global interconnectivity is 20.17 percent in the pre-COVID-19 period and 22.77 percent in the post-COVID-19 period. That after COVID-19 infection, total spillover effects increased dramatically, with approximately 34.58 percent of interconnectedness in all sectors.
On the other hand, the horizontal red line suggests a 5 percent level of a significant relationship between the variables. Table 8 depicts the imagined bureaucratic politics mechanism. China renewable energy preference might differ from one country to the next, and are impacted by leadership and a variety of other political issues. To engage in sustainable development at this point, a system to incorporate environmental and societal advantages into climatic goals is critical. The action frame specifies the goal's many targets. The green financial market is better integrated with copper RE and fossil fuels during the COVID-19 pandemic period. This stage entails all actions necessary to formulate solid policy and political approaches before execution. The highest spillovers between pairs occur when switching from RE markets (2.39 percent, 4.33 percent) to fossil fuel energy (1.30 percent, 3.60 percent) (4.77 percent, 09.03 percent). Furthermore, a proper feedback mechanism is required to modify tactics and improve implementation efficacy.Table 8 Robustness check.
Table 8 Dependent variable: Hazard of Investment
Variables 1 2 3 4 5 6 7 8 9
R&D Dummy −3.306∗∗ −2.287∗∗∗ −2.299∗∗∗ −0.667∗∗∗ −0.670∗∗∗ 0.0403 0.350 −0.350 −0.235
R&D (0.287) (0.306) (0.305) (0.305) (0.327) (0.374) (0.366) (0.352) (0.355)
Post-COVID −2.676∗∗∗ −2.798∗∗∗ −2.773∗∗∗ −0.889∗∗∗ −2.026∗∗∗ −0.558∗∗ −0.502∗ −0.595∗∗ −0.565∗∗
Natural resource (0.287) (0.275) (0.284) (0.275) (0.266) (0.366) (0.355) (0.334) (0.334)
KZ −2.858∗∗∗ −3.088∗∗∗ −3.084∗∗∗ −2.263∗∗∗ −2.254∗∗∗ −0.466 −0.277 −0.345 −0.296
WW (0.348) (0.357) (0.365) (0.222) (0.336) (0.446) (0.466) (0.388) (0.404)
ROA −4.638∗∗∗ −3.500∗∗∗ −3.532∗∗∗ −2.637∗∗∗ −2.624∗∗∗ −0.895∗∗ −0.505 −0.809∗∗∗ −0.962∗∗
ROE (0.460) (0.430) (0.436) (0.447) (0.464) (0.566) (0.538) (0.455) (0.463)
Sales growth (0.00732) (0.00672) (0.00677) (0.0205) (0.0275) (0.0286) (0.0237)
Tobin's Q −0.00883∗∗∗ −0.0246∗∗∗ −0.00822∗∗ −0.008534 −0.0245∗∗ −0.0293∗∗∗ −0.0294∗∗∗
Firm size (0.00267) (0.00289) (0.00462) (0.00584) (0.00704) (0.00577) (0.00567)
Firm age 0.648∗∗∗ 0.846∗∗∗ 0.547∗∗ −0.735∗ −0.0434 0.522∗ 0.485∗
Note: in parentheses ***p < 0.01, **p < 0.05, *p < 0.1.
In the COVID-19 pandemic period, the spillover effects across these three markets are greater than in the pre-COVID-19 period. Meanwhile, RE and green recovery have the largest spillover effects, implying that the metal market contributes more to overall connectedness. Before the COVID-19 outbreak, the value of net connectivity alternated between positive and negative. This suggests that the importance of these eight variables shifts throughout time. However, during the ongoing COVID-19 pandemic, financial variable and RE are the main net communicators of overflow. The function and prominence of international organisations must be strengthened, since a return to the multilateral paradigm for addressing global concerns appears to be the most sensible course of action. The analysis found that green financial allocation for renewable energy investment is 98% significant. In addition to typical climate change activities, lowering global emissions and promoting renewable energy investment with green financial energy can provide better results.
When renewable energy investments are combined and regressed for 2021, the results are favorable. Green bonds have little impact on renewable energy investments in the first year of COVID-19. Except for Model 7, green funding favors renewable energy sources with factors of 0.3956 and 0.67545. Green finance encourages investment in solar, wind, and hydro. The mentioned findings are congruent with (Mohammadi et al., 2015), who found substantial and good results. Renewable energy and energy efficiency are key to any energy policy adjustment.
Green standards encourage solar, wind, and hydro energy investment sources with 0.423, 0.6754, and 0.7654, respectively. More green regulations, such environmental levies, can stimulate greener energy sources in China. This is due to a change in renewable and clean energy investment sources, an environmental panacea.
There is a complicated relationship between several SDGs, with one influencing the other in a synergic or trade-off impact (Reghenzani et al., 2019). As a result, knowing the connections between the SDGs is critical for determining the best path to achieving the objective with the least amount of work. The authors provide a fresh quantitative analysis to demonstrate the SDGs connection. Interaction between SDGs can be seen in two ways. Progress on one goal can impact other goals, and progress on one goal can depend on progress on another.
The term implies the aim affects others. According to dynamic-wind energy, Green bonds and green rules have a big, positive influence on wind energy investment. Green bonds and green standards have a big influence, as according them. Table 8 shows the moderating influence of green regulation on Inv3, with the interaction term (GPR*GREENREG) being significantly negative but lower than the direct negative impact of GPR, which was 0.138, significant at 1%.
Although green bonds are appealing, equity financing may also be used to invest in clean energy and green technologies(Callens and Tyteca, 1999). In recent years, it has been shown that many stockholders are unwilling to participate in sin-stocks that are hazardous to the ecosystem and human health or exploit social well-being, regardless of their gains. Over several generations, there has been a boom in environmental and socially conscious share expenditures. These expenditures concentrate on the company's policies on environmental and social issues such as climate change, as well as corporate governance. Despite the COVID-19 pandemic, sustainable spending throughout the world totaled USD 36.3 trillion, a 15percentage increase in two years. Several studies have shown that the shares in the Environmental and Social Accountability Index can withstand market downturns, such as the international financial crisis, commodities price shocks, or the COVID-19 outbreak(Ponce and Khan, 2021). Using stock markets to finance clean energy and green technology initiatives has several benefits. Investors benefit from this market's disclosure standards because it creates a more secure environment and allows for more investment. In addition, the company's ownership is distributed among(Sigala, 2020) stakeholders, which suggests that these stockholders will have different viewpoints on the initiatives, which might lead to a better appraisal.
The relationship of SDG with other targets is depicted in Table 8. The shift to a low-carbon economy is the first and most important. Furthermore, the sample size for this study was limited to 25 energy companies operating in China; this produces a lot of job possibilities and reduces energy importation, which helps the economy grow(Khan et al., 2021). As renewable energy grows, companies will be under increased pressure to support the energy transition, and innovations in renewable will have piled up as a result of improved collaborative circles throughout the accelerated transition period.
After evaluating and discussing the results of the Markov-Switching models, Table 7 shows evidence of post estimation diagnostics(Zahid et al., 2022). Breusch-Godfrey test, Durbin Watson test, heteroskedasticity, skewness, and kurtosis all show up in the results. . These studies, conducted before the Covid-19, show that natural resource commodity price volatility has no impact on a country's macroeconomic performance. On the other hand, uncertainty causes panic and has a negative impact on economic and manufacturing activity. This has a negative impact on the country's economic success. Focusing on energy transition while keeping environmental limits in mind will result in pollution-free energy generation and job possibilities and economic growth(Khan et al., 2022). This also entails addressing poverty issues to some level, such as energy availability and affordability issues, which can be gradually addressed with the help of quality education. With the rapid spread of clean energy, green techniques in SDG 9 will be well-established, and innovations, particularly in recycling, reusing, turning waste energy to useful energy, and boosting efficiency, will all contribute to instilling sustainability in every action. Plastic usage and disposal are two further adjustments that the world requires (Sharaunga et al., 2019).Table 7 Covid-19 correlation exploration.
Table 7 (1) (2) (3)
Probit Tobit Fixed Effect
DID result −0.070 0.007*** 0.007***
(0.041) (0.002) (0.001)
DID Effect*Confirmed cases 0.018** 0.001*** 0.002***
(0.004) (0.000) (0.000)
Financial growth 0.070*** −0.001 0.005*
(0.030) (0.001) (0.002)
Tobin's Q −0.011 0.009*** 0.007***
(0.010) (0.002) (0.002)
Firm Size 0.098*** −0.009*** −0.005***
(0.021) (0.000) (0.000)
Firm Age −0.455*** −0.015*** −0.016***
(0.038) (0.001) (0.001)
Constant −2.171*** 0.199*** 0.245***
(0.499) (0.008) (0.009)
Year Yes Yes Yes
RE Industry Yes Yes Yes
Observations 5377 5377 5377
R-squared 0.180
Note: in parentheses ***p < 0.01, **p < 0.05, *p < 0.1.
5 Conclusions and policy implications
After the COVID-19 outbreak, this study examines the influence of modifications in China's Sustainable Growth Goals (SDGs)development goals and natural resources utilization for green economic recovery on Chinese enterprises' by employing econometric estimation on the period of 2010–2020.As a result, the post-COVID world emphasizes the necessity for long-term development and methods compatible with the ecosystem. We proposed that this study be used as a roadmap to steer the post-pandemic scenario onto a sustainable development goals and development of green economic recovery by emphasizing energy sustainability as a strategy to engage in SDG-related efforts.
Including sustainability development goals and green economic recovery objectives in long-term development plans had a considerable impact on energy saving and emissions reduction, lowering energy consumption intensity by 3.33 percent and carbon emission intensity by 4.23 percent. A growing trend toward such techniques could yield even better outcomes for renewable energy investment. Furthermore, during the outbreak of the COVID-19 pandemic, the correlation between the two sets of indicators increased dramatically. Our findings also imply that investors who choose to go green will not lose money in terms of risk-adjusted returns. It is easier for firms to direct their operations now that investors may convert to green investments without sacrificing financial rewards. Renewable and sustainable energy transitions are more important than ever before, as help to boost employment prospects and influence market dynamics in a unique way. The ideas for accelerating the transition are presented through the eyes of the power plant, transportation, and construction industries. The importance of prioritising investment and the employment picture and labor market developments that are significantly influenced (in a favorable way) by the energy transition are stressed. The energy sector's digital transformation benefits the sustainable energy sector in various ways. To determine the prioritised strategy in light of current pandemic consequences, green policies play an important role in lowering the negative impact of geopolitical risk on hydro energy investment.
On the other hand, when it comes to determining the political viability of energy sustainability, both developing and industrialised countries use a variety of methodologies. Unilateral approaches are represented in one extreme scenario, whereas multilateral approaches are highlighted in the other. Furthermore, the reality appears to be less encouraging, given the lacklustre response to the pandemic and the plan for a rapid increase of fossil fuel use even in affluent countries, both of which exposed multilateralism's flaws and emphasised a general preference for self-interested acts.
5.1 Policy implications
Overall, this article serves as a reminder that a well-designed, environmentally friendly fiscal policy can aid post-pandemic economic recovery and the transition to long-term growth. These results point to two major policy consequences. First, corporate managers must adopt a green approach to financial liquidity management in terms of management dynamics. As a result, resolving all of these constraints will be a helpful approach for future investigations. Identifying and implementing common ground remains beneficial during the recovery period, but after a normal situation has been restored, much attention must be paid to long-term development. Whether or not the SDGs can be achieved by 2030, putting out the greatest effort to do so is what matters most and should be the top priority. The authors of this study propose that sustainable development be viewed through the lens of energy sustainability.
Funding
Beijing Municipal Philosophy and Social Science Planning Office "Research on the Coordinated Development of Beijing-Tianjin-Hebei Financial Agglomeration and Industrial Structure Upgrading" (16YJB037).
Author statement
Shikun Zhang: In the process of writing the article, the first author participated in the idea of the article and the collation and analysis of data, and the; Muhammad Khalid Anser: carried out the design of relevant methods, project support, data collection and proofreading, Michael Yao-Ping Peng: Reviewing, Editing, Monitoring, Chunchun Chen: Editing, English check, reviewing and Supervision.
Ethics approval and consent to participate
Not applicable.
Consent for publication
All of the authors consented to publish this manuscript.
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| 0 | PMC9744703 | NO-CC CODE | 2022-12-15 00:01:54 | no | Resour Policy. 2022 Dec 13;:103182 | utf-8 | Resour Policy | 2,022 | 10.1016/j.resourpol.2022.103182 | oa_other |
==== Front
Vacunas
Vacunas
Vacunas
1576-9887
1578-8857
Elsevier España, S.L.U.
S1576-9887(22)00193-5
10.1016/j.vacun.2022.11.002
Original
Knowledge And Attitudes Toward the COVID-19 Vaccine Among India's General Rural Population
Conocimiento y actitudes hacia la vacuna contra la COVID-19 entre una población rural general de IndiaVenkataraman Rajesh
Yadav Umesh
Shrestha Yogendra ⁎
Narayanaswamy Sindhu Shree
Basavaraju Shree Harsha Pura
Department of Pharmacy Practice, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B G Nagara, India-571448.
⁎ Corresponding author at: Department of Pharmacy Practice, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, Mandaya, Karnataka.
13 12 2022
13 12 2022
4 4 2022
26 11 2022
© 2022 Elsevier España, S.L.U. All rights reserved.
2022
Elsevier Inc.
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Introduction
Even after the enforcement of the lockdown, the government was unable to control the spread of the COVID-19 infection. Vaccination is the only remaining hope for preventing and controlling COVID-19 infections. The knowledge and attitude of the recipients can influence vaccine acceptance. In this study, we aim to assess the knowledge and attitude toward the COVID-19 vaccine among the general rural population of India.
Methodology
A community-based, prospective, cross-sectional study was conducted from May 2021 to October 2021 in the rural part of the Mandya district of Karnataka, India. Individuals over the age of 18 who met the Ministry of Health and Family Welfare's vaccination eligibility criteria were included in the study. Demographic details of participants and assessment of knowledge and attitude towards the COVID-19 vaccine were done in a designed and validated data collection form.
Results
The study included 596 participants, with females dominating males by 54.9 % (327). The average age of the participants was 31 years. Among them, 81.71% (487) had adequate knowledge, and 81.5% (486) had a positive attitude towards the COVID-19 vaccine. Females (85.3%, 279) tend to have a more positive attitude than males (77%, 207). Positive attitude participants (86.86 %, 423) have a higher level of knowledge about the COVID-19 vaccine than negative attitude participants (57.79 %, 63).
Conclusion
In the study, we found that 81.71% had adequate knowledge and 81.5% had a positive attitude toward the COVID-19 vaccine.
Introducción
Incluso tras la obligatoriedad del confinamiento el gobierno fue incapaz de controlar la propagación de la infección por COVID-19. La vacuna es la única esperanza que queda para prevenir y controlar las infecciones por COVID-19. El conocimiento y la actitud de los receptores pueden influir en la aceptación de la vacuna. En este estudio, nuestro objetivo fue evaluar el conocimiento y la actitud hacia la vacuna contra la COVID-19 entre la población rural general de India.
Metodología
Se realizó un estudio transversal, prospectivo y con base comunitaria de mayo a octubre de 2021 en la zona rural del distrito Mandya de Karnataka, India. Se incluyó en el estudio a los individuos mayores de 18 años que cumplieron los criterios de elegibilidad del Ministerio de Sanidad y Bienestar Familiar. Los datos demográficos de los participantes y la evaluación del conocimiento y la actitud hacia la vacuna contra la COVID-19 se incluyeron en un formulario de recopilación de datos diseñado y validado.
Resultados
El estudio incluyó a 596 participantes, siendo más numerosas las mujeres que los hombres en un 54,9 % (327). La edad media de los participantes fue de 31 años. Entre ellos, el 81,71% (487) tenía un conocimiento adecuado, y el 81,5% (486) una actitud positiva hacia la vacuna contra la COVID-19. Las mujeres (85,3%, 279) tendieron a tener una actitud más positiva que los hombres (77%, 207). Los participantes con actitud positiva (86,86 %, 423) tuvieron un mayor nivel de conocimiento sobre la vacuna contra la COVID-19 que los participantes con actitud negativa (57,79 %, 63).
Conclusión
En el estudio, encontramos que el 81,71% tuvo un conocimiento adecuado, y el 81,5% una actitud positiva hacia la vacuna contra la COVID-19.
Keywords
COVID-19 vaccine
Knowledge
Attitude
Palabras clave
Vacuna contra la COVID-19
Conocimiento
Actitud
==== Body
pmcIntroduction
After being discovered in Wuhan, China, in December 2019, the Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) spread rapidly throughout the world [1,2]. The SARS-CoV-2 virus infected almost all countries and had a significant negative impact on health, society, and the economy [3]. A wide range of medications have been used off-label to treat the disease [4., 5., 6., 7.]. Drugs repurposed for treatment do not show promising results in curing the disease. On the other hand, excessive medication use increased the risk of developing drug-related adverse effects and microbial resistance [8,9]. The government strictly implemented preventive measures such as wearing masks, keeping a safe distance, regular hand washing, avoiding crowds, and locking down to prevent the spread of the disease. Even so, it was unable to stop spreading. Hence, there is no other option than vaccination to prevent the spread of disease and decrease morbidities and motility associated with disease and economic crisis. (See Fig. 1, Fig. 2, Fig. 3 .) (See Table No, Table No, Table No, Table No.4 .)Fig. 1 Distribution of knowledge about COVID vaccine based on gender and vaccination groups.
Fig. 1
Fig. 2 Distribution of attitude towards COVID vaccine based on gender and vaccination groups.
Fig. 2
Fig. 3 Distribution of knowledge about COVID vaccine based on attitude towards COVID vaccine.
Fig. 3
Table No 1 Demographic details of the participants.
Table NoCharacters Frequency Percent
Gender Female 327 54.9
Male 269 45.1
Age 18-45 505 84.7
45-60 77 12.9
Above 60 14 2.3
Habits Alcohol 33 5.5
Smoking 12 2
Occupation Self-employed 173 29
Student 325 54.5
Employed 98 16.5
Socio-economic status 1-5 lakhs 218 36.6
5-10 lakhs 109 18.3
Less than 1 lakhs 269 45.1
Source of information for COVID vaccine Friends and family 50 8.4
Covid warrior 144 24.2
Social media, radio, T V and news 359 60.2
Government agency 43 7.2
Vaccination status Yes 119 20
No 477 80
Table No 2 Descriptive analysis of age, knowledge, and attitude of the participants
Table NoCharacters Mean SD IQR (Q3, Q1)
Age 31.24 15.87 10.75 (34.75, 24)
Knowledge 3.72 0.72 0 (4, 4)
Attitude 2.72 0.66 0 (3, 3)
Table No 3 Correct response to the questionnaire about knowledge and attitudes.
Table NoQuestionnaires Frequency Percentage
Knowledge Single dose of the COVID vaccine is enough to prevent infection. (Q1) 557 93.5%
The reason of inoculating the Covid-19 vaccine is to develop the neutralizing antibodies against COVID-19. (Q2) 568 95.3%
The common side effects of Covid-19 vaccines are Injection site pain, myalgia, fever and chills. (Q3) 523 87.8%
All the age group can be vaccinated. (Q4) 569 95.5%
Participants scored above 80% 487 81.7%
Attitude I think Covid-19 vaccines are safe. (Q5) 542 90.9%
I should not follow the preventive measures after vaccination. (Q6) 517 86.7%
I will recommend my family and friends to get vaccinated (Q7) 563 94.5%
Participants scored above 80% 486 81.5%
Table No.4 Association between variables.
Table No.4 Adequate Knowledge toward COVID vaccine P value Positive Attitude toward COVID vaccine P value
Yes No Yes No
Vaccination Yes 72 (60.5%) 47 (39.5%) < 0.001 61 (51.26%) 58 (48.74%) < 0.001
No 415 (87%) 62 (13%) 425 (89.1%) 52 (10.9%)
Gender Male 210 (78.06%) 59 (21.94%) 0.37 207 (77%) 62 (23%) 0.009
Female 277 (84.7%) 50 (15.3%) 279 (85.3%) 48 (14.7%)
Positive Attitude toward vaccine Yes 423 (86.86%) 64 (13.14%) < 0.001
No 63 (57.79%) 46 (42.21%)
Level of significant 0.05.
COVID-19 vaccines are developed to guide the production of SARS-CoV-2 neutralising antibodies by primarily targeting the surface spike protein which prevents the disease invasion [10,11]. Its top priorities are to combat infection, prevent disease spread, and control the disease [12]. Even after the manufacturer claimed that the vaccine was effective against SARS-CoV-2 [13., 14., 15., 16., 17., 18.], people doubted the vaccine due to its rushed development by skipping steps and spreading rumours about the adverse reaction. It is important to evaluate the general public's knowledge and attitude to vaccination to tackle all potential barriers to vaccination.
The COVID-19 immunisation campaign in India began on January 16, 2021, with the restricted use authorization in the emergency of Covishield®, Covaxin®, and Sputnik V® [2,19]. India's COVID-19 vaccine drive will be the largest and most challenging because of its large population size and diverse socioeconomic background. Before developing a vaccination strategy to achieve the goal of COVID-19 vaccination, authorities must first understand the target population's knowledge and attitude. It aids in determining the lack and cause of hesitancy as well as encouraging participation in the vaccination campaign. The goal of this study is to assess the general rural Indian population's knowledge and attitude toward the COVID-19 vaccine.
Methods and methodology
Study design
A community-based, prospective, cross-sectional study was conducted from May 2021 to October 2021 in the rural part of the Mandya district of Karnataka, India after obtaining ethical clearance from the Institutional Ethics Committee of Adichunchanagiri Hospital and Research Centre (AH & RC), B.G. Nagara (Approval No. IEC/AH&RC/AC/012/2021).
Study population
We obtained 385 as the sample size for the study by using the total population of the Mandya district as the population size, a 5% margin of error, a response distribution of 50%, and a 95% confidence level using Raosoft® sample size calculation software.
Participants
Individuals over the age of 18 who met the Ministry of Health and Family Welfare's vaccination eligibility criteria (https://www.mohfw.gov.in/covid_vaccination/vaccination/index.html) and were willing to consent to participate in the study were included. Individuals with psychological disorders and those under the age of 18 were excluded from the study.
Study instrument
The questionnaire was created using a thorough literature review and expert opinions. The preliminary draught of the questionnaire design was discussed with two academic experts in the field and modified based on their suggestions. The questionnaire was split into two sections: Section A and Section B. Section A was used to collect demographic information, and Section B was used to assess vaccine knowledge and attitudes. The total of seven questions, four for knowledge and three for attitude, shows consistency and was acceptable with a Cronbach’s alpha coefficient of 0.758. Each correct answer received one point, while incorrect answers received zero points. The maximum score for knowledge is 4 and 3 for attitude. Those who scored more than 80% on the knowledge and attitude questionnaire were considered to have adequate knowledge and attitude toward the COVID vaccine.
Study procedure and data collection
The study team was a part of the COVID warriors belonging to AH & RC, Adichunchanagiri University, and were fully vaccinated with available COVID vaccines. Following all the preventive measures, the study team spread into the rural part of the Mandya district, explained the study in detail, and requested to take participants. Data was collected from the general rural population in a data collection form after screening for inclusion criteria and signing a consent form. After the collection of data, participants were explained in detail about the vaccines, their efficacy, side effects, benefits of vaccination, and the requirement for continuation of the preventive measure to prevent the SARS-CoV-2 infection after vaccination.
Statistical analysis
The Statistical Package for the Social Sciences (SPSS) version 26 was used to analyse the data. Gender, habits, occupation, socioeconomic status, source of vaccine information, and vaccination status were represented in frequency and percentage. Age, knowledge, and attitude were represented in the mean, standard deviation (S.D), and interquartile range (IQR). The Chi-Square test was used to determine the relationship between variables.
Results
Demographic details of the participants
The study included 596 participants, with females dominating males by 54.9 % (327). The average age of the participants was 31.24 ± 15.87, with an IQR of 10.75 (34.75, 24). Among them, 20% (119) were inoculated with the available COVID-19 vaccine in their area. News, radio, television, and social media were the primary sources of COVID vaccine information, accounting for 60.3 % (359). Since the study was conducted in rural Mandya, 45.13 % (269) of the participants earn less than one lakh rupees per year, indicating a low socioeconomic status (Table No. 1 & 2).
Knowledge about COVID-19 vaccines
In the assessment of knowledge about COVID-19 vaccines, the mean score was 3.72 ± 0.72 (Table No.2). Of 596, 81.71% (487) had adequate knowledge about the COVID-19 vaccine. 84.7% (277) of the total female participants reported having adequate knowledge and 78.06% (210) of the total male participants reported having adequate knowledge about the COVID-19 vaccine. There was no statistically significant difference in adequate knowledge among males and females (p-value, 0.37). We observed that 60.5% (72) of the vaccinated participants had adequate knowledge and 39.5% (47) had a lack of adequate knowledge. Similarly, 87% (415) of the not-vaccinated participants reported having adequate knowledge and 13% (62) of the total not-vaccinated reported a lack of adequate knowledge. There was a statistically significant difference in adequate knowledge among the vaccinated and not-vaccinated (p-value < 0.001) (Table No. 3 & 4, Fig. No. 1).
Attitude towards COVID-19 vaccines
In the assessment of attitudes towards COVID-19 vaccines, the mean score was 2.72 ± 0.66 (Table No.2). Out of 596, 81.5% (486) had a positive attitude towards the COVID-19 vaccine. 85.3% (279) of the total female participants reported having a positive attitude and 77% (207) of the total male participants reported having a positive attitude towards the COVID-19 vaccine. There was no statistically significant difference in positive attitudes among males and females (p-value < 0.01). We observed that 51.26% (61) of the vaccinated participants had a positive attitude and 48.74% (58) had a negative attitude. Similarly, 89.1% (425) of the not-vaccinated participants reported having a positive attitude and 10.9% (52) of the total not-vaccinated reported having a negative attitude. There was a statistically significant difference in positive attitude among the vaccinated and not-vaccinated (p-value < 0.001) (Table No. 3 & 4, Fig. No. 2).
Association between knowledge and attitude
Among the participants with a positive attitude towards the COVID-19 vaccine, 86.86% (423) had adequate knowledge, and the remaining 13.14% (64) had a lack of adequate knowledge. Of those who had a negative attitude toward a vaccine, 57.79% (63) had adequate knowledge, and the remaining 42.2% (46) lacked adequate knowledge. There was a statistically significant difference in adequate knowledge among positive and negative attitudes (p-value < 0.001) (Table No. 3 & 4, Fig. No. 3).
Discussion
The study assessed the general rural Indian population's knowledge and attitude toward the COVID-19 vaccine. We observed that 81.71% (487) had adequate knowledge and 81.5% (486) had a positive attitude toward COVID-19 vaccines. The studies conducted by Popa GL et al. in Romania and Shekhar R et al. in Greece show greater levels of knowledge than our study [20,21]. While Obarisiagbon OE et al. in Nigeria and Asmara Adella G et al. in Ethiopia show lower levels of knowledge than our study [22,23]. A greater positive attitude towards the COVID-19 vaccine was found in our study than in Obarisiagbon OE et al., in Nigeria; Alle YF et al., in Ethiopia; and Khan ZA et al., in Pakistan [22,24,25]. A similar positive attitude was reported in the study conducted by Jankowska-Polaska B et al. in Poland [26].
We observed no statistically significant difference between the knowledge of males and females (p-value, 0.37). However, females (84.7%, 277) were found to have slightly more knowledge about the COVID-19 vaccine than males (78.06%, 210). The majority of study participants (93.5%) were aware that the full dose of vaccination required two doses of available Covid-19 vaccine, which was higher than Asmare Adella G et al. [23]. Among genders, females (85.3%, 279) tend to have a higher positive attitude than males (77%, 207) (p-value < 0.01). The trust in the safety of the COVID-19 vaccine (90.9%) was the same as reported by Bălan A et al. and higher than Bagic D et al. [27,28]. The majority of study participants (95.4%), which was higher than the percentage reported by Shekhar R et al., Moskova M et al., and Islam MS et al. [21,29,30], wanted to recommend vaccination to their friends and family.
The study shows that there was a statistically significant difference in the level of knowledge between the non-vaccinated and vaccinated (p-value < 0.001). Non-vaccinated participants (87%, 415) appeared to have a higher level of knowledge than vaccinated participants (60.5%, 72) (Fig no.1 & 2). It could be influenced by the government vaccination strategy, where vaccination campaign phase 1 was to protect health care facilities by vaccinating front-line workers, then reduce motility by vaccinating vulnerable individuals (vaccination campaign phase 2), and finally control the disease by vaccinating adults and children (vaccination campaign phase 3) [31]. There were a high number of geriatrics vaccinated and a shortage of vaccine during the study duration, which might have affected the level of knowledge among the vaccinated. The literacy level of Mandya's rural population may have an impact on vaccine knowledge, as the majority relied on news, social media, and radio for information. Moskova M et al also reported radio and television as major sources of information [29].
In the study, there is a statistically significant difference in knowledge about the COVID-19 vaccine between participants with positive attitudes and those with negative attitudes (p-value < 0.001). Positive attitude participants (86.86 %, 423) have a higher level of knowledge about the COVID-19 vaccine than negative attitude participants (57.79 %, 63) (Fig no. 3). This emphasized the significance of maintaining a positive attitude in an attempt to acquire adequate knowledge.
Limitations
The study was carried out during a government-enforced lockdown, which limited the number of participants. Vaccination campaigns phases 1 and 2 ended during the study period, and vaccination campaign phase 3 began, with the maximum number of geriatrics vaccinated and adults waiting in line. These were the limitations of the study.
Conclusion
The study concluded that 81.71% (487) of the total participants had adequate knowledge and 81.5% (486) had a positive attitude toward COVID-19 vaccines. There is no gender difference in knowledge of the COVID-19 vaccine. When compared to the male, the female has a more positive attitude toward the COVID-19 vaccine. Further study with a diverse study population is necessary to corroborate the findings of the study.
Acknowledgement
Firstly, the authors would like to express the most profound gratitude to all of the respondents who participated in this study. Also we would like to thank Adichunchanagiri Hospital and Research Centre for the approval of ethical clearance.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Funding
This study did not receive any particular funding.
Competing interests
The authors declare that they have no potential conflict of interest in the publication of this research output.
==== Refs
References
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3. Islam MS, Siddique AB, Akter R, Tasnim R, Sujan MS, Ward PR, Sikder MT. Knowledge, attitudes and perceptions towards COVID-19 vaccinations: a cross-sectional community survey in Bangladesh. medRxiv. 2021 Jan 1.
4. Gautret P, Lagier JC, Parola P, Meddeb L, Mailhe M, Doudier B, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International journal of antimicrobial agents. 2020 Jul 1;56(1):105949. pmid:32205204
5. Mahmud R, Rahman MM, Alam I, Ahmed KGU, Kabir AKMH, Sayeed SKJB, et al. Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial. J Int Med Res. 2021;49(5). pmid:33983065
6. Al-kuraishy HM, Al-Gareeb AI, Qusty N, Cruz-Martins N, El-Saber Batiha G. Sequential doxycycline and colchicine combination therapy in Covid-19: The salutary effects. Pulm Pharmacol Ther [Internet]. 2021 Apr;67(January):102008. pmid:33727066
7. Arshad S, Kilgore P, Chaudhry ZS, Jacobsen G, Wang DD, Huitsing K, et al. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. International journal of infectious diseases. 2020 Aug 1; 97:396–403. pmid:32623082
8. Shrestha Y. Venkataraman R. Moktan J.B. Mallikarjuna S. Narayan S.S. Madappa M.H. Satya P.A. Impact of Medication Complexity Assessment on Admission to Pharmacotherapy Evaluation in COVID Patients J Young Pharm. 14 3 2022 322 326
9. Shrestha Y, Shivalingegowda RK, Avinash MJ, Kenchegowda SBH, Moktan JB, et al. (2022) The rise in antimicrobial resistance: An obscure issue in COVID-19 treatment. PLOS Global Public Health 2(7): e0000641. doi:10.1371/journal.pgph.0000641
10. Piccoli L. Park Y.J. Tortorici M.A. Czudnochowski N. Walls A.C. Beltramello M. Mapping neutralizing and immunodominant sites on the SARS-CoV-2 spike receptor-binding domain by structure-guided high-resolution serology Cell. 183 4 2020 1024 1042.e21 32991844
11. Shrestha Y. Venkataraman R. The prevalence of inverse health consequences of COVID-19 vaccines: a post-vaccination study Vacunas. 2022 10.1016/j.vacun.2022.03.002 Mar 24. Epub ahead of print. PMID: 35345826; PMCID: PMC8942717
12. Hodgson SH, Mansatta K, Mallett G, Harris V, Emary KR, Pollard AJ. What defines an efficacious COVID-19 vaccine? A review of the challenges assessing the clinical efficacy of vaccines against SARS-CoV-2. The lancet infectious diseases. 2020 Oct 27.
13. Voysey M. Clemens S.A. Madhi S.A. Weckx L.Y. Folegatti P.M. Aley P.K. Angus B. Baillie V.L. Barnabas S.L. Bhorat Q.E. Bibi S. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK The Lancet. 397 10269 2021 99 111 Jan 9
14. Ramasamy M.N. Minassian A.M. Ewer K.J. Flaxman A.L. Folegatti P.M. Owens D.R. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial The Lancet. 396 10267 2020 1979 1993 Dec 19
15. Ella R, Vadrevu KM, Jogdand H, Prasad S, Reddy S, Sarangi V, Ganneru B, Sapkal G, Yadav P, Abraham P, Panda S. Safety and immunogenicity of an inactivated SARSCoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial. The Lancet Infectious Diseases. 2021 Jan 21.
16. Ella R, Reddy S, Jogdand H, Sarangi V, Ganneru B, Prasad S et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, phase 2 trial, and 3-month follow-up of a double-blind, randomised phase 1 trial. The Lancet Infectious Diseases. 2021 Mar 8.
17. Logunov D.Y. Dolzhikova I.V. Zubkova O.V. Tukhvatullin A.I. Shcheblyakov D.V. Dzharullaeva A.S. Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia The Lancet. 396 10255 2020 887 897 Sep 26
18. Logunov D.Y. Dolzhikova I.V. Shcheblyakov D.V. Tukhvatulin A.I. Zubkova O.V. Dzharullaeva A.S. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia The Lancet. 397 10275 2021 671 681 Feb 20
19. Kumar V.M. Pandi-Perumal S.R. Trakht I. Thyagarajan S.P. Strategy for COVID19 vaccination in India: the country with the second highest population and number of cases NPJ Vaccines. 6 1 2021 1 7 33398010
20. Popa G.L. Muntean A.A. Muntean M.M. Popa M.I. Knowledge and attitudes on vaccination in southern romanians: a cross-sectional questionnaire Vaccines. 8 4 2020 1 7 10.3390/vaccines8040774
21. Shekhar R. Sheikh A.B. Upadhyay S. Singh M. Kottewar S. COVID19 vaccine acceptance among health care workers in the United States Vaccines. 9 2021 1 15
22. Obarisiagbon O.E. Mokogwu N. Assessment of Knowledge, Attitude and Factors Influencing Uptake of COVID-19 Vaccine among Traders at Edaiken Market, Uselu, Benin City, Edo State Nigeria. West Afr J Med. 39 4 2022 327 335 35488853
23. Asmare Adella G. Knowledge and attitude toward the second round of COVID-19 vaccines among teachers working at southern public universities in Ethiopia Hum Vaccin Immunother. 18 1 2022 2018895 10.1080/21645515.2021.2018895 Dec 31 35172683
24. Alle Y.F. Oumer K.E. Attitude and associated factors of COVID-19 vaccine acceptance among health professionals in Debre Tabor Comprehensive Specialized Hospital, North Central Ethiopia; 2021: cross-sectional study Virusdisease. 32 2 2021 272 278 10.1007/s13337-021-00708-0 Jun 34222565
25. Khan Z.A. Allana R. Afzal I. Ali A.S. Mariam O. Aslam R. Shah I.A. Allana A. Haider M.M. Jandani R. Khan Z. Siddiqui A.M. Shah J.A. Butt U. Assessment of attitude and hesitancy toward vaccine against COVID-19 in a Pakistani population: A mix methods survey Vacunas. 23 2022 S26 S32 10.1016/j.vacun.2021.08.002 May 34512220
26. Jankowska-Polańska B. Sarzyńska K. Czwojdziński E. Świątoniowska-Lonc N. Dudek K. Piwowar A. Attitude of Health Care Workers and Medical Students towards Vaccination against COVID-19 Vaccines (Basel). 10 4 2022 535 35455284
27. Bălan A. Bejan I. Bonciu S. Eni C.E. Ruță S. Romanian Medical Students' Attitude towards and Perceived Knowledge on COVID-19 Vaccination Vaccines (Basel). 9 8 2021 854 Aug 4 34451979
28. Bagic D. Suljok A. Ancic B. Determinants and reasons for coronavirus disease 2019 vaccine hesitancy in Croatia Croat. Med. J. 63 2022 89 97 10.3325/cmj.2022.63.89 35230010
29. Moskova M. Zasheva A. Kunchev M. Popivanov I. Dimov D. Vaseva V. Kundurzhiev T. Tsachev I. Baymakova M. Students' Attitudes toward COVID-19 Vaccination: An Inter-University Study from Bulgaria Int J Environ Res Public Health. 19 16 2022 9779 36011415
30. Islam M.S. Siddique A.B. Akter R. Tasnim R. Sujan M.S.H. Ward P.R. Sikder M.T. Knowledge, attitudes and perceptions towards COVID-19 vaccinations: a cross-sectional community survey in Bangladesh BMC Public Health. 21 1 2021 1851 Oct 13 34645399
31. Government of India, Ministry of Health and Family Welfare. Liberalised Pricing and Accelerated National Covid-19 Vaccination Strategy, 21st April 2021. Available at: https://www.mohfw.gov.in/pdf/LiberalisedPricingandAcceleratedNationalCovid19VaccinationStrategy2042021.pdf
| 0 | PMC9744704 | NO-CC CODE | 2022-12-15 00:01:54 | no | Vacunas. 2022 Dec 13; doi: 10.1016/j.vacun.2022.11.002 | utf-8 | Vacunas | 2,022 | 10.1016/j.vacun.2022.11.002 | oa_other |
==== Front
Eur Neuropsychopharmacol
Eur Neuropsychopharmacol
European Neuropsychopharmacology
0924-977X
1873-7862
Elsevier B.V. and ECNP.
S0924-977X(22)00912-9
10.1016/j.euroneuro.2022.12.001
Correspondence
Effectiveness of Fluvoxamine at preventing COVID-19 infection from turning severe
Boretti Alberto ⁎
Independent Scientist, Johnsonville Road, Johnsonville, Wellington 6037, New Zealand
⁎ Corresponding author.
13 12 2022
13 12 2022
© 2022 Elsevier B.V. and ECNP. All rights reserved.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Keywords
Fluvoxamine
COVID-19
Cytokines
Respiratory disease
Editor: Dr Jose Sanchez
==== Body
pmcMany antivirals have been shown effective at preventing COVID-19 infection from turning severe, especially if used in the early stages of infection, often in combination with antibiotics and supplements (c19early.org/). Fluvoxamine, which is not an antiviral, nor an antibiotic but an antidepressant of the selective serotonin reuptake inhibitor class, was first shown effective in preventing serious consequences of COVID-19 infection in hospitalized patients during a placebo-controlled, randomized, trial reported in November 2020. According to (Reis et al., 2022), Fluvoxamine reduced both the risk of death and the need for intensive care in acutely symptomatic COVID-19 patients. An animal model (Rosen et al., 2019) first noticed as Fluvoxamine reduced inflammation in mice with sepsis. The rationale behind the use of Fluvoxamine for COVID-19 infection was then the opportunity to benefit from the anti-inflammatory action of this drug when inflammation in COVID-19-infected patients was excessive.
Fluvoxamine mechanism of action on COVID-19 infection is everything but intuitive. While its use is aimed at conditions such as depression and obsessive-compulsive disorder, it also reduces immune responses and alleviates tissue damage. Especially these two effects are acknowledged for the achievement in the trial (Reis et al., 2022). Other trials have been performed with Fluvoxamine, unfortunately not that many, small in size, and everything but free from criticism, same as (Reis et al., 2022). At present, the database of all Fluvoxamine COVID-19 studies (c19early.org/ 2022) includes 13 clinical trials which are used to summarize the benefits as shown in Figure 1 .Fig. 1 A. Random effects meta-analysis. B. Scatter plot showing the most serious outcome in all studies, along with the result of random effects meta-analysis. C. History of all reported effects (chronological within treatment stages). Images from (c19early.org/ 2022). Credit c19early.org. Supporting works are Reis doi.org/10.1016/S2214-109X(21)00448-4, Lenze doi.org/10.1001/jama.2020.22760, Seftel doi.org/10.1093/ofid/ofab050, Lenze dcricollab.dcri.duke.edu/sites/NIHKR/KR/GR-Slides-08-20-21.pdf, Seo doi.org/10.3947/ic.2021.0142, Bramante doi.org/10.1056/NEJMoa2201662, Pineda doi.org/10.1101/2022.09.27.22280428, Calusic doi.org/10.1111/bcp.15126, McCarthy doi.org/10.1101/2022.10.17.22281178, Oskotsky doi.org/10.1001/jamanetworkopen.2021.33090, Fritz doi.org/10.1038/s41398-022-02109-3, Diaz doi.org/10.4088/PCC.22br03337 and Trkulja doi.org/10.21203/rs.3.rs-2239187/v1.
Fig 1
All the proposed mechanisms of action for fluvoxamine against COVID-19 infection are also described in (c19early.org/ 2022). It is a functional inhibitor of acid sphingomyelinase (FIASMA). Inhibition of the ASM/ceramide system activated by SARS-CoV02 to facilitate the entry of the virus may prevent viral entry. It may influence σ-1 (S1R) receptor activation reducing excessive cytokine production. It may inhibit platelet activation contributing to COVID-19 severity. It may have lysosomotropic properties interfering with endolysosomal viral trafficking used by SARS-CoV-2 to leave infected cells. It may increase intracellular heme oxygenase (HO-1) thus reducing the COVID-19 risk which is correlated to low HO-1. It is a cytoprotective and anti-inflammatory agent. Fluvoxamine may decrease mast cell degranulation reducing the cytokine storm. It may inhibit CYP1A2 and CYP2C19 thus increasing the level of melatonin which has beneficial effects on COVID-19 infection.
All the COVID-19 treatments have been working better in the early stages of infection, as SARS-CoV-2 elimination is a race against viral build-up. While the best results have been achieved by using drugs with antiviral action, Fluvoxamine, which has been mostly working as an anti-inflammatory agent, still had its merit. The few trials conducted so far have been positive. By using the relative risk ratio RR (risk of an event in the exposed group versus the risk of the event in the other nonexposed group (Ranganathan et al., 2015)), in the list of substances that had a positive impact on COVID-19 infection patients of (c19early.org/ 2022), Fluvoxamine is ranked 31st, based on an improvement of 31% (RR=0.69, CI=0.57-0.83) compared to control, from 13 studies and 34,828 patients. Given the many different mechanisms of action, fluvoxamine may still have use in the few cases of patients infected by the current variants of SARS-CoV-2 and facing more serious effects mostly because of excessive cytokine production.
The above conclusions are consistent with the very recent findings of the meta-analysis (Fico et al., 2022) which investigated the role of several psychotropic drugs, including antidepressants (AD), mood stabilizers, and antipsychotics (AP), which have all been suggested to have positive effects in the treatment of COVID-19. Based on the review of the relevant articles published up to December 13, 2021, 29 studies total, of whom 15 were clinical, 9 of them quantitative, 9 preclinical, and 5 computational, the relative risk ratio RR as well as the odds ratio OR (odds of an event in the exposed group versus the odds of the event in the nonexposed group (Ranganathan et al., 2015)) was used to assess the efficacy. AD did not increase the risk of severe infection, RR= 1.71, CI=0.65-4.51, or mortality, as RR=0.94, CI=0.81-1.09. Specifically, Fluvoxamine was associated with a reduced risk of mortality, OR=0.15, CI=0.02-0.95. AP increased the risk of severe infection, RR=3.66, CI=2.76-4.85, and mortality OR=1.53, CI=1.15-2.03. Ref. (Fico et al., 2022) concluded as Fluvoxamine could have been beneficial for COVID-19 infection due to its anti-inflammatory and antiviral potential, while evidence on other AD is controversial, which is consistent with the conclusion of (c19early.org/ 2022) and this work.
Funding
No funding.
Ethics approval statement
Not applicable.
Contributorship Statement
Single author.
Declaration of Competing Interest
No competing interests.
Acknowledgements
Nothing to acknowledge.
==== Refs
References
c19early.org/.
Fico G. Isayeva U. De Prisco M. Oliva V. Solè B. Montejo L. Grande I. Arbelo N. Gomez-Ramiro M. Pintor L. Carpiniello B. Psychotropic drug repurposing for COVID-19: a Systematic Review and Meta-Analysis European Neuropsychopharmacology 2022 10.1016/j.euroneuro.2022.10.004 doi.org/
Ranganathan P. Aggarwal R. Pramesh C.S. Common pitfalls in statistical analysis: Odds versus risk Perspectives in clinical research 6 4 2015 222 10.4103/2229-3485.167092 doi.org/ 26623395
Reis G. dos Santos Moreira-Silva E.A. Silva D.C.M. Thabane L. Milagres A.C. Ferreira T.S. Dos Santos C.V.Q. de Souza Campos V.H. Nogueira A.M.R. de Almeida A.P.F.G. Callegari E.D. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial The Lancet Global Health 10 1 2022 e42 e51 10.1016/S2214-109X(21)00448-4 doi.org/ 34717820
Rosen D.A. Seki S.M. Fernández-Castañeda A. Beiter R.M. Eccles J.D. Woodfolk J.A. Gaultier A. Modulation of the sigma-1 receptor–IRE1 pathway is beneficial in preclinical models of inflammation and sepsis Science translational medicine 11 478 2019 eaau5266 10.1126/scitranslmed.aau5266 doi.org/ 30728287
| 0 | PMC9744705 | NO-CC CODE | 2022-12-15 00:01:54 | no | Eur Neuropsychopharmacol. 2022 Dec 13; doi: 10.1016/j.euroneuro.2022.12.001 | utf-8 | Eur Neuropsychopharmacol | 2,022 | 10.1016/j.euroneuro.2022.12.001 | oa_other |
==== Front
J Crit Care
J Crit Care
Journal of Critical Care
0883-9441
1557-8615
Elsevier Inc.
S0883-9441(22)00206-4
10.1016/j.jcrc.2022.154177
154177
Article
Letter to the editor: “Clinical characteristics, physiological features, and outcomes associated with hypercapnia in patients with acute hypoxemic respiratory failure due to COVID-19---insights from the PRoVENT-COVID study”
Bhattacharya Dipasri a
Bhakta Pradipta b*
O'Brien Brian c
Karim Habib Md Reazaul d
Esquinas Antonio M. e
a Department of Anaesthesiology, Pain Medicine, and Critical Care, R. G. Kar Medical College, Kolkata, West Bengal, India
b Department of Anaesthesiology and Intensive Care, Hull University Teaching Hospital NHS Trust, Hull, East Yorkshire, United Kingdom
c Department of Anaesthesiology and Intensive Care, Cork University Hospital, Cork, Ireland
d Department of Anaesthesiology and Critical Care, All India Institute of Medical Sciences, Raipur, India
e Critical Care Specialist and Staff Physician, Intensive Care Unit, Hospital Morales, Meseguer, Murcia, Spain
* Corresponding author.
26 10 2022
2 2023
26 10 2022
73 154177154177
© 2022 Elsevier Inc. All rights reserved.
2022
Elsevier Inc.
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Keywords
COVID-19
ARDS, lung protective ventilation
Hypercapnia
Outcomes
==== Body
pmcDear Editor,
Authors of the PRoVENT-COVID study reported that hypercapnic patients developed more acute respiratory distress syndrome (ARDS), incurred more venous thromboembolic events, with higher ventilation ratios and longer hospital stays but without having a significant impact on the morbidity or mortality [1]. We would like to offer the following points for further consideration.
Firstly, lung protective ventilation using lower tidal volume and higher respiratory rate is the cornerstone of the management of patients with severe ARDS, including that attributable to Covid-19, with the potential consequence of hypercapnia. The latter has significant pathophysiological effects and may itself increase hospital mortality [2]. On the contrary, there is also ample evidence to suggest that hypercapnia may have a therapeutic potential in ARDS [3]. Excess carbon dioxide (CO2), generated by the catabolic processes of ARDS, can lead to better survival [4]. Also, as a paradox, obesity has been proved to be protective in ARDS [5]. Notably, most obese patients in this study developed hypercapnia. We would like to know whether authors have thought both these sides of hypercapnia during interpretation of their data or not.
Secondly, ventilatory ratio, defined as [minute ventilation (ml/min) × partial pressure of arterial CO2 tension (mm Hg)]/(predicted body weight × 100 × 37.5), is a simple bedside index of assessing the efficiency of mechanical ventilation [6]. It correlates well with the fraction of dead space ventilation (VD) in ARDS. A higher value, being indicative of increased VD and inadequate minute ventilation, leads to higher mortality [6]. In this study, although the ventilatory ratio was calculated, but its correlation with inevitable hypercapnia was not highlighted.
Finally, hypoxemia, quantified by the ratio of partial pressure arterial oxygen tension and fraction of inspired oxygen concentration (PaO2/FiO2), does not necessarily assess the alveolar ventilation and physiological dead space which reflect the overall efficacy of the lungs to eliminate the CO2 load. Although lower PaO2/FiO2 may indicate severity of ARDS as per the Berlin criteria, but it may not gauge the adequacy of alveolar ventilation which is the most important determinant of overall outcome [6].
We congratulate the authors for their excellent thought-provoking study. However, to evaluate the overall outcomes of this study, we would like authors' response on these points.
Dipasri Bhattacharya,
Pradipta Bhakta,
Brian O'Brien,
Habib Md Reazaul Karim,
Antonio M. Esquinas.
Authors and their individual contribution
1. Dr. Dipasri Bhattacharya: Was involved in analysis of the article, writing, and editing the letter.
2. Dr. Pradipta Bhakta: Was involved in analysis of the article, writing, and editing the letter.
3. Dr. Brian O'Brien: Was involved in analysis of the article, writing, and editing the letter.
4. Dr. Habib Md Reazaul Karim: Was involved in analysis of the article, writing, and editing the letter.
5. Dr. Antonio M. Esquinas: Was involved in analysis of the article, writing, and editing the letter.
Financial support
No external funding supported the preparation of this manuscript. The authors have no financial and/or personal relationships with other people or organizations that might inappropriately influence our work.
Declaration of Competing Interest
The authors report no conflicts of interest.
==== Refs
References
1 Tsonas A.M. Botta M. Horn J. Morales-Quinteros L. Artigas A. Schultz M.J. PRoVENT-COVID Collaborative Group Clinical characteristics, physiological features, and outcomes associated with hypercapnia in patients with acute hypoxemic respiratory failure due to COVID-19---insights from the PRoVENT-COVID study J Crit Care 69 2022 Jun 154022 10.1016/j.jcrc.2022.154022 [Epub 2022 Mar 24. PMID: 35339900; PMCID: PMC8947815]
2 Nin N. Muriel A. Peñuelas O. Brochard L. Lorente J.A. Ferguson N.D. Severe hypercapnia and outcome of mechanically ventilated patients with moderate or severe acute respiratory distress syndrome Intensive Care Med 43 2 2017 200 208 10.1007/s00134-016-4611-1 28108768
3 Hickling K.G. Lung-protective ventilation in acute respiratory distress syndrome: protection by reduced lung stress or by therapeutic hypercapnia? Am J Respir Crit Care Med 162 6 2000 2021 2022 10.1164/ajrccm.162.6.ed12-00d 11112102
4 Fuller B.M. Mohr N.M. Drewry A.M. Ferguson I.T. Trzeciak S. Kollef M.H. Partial pressure of arterial carbon dioxide and survival to hospital discharge among patients requiring acute mechanical ventilation: a cohort study J Crit Care 41 2017 29 35 10.1016/j.jcrc.2017.04.033 28472700
5 Ni Y.N. Luo J. Yu H. Wang Y.W. Hu Y.H. Liu D. Can body mass index predict clinical outcomes for patients with acute lung injury/acute respiratory distress syndrome? A meta-analysis Crit Care 21 1 2017 36 10.1186/s13054-017-1615-3 28222804
6 Sinha P. Calfee C.S. Beitler J.R. Soni N. Ho K. Matthay M.A. Physiologic analysis and clinical performance of the Ventilatory ratio in acute respiratory distress syndrome Am J Respir Crit Care Med 199 3 2019 333 341 10.1164/rccm.20184-0692OC 30211618
| 36307309 | PMC9744706 | NO-CC CODE | 2022-12-15 00:02:10 | no | J Crit Care. 2023 Feb 26; 73:154177 | utf-8 | J Crit Care | 2,022 | 10.1016/j.jcrc.2022.154177 | oa_other |
==== Front
J Pediatr (Rio J)
J Pediatr (Rio J)
Jornal de Pediatria
0021-7557
1678-4782
Published by Elsevier Editora Ltda. on behalf of Sociedade Brasileira de Pediatria.
S0021-7557(22)00128-0
10.1016/j.jped.2022.11.004
Review Article
Vaccination coverage in children in the period before and during the COVID-19 pandemic in Brazil: a time series analysis and literature review
Domingues Carla Magda Allan S. ab⁎
Teixeira Antônia Maria da Silva c
Moraes José Cássio de de
a Universidade de Brasília (UnB), Medicina Tropical, Brasília, DF, Brazil
b Organização Panamericana da Saúde, Brazil
c Universidade Federal da Bahia (UFBA), Saúde Coletiva, Salvador, BA, Brazil
d Universidade de São Paulo (USP), Saúde Pública, São Paulo, SP, Brazil
e Faculdade de Ciências Médicas, Santa Casa de São Paulo, São Paulo, SP, Brazil
⁎ Corresponding author.
13 12 2022
13 12 2022
14 9 2022
29 11 2022
© 2022 Published by Elsevier Editora Ltda. on behalf of Sociedade Brasileira de Pediatria.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Objective
To evaluate the behavior of VCR and VCH, per municipality and per vaccines offered at the NVC, to identify priority areas for intervention.
Methods
Descriptive study of a time series, using secondary data and accompanied by a narrative review of the literature evaluating VCR and VCH. Vaccines offered to children under one year and to those aged one year in the pre-pandemic period of COVID-19 (2015 to 2019) were selected and compared to those offered during the pandemic period (2020 and 2021).
Results and discussions
The decrease in VCR and VCH is a process that precedes the COVID-19 pandemic but was intensified during this period. In 2021, the VCR was around 70% for most vaccines. This phenomenon encompasses the entire country; however, it is more intense in the states/municipalities located in the north and northeast regions, suggesting greater difficulty in accessing health services.
Conclusions
Low and heterogeneous VCR requires the adoption of practices that were previously implemented, establishing partnerships with governmental and non-governmental institutions, with adequate communication, active search for non-compliance and non-adherence to the regular vaccination program, adopting intra- and extramural vaccination strategies, to reverse the current situation and reduce the risk of recurrence of diseases that have been already controlled and eliminated.
Keywords
Vaccination
Vaccination coverage
Indicators
Vaccine refusal
==== Body
pmcIntroduction
The National Immunization Program (PNI, Programa Nacional de Imunizações), coordinated by the Ministry of Health, jointly with the State (SES, Secretaria de Estado da Saúde) and Municipal (SMS, Secretaria Municipal da Saúde) Health Secretariats, has established itself as an efficient public policy by carrying out interventions at the national level, with an impact on the morbidity and mortality profile of the Brazilian population, in the last 49 years of its trajectory, adapting to the changes that occurred over time in the political, epidemiological and social fields.1
The National Vaccination Calendar (CNV, Calendário Nacional de Vacinação) offers children universal coverage of a total of 15 vaccines, of which nine are indicated in the first year of life and six in the second year of life, which constitutes the basic vaccination schedule.2
If the recommendations regarding the age for the child's vaccination are followed, as well as the simultaneity in the administration of vaccine doses in each visit to the vaccination centers, compliance with the basic vaccination schedule is attained at 15 months of life and required at least nine visits to the health service units, finishing the entire vaccination schedule at the tenth visit indicated at four years of age.2
In the 1970s, the vaccine-preventable diseases were endemic, with a high burden of morbidity and mortality, with approximately 100,000 cases of measles and 80,000 cases of pertussis, 10,000 cases of poliomyelitis and diphtheria being recorded. Based on the structuring and strengthening of vaccination actions throughout the country, guaranteeing universal access to all vaccines offered at the CNV, it was possible to reduce regional and social inequalities, making vaccination available to all Brazilians, in all locations, whether they were easy or difficult to access.3
The last case of poliomyelitis was recorded in 1989 and, in 1994, the country received the certification of disease eradication in the American continent. Although poliomyelitis is a distant memory in most parts of the world, the disease still exists in Pakistan and Afghanistan, associated with poliovirus type 1, and mainly affects children under five years old. The poliomyelitis virus causes irreversible paralysis (usually in the lower limbs) in every 200 infections. Among those with the paralytic form, 5% to 10% die.4 In 2015, the World Health Organization (WHO) declared the wild poliovirus type 2 to be eradicated, and in 2019, the poliovirus 3.5
Up to June 2022, there have been confirmed cases of polio by the wild poliovirus type 1 in Pakistan, Afghanistan, Malawi and Mozambique. Due to the low Vaccine Coverage Rates (VCR) in several countries, especially the ones that continue to use the oral poliomyelitis vaccine, cases of poliomyelitis derived from the vaccine have been recorded, jeopardizing the goal of global eradication of the disease.5
Measles is a highly contagious viral disease and remains a major cause of death in children worldwide, despite the availability of a safe and effective vaccine. Vaccination actions have dramatically reduced deaths caused by measles, with a 73% decrease between 2000 and 2018 worldwide.6
Pneumococcal disease, in its various clinical forms, represents an important cause of morbidity and mortality. The WHO estimates that one million deaths occur per year caused by invasive pneumococcal disease, most of them in children under five years of age.7 , 8 Among children who survive an episode of pneumococcal meningitis, a significant proportion is affected by long-term impairments, such as hearing loss, language disorders, intellectual disability, motor abnormalities, and visual disturbances.8
Since the introduction of the 10-valent pneumococcal conjugate vaccine (PCV10) in the CNV in the Americas, a significant reduction in all disease outcomes has been observed. In a systematic review that evaluated the effectiveness and impact of vaccination in the countries of the region, reductions of 8.8 to 37.8% were observed for hospitalizations due to radiologically confirmed pneumonia; of 7.4 to 20.6% due to clinical pneumonia; 13.3 to 87.7% for hospitalizations due to meningitis and of 56 to 83.3% for hospitalizations due to invasive pneumococcal disease (IPD), varying by age, the definition of clinical outcome, type of vaccine used (PCV10 vs. PCV13) and study design.9
Regarding the diseases protected by vaccines containing DTP components – diphtheria, tetanus and pertussis – there was a significant decrease in annual incidences. As the VCR increased, diphtheria cases decreased from 0.45/100,000 inhabitants in 1990 to less than 5 cases per year from 2016 onwards, and only one case was confirmed in 2021 (Table 1 ).Table 1 Number of cases and incidence coefficientsa of vaccine-preventable diseases per type of disease and year, Brazil, 1982 and 2021.
Table 1Year Poliomyelitis Measles Rubella Diphtheria Pertussis Neonatal tetanus Accidental tetanus Haemophilus meningitis Pneumococcal meningitis Meningococcal Disease
Number of cases Incidence coefficients Number of cases Incidence coefficients Number of cases Incidence coefficients Number of cases Incidence coefficients Number of cases Incidence coefficients Number of cases Incidence coefficients Number of cases Incidence coefficients Number of cases Incidence coefficients Number of cases Incidence coefficients Number of cases Incidence coefficients
1982 69 0.1 39,370 31.0 ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗
1983 45 0.0 58,257 46.0 ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗
1984 84 0.1 80,879 63.0 ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗
1985 329 0.3 75,993 58.0 ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗
1986 612 0.5 129,942 97.0 ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗
1987 196 0.2 66,059 48.0 ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗
1988 106 0.1 26,179 19.0 ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗
1989 35 0.03 22,853 16.0 ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗ ˗
1990 0 0.00 61,471 42.7 ˗ ˗ 640 0.45 15,329 10.69 291 0.20 1,548 1.07 ˗ ˗ 1,584 1.1 4,976 3.45
1991 0 0.0 45,632 31.1 ˗ ˗ 495 0.34 7,252 4,94 267 0.18 1,460 0.99 ˗ ˗ 1,591 1.1 4,855 3.31
1992 0 0.0 7,697 5.2 ˗ ˗ 276 0.19 5,155 3,45 233 0.16 1,312 0.88 ˗ ˗ 1,560 1.0 4,928 3.31
1993 0 0.0 2,396 1.6 ˗ ˗ 252 0.17 5,388 3,56 215 0.14 1,282 0.85 ˗ ˗ 1,784 1.2 5,931 3.91
1994 0 0.0 1,262 0.8 ˗ ˗ 245 0.16 4,098 2,67 171 0.11 1,043 0.68 ˗ ˗ 1,616 1.1 6,368 4.14
1995 0 0.0 972 0.6 ˗ ˗ 171 0.11 3,798 2,44 131 0.08 979 0.63 ˗ ˗ 1,697 1.1 7,195 4.62
1996 0 0.0 3,326 2.1 ˗ ˗ 181 0.12 1,245 0,79 93 0.06 1,025 0.65 ˗ ˗ 1,615 1.0 7,321 4.66
1997 0 0.0 53,664 33.6 32,825 20.6 140 0.09 3,036 1,90 101 0.06 895 0.56 ˗ ˗ 1,542 1.0 6,325 3.96
1998 0 0.0 2,781 1.7 6,794 4.2 81 0.05 4,097 2,53 74 0.05 705 0.44 ˗ ˗ 1,353 0.8 6,061 3.75
1999 0 0.0 908 0.6 14,502 8.8 58 0.04 1,670 1,02 66 0.04 744 0.45 ˗ ˗ 1,408 0.9 5,235 3.19
2000 0 0.0 36 0.02 15,413 9.3 58 0.03 1,454 0.88 42 0.03 520 0.31 ˗ ˗ 1,083 0.6 4,238 2.50
2001 0 0.0 1 0.00 5,867 3.4 29 0.02 883 0.51 37 0.02 578 0.34 382 0.22 1,238 0.72 4,108 2.38
2002 0 0.0 1 0.00 1,480 0.8 52 0.03 749 0.43 35 0.02 608 0.35 221 0.13 1,240 0.71 3,727 2.13
2003 0 0.0 2 0.00 563 0.3 50 0.03 1,033 0.58 16 0.01 500 0.28 173 0.10 1,428 0.81 3,344 1.89
2004 0 0.0 0 0.00 401 0.2 18 0.01 1,339 0.74 18 0.01 473 0.26 157 0.09 1,366 0.76 3,654 2.04
2005 0 0.0 6 0.00 233 0.1 23 0.01 1,269 0.69 12 0.01 454 0.25 115 0.06 1,286 0.70 3,313 1.80
2006 0 0.0 57 0.03 1,612 0.9 11 0.01 790 0.42 9 0.005 442 0.24 143 0.08 1,355 0.73 3,050 1.63
2007 0 0.0 0 0.00 8,753 4.8 5 0.003 870 0.47 5 0.003 354 0.19 135 0.07 1,073 0.57 2,425 1.28
2008 0 0.0 0 0.00 2,173 1.1 8 0.004 1,427 0.75 6 0.003 356 0.19 124 0.06 1,053 0.56 2,616 1.38
2009 0 0.0 0 0.00 0 0.0 6 0.003 979 0.51 4 0.002 332 0.17 108 0.06 1,065 0.56 2,904 1.52
2010 0 0.0 68 0.04 0 0.0 33 0.017 605 0.32 7 0.004 326 0.17 145 0.08 1,167 0.61 3,003 1.57
2011 0 0.0 43 0.02 0 0.0 5 0.003 2,248 1.17 6 0.003 335 0.17 131 0.07 1,213 0.63 2,835 1.47
2012 0 0.0 2 0.00 0 0.0 0 0.000 5,448 2.81 2 0.001 319 0.16 148 0.08 1,085 0.56 2,529 1.30
2013 0 0.0 220 0.11 0 0.0 5 0.002 6,467 3.22 3 0.001 283 0.14 104 0.05 1,061 0.55 2,101 1.08
2014 0 0.0 876 0.43 0 0.0 6 0.003 8,614 4.25 1 0.000 271 0.13 116 0.06 947 0.49 1,612 0.83
2015 0 0.0 214 0.10 0 0.0 16 0.008 3,110 1.52 0 0.000 286 0.14 117 0.06 927 0.48 1,302 0.67
2016 0 0.0 0 0.00 0 0.0 4 0.002 1,330 0.65 1 0.000 243 0.12 105 0.05 923 0.45 1,117 0.54
2017 0 0.0 0 0.00 0 0.0 5 0.002 1,898 0.97 0 0.000 230 0.11 131 0.06 1,023 0.49 1,135 0.55
2018 0 0.0 10,326 5.06 0 0.0 1 0.000 2,164 1.10 0 0.000 198 0.10 135 0.07 920 0.45 1,032 0.51
2019 0 0.0 20,901 9.91 0 0.0 3 0.001 1,545 0.72 0 0.000 222 0.101 168 0.08 1,072 0.49 1,060 0.50
2020 0 0.0 8,448 4.0 0 0.0 2 0.001 243 0.10 1 0.000 177 0.083 32 0.01 348 0.16 384 0.17
2021 0 0.0 668 2.8 0 0.0 1 0.000 130 0.06 0 0.000 161 0.075 62 0.03 373 0.14 260 0.12
Source: data extracted from the Notifiable Diseases Information System (http://portalsinan.saude.gov.br/dados-epidemiologicos-sinan, accessed on August/12/2022).
a Neonatal tetanus incidence rate per 100,000 children under 1 year of age.
The incidence of pertussis has also shown an important reduction, decreasing from 10.6 cases/100,000 inhabitants in 1990 to 0.9 cases/100,000 inhabitants in 2000. As of 2011, there was an increase in incidence rates, reaching 4.2 cases /100,000 inhabitants in 2014, and a further decrease from that year onwards, coinciding with the implementation of the triple acellular vaccine (diphtheria, tetanus and acellular pertussis) for pregnant women. This strategy aimed at inducing the production of high antibody titers against pertussis in pregnant women, allowing the transplacental transfer of these antibodies to the fetus.10 In 2016, 1,334 cases were confirmed and in 2021 only 130 cases (Table 1).
The role that immunization plays in improving the quality of life of the population is unquestionable, as the high vaccination coverage achieved in the national context has had a strong impact on the morbidity and mortality profile of vaccine-preventable diseases in the country. These results are attributed to the success of the PNI, part of the Brazilian Unified Health System (SUS, Sistema Único de Saúde), which throughout its existence acquired the trust of the population by adhering to both routine and campaign actions, in addition to its acknowledged importance due to its dynamism, incorporating new products to the CNV, particularly as of the second half of the 2000s.
However, if in the past the country made progress in achieving good results in immunization to the point of having an impact on the occurrence of diseases with a high incidence in childhood, mainly, the most recent VCR data showed that in recent years it has progressively decreased, more markedly as of 2016. This situation was aggravated in 2020 and 2021, coinciding with the occurrence of the Covid-19 pandemic, which brought important changes to the routines of the population and health services, impacting vaccination, such as the recommendation of social isolation with the aim of attenuating the risks of the disease transmission, thus limiting visits to vaccination units.
For these achievements to be maintained, it is necessary that surveillance and immunization actions be carried out adequately, meeting the goals established by the Ministry of Health. Two indicators are monitored by the PNI to identify areas at risk of reintroduction of vaccine-preventable diseases if these goals are not met, namely: VCR and vaccine coverage homogeneity (VCH).
Aiming at evaluating the behavior of VCR and VCH, per municipalities and the vaccines offered to children under one year of age and those aged one year, an attempt was made to compare the periods before and during the Covid-19 pandemic, aiming to identify the priority areas for intervention.
Methods
The vaccination schedule for children under one year of age includes eight vaccines: BCG, Hepatitis B ≤ 30 days, meningococcal C conjugate vaccine (meningo C), 10-valent pneumococcal conjugate vaccine (PCV10), monovalent human rotavirus (RV1), poliomyelitis (IPV), pentavalent (penta - DTP/HB/Hib) and Yellow Fever (YF). The Influenza vaccine is also offered in the National Flu Vaccination Campaign, totaling nine offered vaccines.
A descriptive time series analysis was carried out, using secondary data and accompanied by a narrative review of the literature on the behavior of the vaccination performance indicators - VCR and VCH - per municipalities and by the vaccines indicated in the CNV for this target group, in the pre-pandemic period of Covid-19 (2015 to 2019), comparing data from the pandemic period (2020 and 2021).
To calculate the VCR, the vaccine schedule of those vaccinated in the public vaccination service that received the rotavirus, penta, poliomyelitis, meningo C and PCV10 vaccines, had the doses of vaccines that contain similar components offered by private vaccination services accounted for: rotavirus, pentavalent, hexavalent (DTP/HB/Hib/IPV), acellular pentavalent (DTP/Hib/IPV), ACWY meningococcal and 13-valent pneumococcal, provided that the private vaccination clinics are registered in the National Immunization Program Information System (SIPNI, Sistema de Informação do Programa Nacional de Imunizações) and are correctly transmitting vaccination data.
The VCR of the years in the period from 2015 to 2019 was evaluated and the increment (percentage of increase or decrease) and the difference in percentage points in the year 2019 compared to the year 2015 (pre-pandemic) were estimated. Then, the same calculation was applied for the years 2020, a pandemic year, in relation to the year 2019; and for the year 2021, the year in which the vaccination campaign against Covid-19 was implemented, in relation to the year 2020.
For the same period, the increment was estimated by dividing the later coverage by the earlier one, multiplying by 100, and subtracting from 100 (later VCR/earlier VCR *100-100). The difference in VCR in percentage points was measured by subtracting the previous VC from the subsequent one, year by year, in the same period.
The parameters established by the PNI for VC were used as the basis for the analysis: 90% for BCG and rotavirus vaccines and 95% for the other vaccines. The numerator for calculating the VCR comprises the total number of doses that complete the vaccination schedule (BCG - single dose; YF - initial dose; HepB - dose ≤30 days; meningo C and PCV10 and rotavirus second dose; IPV and penta-third dose). The denominator was the number of births that occurred in the respective year, obtained from the National System of Live Births (SINASC, Sistema Nacional de Nascidos Vivos), multiplying it by 100. The VC reports available on the DATASUS website were used.
The VCH was estimated per municipality, year by year in the period from 2015 to 2021, using the total number of Brazilian municipalities with adequate VCR (attained target) for each vaccine in the numerator and the total number of municipalities in the denominator, multiplying it by 100.
The VCH between vaccines was estimated using the total number of vaccines with achieved VCR in the numerator and the total number of vaccines (eight) that make up the vaccination schedule for children under one year of age in the denominator, multiplying by 100, using the strata in percentages (%) of zero, 12.5, 25, 50, 75 and 100% with adequate VCR, according to the possible percentage of vaccines with adequate coverage (zero to eight vaccines).
The analysis comprised the national, state and municipal contexts. The VCR of each vaccine within the municipalities was stratified and depicted as maps in the VC strata <80%;80<95% and ≥95%. The VC strata <80%, 80<90% and ≥90% were defined for the BCG and rotavirus vaccines. The VCH between vaccines was estimated by FU and municipalities and the proportional distribution of municipalities according to the percentage of vaccines with adequate VCR.
The data for the analysis were extracted from the SIPNI, on 07/11, 07/12 and 07/13 in 2021, with no change in values in the period, which were available on the website of the Department of Informatics of the Unified Health System (DATASUS), at http://sipni.datasus.gov.br (tabnetBD), of public domain. These are secondary data, tabulated and grouped per vaccine and by year, consolidated by national, state and municipal instances. They are depicted in the document as tables, graphs, using the Microsoft Office Excel application, version 8, or maps were built using the data tabulation tool developed by DATASUS, Tabwin415, of free access.
Data on the incidence of vaccine-preventable diseases were obtained from the Department of Immunizations and Vaccine-preventable Diseases/General Coordination of the National Immunization Program - Health Surveillance Secretariat - Ministry of Health (DEIDT CGPNI/ /SVS/MS -Departamento de Imunizações e Doenças Imunopreveníveis/Coordenação Geral do Programa Nacional de Imunizações - Secretaria de Vigilância em Saúde - Ministério da Saúde) and extracted from the Notifiable Diseases Information System (SINAN) (http://portalsinan.saude.gov.br/dados-epidemiologicos-sinan, accessed on 08 /03/2022).
Results and discussions
Data available on VCR since 1980 showed that, until the mid-1990s, in Brazil, vaccine coverage in the child calendar, at the time Bacillus Calmette Guérin - BCG; bacterial triple vaccine (diphtheria, tetanus and pertussis - DTP); measles and oral poliomyelitis; were below the targets established by the PNI. However, in the middle of the same decade, there was a significant increase in vaccination rates, remaining, as a rule, high until the mid-2010s, then progressively decreasing.11
Coinciding with the decrease in VCR for the group of CNV vaccines, expanded over the years, followed by the replacement of the aggregated data record by the nominal record with the implementation of the SIPNI, which was intensified as of 2015, and the replacement by the Primary Health Information System (Sistema de Informação da Primária a Saúde) e-SUS APS, which was completed in January 2020 in the country.12
Although the vaccination data were collected individually in the vaccination unit, the registration in the system occurred in an aggregate manner and by place of vaccination, thus compromising, in part, the data analysis; for instance, municipalities with a high VCR did not necessarily have its population adequately vaccinated, but it was due to the vaccination of children who lived in other locations.12
The implementation of the individualized registry and by the origin of the vaccinated individual is aimed at reducing estimation errors and, particularly, at reducing possible duplication of records, monitoring the individual situation, and enabling the analysis of performance vaccination indicators closer to reality, although it does not eliminate data quality problems, such as record errors.12
The decrease in VCR and VCH since then has been attributed to the inadequate integration of databases, and more recently to the effects of the Covid-19 pandemic that caused an overload for immunization services.
However, the resurgence of diseases, such as measles that preceded the pandemic, demonstrated the existence of accumulated susceptible individuals due to heterogeneous VCR over the years, who were capable of becoming ill in the presence of the infectious agent.
In 2016, the Americas received the measles elimination certification from the Pan-American Health Organization (PAHO). However, due to the low VCR related to the triple viral vaccine (measles, rubella and mumps), there was an accumulation of susceptible individuals and a resurgence of measles circulation in Brazil in 2018. After more than two years of sustained transmission, Brazil lost the title of free of autochthonous virus circulation area.13
Between 2018 and 2020, 39,695 measles cases were confirmed. In 2020, a total of 9 countries in the Summit of the Americas reported measles cases and deaths.14 , 15
It is important to note that the reduction in the VCR in recent years is multifactorial. It is necessary to understand which factors are contributing to this decrease, highlighting the lack of knowledge about the importance of vaccination, vaccine hesitation, fake news published especially on social networks about the harm that vaccines can cause to one's health, the partial shortage of some products, operational problems in carrying out the vaccination, ranging from inadequate data recording to difficult access to the health unit. Understanding these factors is extremely important to seek new paths, aiming to re-establish the high VCR achieved until a few years ago.16 , 17
As a result of the decrease in the circulation of several vaccine-preventable diseases, prevention is placed in the background, often believed to be unnecessary. As of 2012, the WHO, reaffirming the importance of this issue and its implications, seeks to understand this phenomenon aiming to gather evidence for the development of public health interventions and, thus, revert this situation. Vaccine hesitation was defined as a delay in carrying out the vaccination schedule or refusal to receive the recommended vaccines, despite their availability in health services.18
These are, therefore, complex issues, as they involve cultural, social and economic aspects and vary over time, location and types of vaccines being used in the different vaccination programs. It should be understood as a continuous process that permeates from hesitant individuals who accept only a few vaccines and others who deliberately delay the vaccines, not accepting the recommended vaccination schedule, to those who refuse to vaccinate, regardless of the immunobiologicals being offered.18 In 2019, the WHO considered “vaccine hesitation” as one of the ten biggest global health threats.19
The insufficient structure of the vaccination network to meet the demand, with the distribution of numbers and limited hours to serve the population; lack of human or material resources, and partial shortage of immunobiologicals, especially for vaccines in the child calendar, has contributed to the decrease in access to vaccination in Brazil.20 Together with the misleading perception of parents that, due to the low risk of illness, it is no longer necessary to vaccinate their children, the lack of knowledge of which vaccines constitute the children's vaccination schedule, the fear that vaccines will cause adverse reactions or overload the children's immune system and the anti-vaccination movement that is growing in the country, although apparently not yet as significant, are reasons for the current scenario of the decrease in VCR.17 , 21
The VCR in Brazil, regarding the eight vaccines that comprise the vaccination schedule for children under one year of age, has shown important variations in its results, with a decrease in rates from 2015 to 2021, with a slight increase in rates for all vaccines in 2018. In that year, there was an intense mobilization of all sectors of SUS, in an attempt to rescue the VCR. However, these actions did not continue in 2019, and all vaccines had their VCR below the target (Table 2 ).Table 2 Vaccination coverage, increment of coverage and homogeneity of coverage between vaccines at <1 year of age and 1 year of age per type of vaccines and year, Brazil, 2015 to 2021*.
Table 2Target group Type of vaccine 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021
< one year old BCG 105.7 107.4 107.3 105.1 95.6 98.0 99.7 86.7 74.3 69.0
Hepatitis B ≤ 30 days Nd nd 88.5 90.9 81.8 85.9 88.4 78.6 64.1 62.0
Human Rotavirus 86.4 93.5 93.4 95.4 89.0 85.1 91.3 85.4 77.3 70.5
Meningococcus C 96.2 99.7 96.4 98.2 91.7 87.4 88.5 87.4 78.6 70.9
Penta (DTP/Hib/HB) 93.8 95.9 94.8 96.3 89.3 84.2 88.5 70.8 77.2 70.4
Pneumococcal 88.4 93.6 93.4 94.2 95.0 92.2 95.3 89.1 81.3 73.5
Poliomyelitis 96.5 100.7 96.8 98.3 84.4 84.7 89.5 84.2 76.2 69.9
Yellow fever 49.3 51.5 46.9 46.3 44.6 47.4 59.5 62.4 57.3 57.7
One year old Triple viral 1st dose 99.5 107.5 112.8 96.1 95.4 86.2 92.6 93.1 79.7 73.5
Triple viral 2nd dose Nd 68.9 92.9 79.9 76.7 72.9 76.9 81.6 62.9 51.7
Varicella Nd nd nd nd nd nd nd nd 72.4 65.0
Pneumococcal (1st booster) Nd 93.1 87.9 88.4 84.1 76.3 82.0 83.5 71.5 65.4
Meningococcus C (1st booster) Nd 92.3 88.6 87.9 93.9 78.6 80.2 85.8 76.0 68.0
Poliomyelitis (1st booster) Nd 92.9 86.3 84.5 74.4 73.6 72.8 74.6 68.5 59.9
Hepatitis A Nd 0.0 60.1 97.1 71.6 78.9 82.7 85.0 75.2 66.9
DTP (1st booster) Nd 91.0 86.4 85.8 64.3 72.4 73.3 57.1 76.2 63.0
Four years old and pregnant women DTP (2nd booster) 4 years Nd 0.0 2.4 nd nd 66.1 68.5 53.7 73.3 57.7
Poliomyelitis (2nd booster) 4 years Nd nd nd nd nd 62.3 63.6 68.5 67.4 54.3
dT/dTpa pregnant women Nd 50.7 43.5 45.6 31.5 34.7 45.0 45.0 22.9 18.9
dTpa pregnant women Nd nd nd 45.0 33.8 42.4 60.2 63.2 46.4 43.1
Source: sipni.datasus.gov, preliminary data from 2020 and 2021, accessed on 07/11/2022.
Highlight in red for VC < target and negative values for percentage decrease in VCR comparing the Covid-19 pre-pandemic and pandemic periods
In the pre-pandemic period, when comparing the year 2015 with 2019 for YF alone, a 34% increase in the VCR was identified, probably attributed to the increase in the use of this vaccine in geographic areas that were not considered as recommended for YF vaccination.
The worst performance was observed for the penta vaccine, which showed a 26.5% decrease. In 2019, there was a significant shortage in the second semester, certainly contributing to this decrease.
Historically, the VCR of the BCG vaccine has been high, surpassing the rate of 100% of children under one year of age. However, as of 2016 it also began to show a decline, albeit remaining above the target of 90% until the year 2018. The increment in the VCR was negative, with a 17.5% decrease. For the other vaccines, the decrease was between 5.5% for PCV10 and 14.3% for IPV (Table 2).
The situation worsened in the pandemic period (2020 - 2021), with a decrease for almost all VCRs of around 8%, with the exception of hepatitis B≤30 days, which was 3.2% and YF, which showed a small increase (0.7%) (Table 2). The VCH between vaccines for the same period decreased from 62.5% to “zero” and since 2019, no vaccine has reached the VC target established by the PNI in the national context (Table 2).
Considering the simultaneity of vaccination schedules, variations were observed between them that indicate a missed opportunity for vaccination during the child's visit to the health service. For vaccines with simultaneous two-dose schedules – rotavirus and PCV10 – there were differences in coverage that varied from 1 percentage point higher for rotavirus in 2015 to 7 percentage points higher for PCV10. In general, they were higher for PCV10, indicating a delayed full vaccine schedule when the child has already lost the opportunity to receive the second dose of the rotavirus vaccine, given the restriction on the administration of the second dose of this vaccine as of 8 months of life (Table 2).
In relation to the penta and IPV vaccines, simultaneous three-dose schedule vaccines, the year-by-year difference in coverage was lower compared to the VCR of the two-dose vaccines and, in general, they were higher for the penta vaccine. A marked difference was observed in 2019, between the VCR of these vaccines, being around 14% higher for IPV (Table 2).
For vaccines administered as of one year of age in the pre-pandemic period, there was an increase only for the triple viral vaccine (measles, rubella and mumps) (2%); however, it did not reach the recommended target, with the decrease ranging from 2.4% for meningo C booster dose up to 33.5% for DTP booster dose. There was a decrease in all vaccines during the pandemic period (Table 2).
Homogeneity of vaccination coverage between vaccines by Federation Unit
The VCH between vaccines per Federation Unit (FU) over the analyzed years showed a reduction in the number of vaccines with adequate VC in each FU. In 2015, only 10 of the 27 FUs achieved adequate VC for at least 75% of the eight vaccines. In the year 2021, except for Amapá and the Federal District (Distrito Federal, DF), which reached the VC goal for 01 of the 8 vaccines (12.5%) offered to children under one year of age, the VCH was zero percent in the other FUs (Table 3 ).Table 3 VCH between vaccinesa in the child calendar in children under one year of age, per Federation Unit, Brazil, 2015 to 2021.
Table 3FU 2015 2016 2017 2018 2019 2020 2021
RO 100.0 100.0 75.0 75.0 37.5 0.0 0.0
AC 12.5 12.5 12.5 12.5 37.5 0.0 0.0
AM 37.5 12.5 12.5 12.5 25.0 0.0 0.0
RR 62.5 37.5 62.5 37.5 37.5 25.0 0.0
PA 12.5 0.0 0.0 0.0 0.0 0.0 0.0
AP 25.0 50.0 12.5 12.5 25.0 0.0 12.5
TO 62.5 37.5 12.5 50.0 50.0 12.5 0.0
MA 37.5 12.5 12.5 25.0 0.0 0.0 0.0
PI 0.0 0.0 12.5 12.5 0.0 0.0 0.0
CE 87.5 87.5 87.5 87.5 50.0 0.0 0.0
RN 37.5 0.0 0.0 25.0 0.0 0.0 0.0
PB 37.5 12.5 12.5 50.0 62.5 0.0 0.0
PE 75.0 50.0 12.5 50.0 25.0 0.0 0.0
AL 37.5 12.5 12.5 87.5 37.5 0.0 0.0
SE 37.5 12.5 12.5 50.0 0.0 0.0 0.0
BA 25.0 0.0 0.0 0.0 0.0 0.0 0.0
MG 75.0 25.0 12.5 75.0 37.5 0.0 0.0
ES 75.0 37.5 12.5 37.5 37.5 0.0 0.0
RJ 62.5 62.5 25.0 12.5 0.0 0.0 0.0
SP 75.0 25.0 37.5 37.5 0.0 0.0 0.0
PA 75.0 37.5 25.0 25.0 50.0 0.0 0.0
SC 87.5 62.5 50.0 25.0 50.0 12.5 0.0
RS 37.5 12.5 12.5 25.0 12.5 0.0 0.0
MS 100.0 75.0 50.0 62.5 75.0 0.0 0.0
MT 87.5 62.5 12.5 50.0 37.5 0.0 0.0
GO 50.0 12.5 0.0 12.5 0.0 0.0 0.0
DF 12.5 100.0 25.0 12.5 25.0 12.5 12.5
BR 62.5 25.0 12.5 37.5 0.0 0.0 0.0
PBM
a Proportion of vaccines in the child calendar with adequate vaccination coverage (8 vaccines).
Source: sipni.datasus.gov.br. Preliminary data for 2020 and 2021 accessed on 07/13/2022.
Vaccination coverage and homogeneity of coverage in the context of municipalities
Available data for the 5,570 municipalities showed that the proportion of these municipalities with adequate VC was below 70% (target) of them throughout the analyzed historical series (2015 to 2021), except for the rotavirus vaccine in the year 2015. It ranged from 54.9% to 21.3% in the years 2015 and 2021 for the BCG vaccine and the percentage of municipalities with adequate VC for the hepatitis B vaccine decreased by around 50% year by year when compared to BCG, despite the simultaneous recommendation (Table 4 ).Table 4 VCH per municipalitya according to the type of vaccines in the child calendar of children under one year of age and aged one year, Brazil, 2015 and 2021.
Table 4Year BCG HepB < 30 days Meningo C Rotavirus Pneumo 10 IPV Penta (DTP/HB/Hib) Triple viral 1st dose
2015 54.9 27.7 65.5 71.3 60.7 61.6 64 58.7
2016 44.6 19 54.3 60 59.5 43.1 50.5 58.6
2017 51.9 25.4 48.7 53.8 56 44.3 43.5 44.9
2018 59 34.1 54 67.5 63.2 54.1 53.5 55.2
2019 43.4 24.3 46.6 53.2 48.9 39.8 22.4 56
2020 30 13.1 39.5 46.2 43.1 37.6 41.5 42.9
2021 21.3 10.5 24.6 31.1 27.6 25.6 26.1 31.4
a Proportion of Brazilian municipalities of the 5,570 showing VCR with achieved target.
Source: sipni.datasus.gov.br. Preliminary data from 2020 and 2021, accessed on 07/13/2022.
The penta and IPV vaccines in 2015 showed 61.6% and 64% of municipalities with adequate VCR. In 2019, following the same order, 39.8% and 22.4% of the municipalities reached the coverage target. The biggest difference in 2019 for the penta vaccine can be explained by penta shortages. However, in 2020, while 41.5% of the municipalities reached the penta goal, only 37.6% reached it for poliomyelitis, reiterating the loss of opportunity for vaccination, given that there was no shortage of the polio vaccine.
In 2021, when almost all efforts were focused on meeting the demand imposed by the vaccination campaign against Covid-19, the VCH was below 30% of municipalities for all vaccines, in a process that proved to be progressive during that period. The VCH between the vaccines in the municipalities decreased considerably, similar to what was observed in relation to the FUs. There was a progressively greater concentration of darker blue on the maps, reflecting a smaller number of municipalities with more vaccines with adequate coverage, being accentuated in the pandemic period of Covid-19 (2020 and 2021) and more frequent in the states of the north and northeast regions (Figure 1 ).Figure 1 VCH between vaccines in the child calendar, according to the municipalities, Brazil, 2015 to 2021.a Source: sipni.datasus.gov.br on 07/13/2022. aPreliminary data from 2020 and 2021.
Fig 1
The distribution of municipalities according to the number of vaccines with adequate VC showed that in the seven years of the historical series, municipalities that did not attain the vaccination target (zero%) were proportionally more frequent.
In general, the VCR maintains a common characteristic, showing extreme values for any vaccine and target group. These atypical extreme values are common in municipalities with small populations (fewer than 100 children), where data quality is more compromised, as any variation in the birth rate and/or registration of an applied dose alters the behavior of target indicator achievement, with a VCR much above 100%.
Considering that the VCH indicator includes in the numerator all vaccines that reached the target, regardless of overestimated values due to underestimation of the denominators or overnumbering of the numerator for the calculation of the VCR, in a way it places limitations on the VCH indicator, whether for each vaccine in the context of the municipalities (homogeneity between municipalities for each vaccine), or for the group of vaccines in each municipality.
Based on the year 2021, for the BCG vaccine given at birth, the variation in the VCR ranged from zero (61 municipalities without information) to 490%. The same was verified in relation to the hepatitis B vaccine ≤30 days in children up to 30 days old, although it is recommended together with the BCG vaccine at birth. For this vaccine, there are no data in the national database in 100 municipalities and 419 of the 5,570 municipalities recorded a coverage > 100%. PCV10, rotavirus, penta, IPV, meningo C and YF vaccines showed values with variation in indices ranging from zero to 550% of the VCR.
Therefore, it is reasonable to note that overestimated or underestimated VCR at the levels at which these indices are, is questionable, and could not be included in the context of adequate VC and therefore, despite being a good indicator to suggest "population immunity", it should be seen with caution.
Conclusions
The present evaluation has limitations due to the quality of the information (VCR outliers), as well as the integrity of the database compromised by the inadequate integration of information systems on vaccination data.
However, for the available data, when evaluating vaccination coverage by vaccine and homogeneity of coverage by the municipality and between vaccines in the different spheres of PNI management, a significant reduction in these indicators was observed in the pre-and pandemic periods of Covid-19, intensified in this last period due to the overload of services, prioritizing attention to the serious health situation that the world has experienced and because of it, the initial recommendations for social isolation, despite the fact that the pandemic is not an isolated cause of the also serious problem that represents the decline in vaccination coverage in the country.
It is an issue that encompasses the set of all Brazilian municipalities; however, the results are less favorable in the North and Northeast regions, possibly related to access to vaccination services, availability of products, and not least, the difficulties of geographical access.
It is necessary, when developing intervention strategies prioritizing situations of greater vulnerability, to incorporate these areas, not eliminating situations of concern in the other regions of the country. Additional efforts must be implemented to encompass all Brazilian municipalities since the current scenario of vaccination coverage in the country is a serious one. Like measles, there may be a resurgence of other diseases, if the VCR and VCH remain as low as seen in recent years.
It is urgent to seek partnerships and strategies to reverse this situation. Adequate communication and professional qualification are important issues, aiming to prepare the services to understand the importance of vaccination for all vaccines and target groups, given the complexity of the PNI vaccination schedule, being essential to guarantee the number of qualified professionals as well as the supply of vaccines in all services.
The current scenario is a matter of concern and requires urgent intervention measures under the penalty of compromising the entire history of the PNI achievements in its almost 50 years of existence, especially regarding the impact on preventable diseases throughout the country.
Conflicts of interest
The authors declare no conflicts of interest.
==== Refs
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| 0 | PMC9744707 | NO-CC CODE | 2022-12-15 00:04:04 | no | J Pediatr (Rio J). 2022 Dec 13; doi: 10.1016/j.jped.2022.11.004 | utf-8 | J Pediatr (Rio J) | 2,022 | 10.1016/j.jped.2022.11.004 | oa_other |
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Environ Impact Assess Rev
Environ Impact Assess Rev
Environmental Impact Assessment Review
0195-9255
0195-9255
Published by Elsevier Inc.
S0195-9255(22)00279-7
10.1016/j.eiar.2022.107013
107013
Article
Perceptions of change in the environment produced by the COVID-19 pandemic: Implications for environmental policy
Hidalgo-Triana N. a⁎
Picornell A. a
Reyes S. b
Circella G. cab
Ribeiro H. d
Bates A.E. e
Rojo J. f
Pearman P.B. ghi
Vivancos J.M. Artes j
Nautiyal S. k
Brearley F.Q. l
Pereña J. a
Ferragud M. m
Monroy-Colín A. n
Maya-Manzano J.M. oac
Ouachinou J.M.A. Sènami p
Salvo-Tierra A.E. q
Antunes C. r
Trigo-Pérez M. a
Navarro T. a
Jaramillo P. s
Oteros J. t
Charalampopoulos A. u
Kalantzi O.I. v
Freitas H. w
Ščevková J. x
Zanolla M. a
Marrano A. y
Comino O. z
Roldán J.J. a
Alcántara A.F. aa
Damialis A. u
a University of Málaga, Faculty of Sciences, Department of Botany and Plant Physiology (Botany Area), 29010 Málaga, Spain
b University of Málaga, Faculty of Philosophy and Letters, Department of Geography (Geographic Analysis Research Group), Spain
c Institute of Transportation Studies, University of California, Davis, USA
d Department of Geosciences, Environment and Spatial Plannings, Faculty of Sciences, University of Porto and Earth Sciences Institute (ICT), Pole of the Faculty of Sciences, University of Porto, Portugal
e Department of Biology, University of Victoria, Victoria, BC, Canada
f Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain
g Department of Plant Biology and Ecology, Faculty of Science and Technology, University of the Basque Country UPV/EHU, Leioa, Bizkaia 48940, Spain
h IKERBASQUE, Basque Foundation for Science, Plaza Euskadi 5, 48009 Bilbao, Spain
i BC3 Basque Centre for Climate Change, Scientific Campus, University of the Basque Country, 48940 Leioa, Bizkaia, Spain
j Department of Chemistry, Kennedy College of Sciences, UMass Lowell, Lowell, MA 01854, USA
k Centre for Ecological Economics and Natural Resources (CEENR), Institute for Social and Economic Change (ISEC), Nagarabhavi, Bengaluru 560 072, India
l Department of Natural Sciences, Manchester Metropolitan University, Chester Street, Manchester M1 5GD, UK
m University of Valencia, Faculty of Sciences, Spain
n University of Extremadura, Faculty of Sciences, Department of Vegetal Biology, Ecology and Earth Science (Botany Area), 06006 Badajoz, Spain
o Center of Allergy & Environment (ZAUM), Member of the German Center for Lung Research (DZL), Technical University and Helmholtz Center, Munich, Germany
p Laboratoire de Botanique et Ecologie Végétale, Faculté des Sciences et Techniques, Universite d'Abomey-Calavi, Benin
q Technical Director Chair Climate Change on UMA, University of Málaga, Faculty of Sciences, Department of Botany and Plant Physiology (Botany Area), 29010 Málaga, Spain
r Department of Medical and Health Sciences, School of Health and Human Development & Institute of Earth Sciences - ICT, University of Évora, Evora, Portugal
s Fundación Charles Darwin, Puerto Ayora, Isla Santa Cruz, Ecuador
t Department of Botany, Ecology and Plant Physiology, Agrifood Campus of International Excellence CeiA3, Andalusian Inter-University Institute for Earth System IISTA, University of Cordoba, Cordoba, Spain
u Department of Ecology, School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece
v Department of Environment, University of the Aegean, Mytilene 81100, Greece
w University of Coimbra, Department of Life Sciences, Centre for Functional Ecology, 3000-456 Coimbra, Portugal
x Comenius University, Faculty of Natural Sciences, Department of Botany, Révová 39, 811 02 Bratislava, Slovakia
y Phoenix Bioinformatics, Fremont, CA, USA
z Estudios de Flora y Vegetación SL (EFYVE), 29580 Cártama, Málaga, Spain
aa Centro de Cooperación del Mediterráneo de UICN, 29590 Campanillas, Málaga, Spain
ab Department of Geography, Ghent University. 9000 Ghent, Belgium
ac University of Extremadura, Faculty of Sciences, Department of Vegetal Biology Ecology and Earth Science (Botany Area), Badajoz, Spain
⁎ Corresponding author.
13 12 2022
13 12 2022
10701323 8 2022
5 12 2022
8 12 2022
© 2022 Published by Elsevier Inc.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
COVID-19 lockdown measures have impacted the environment with both positive and negative effects. However, how human populations have perceived such changes in the natural environment and how they may have changed their daily habits have not been yet thoroughly evaluated. The objectives of this work were to investigate (1) the social perception of the environmental changes produced by the COVID-19 pandemic lockdown and the derived change in habits in relation to i) waste management, energy saving, and sustainable consumption, ii) mobility, iii) social inequalities, iv) generation of noise, v) utilization of natural spaces, and, vi) human population perception towards the future, and (2) the associations of these potential new habits with various socio-demographic variables. First, a SWOT analysis identified strengths (S), weaknesses (W), opportunities (O), and threats (T) generated by the pandemic lockdown measures. Second, a survey based on the aspects of the SWOT was administered among 2370 adults from 37 countries during the period from February to September 2021. We found that the short-term positive impacts on the natural environment were generally well recognized. In contrast, longer-term negative effects arise, but they were often not reported by the survey participants, such as greater production of plastic waste derived from health safety measures, and the increase in e-commerce use, which can displace small storefront businesses. We were able to capture a mismatch between perceptions and the reported data related to visits to natural areas, and generation of waste. We found that age and country of residence were major contributors in shaping the survey participants ‘answers, which highlights the importance of government management strategies to address current and future environmental problems. Enhanced positive perceptions of the environment and ecosystems, combined with the understanding that livelihood sustainability, needs to be prioritized and would reinforce environmental protection policies to create greener cities. Moreover, new sustainable jobs in combination with more sustainable human habits represent an opportunity to reinforce environmental policy.
Graphical abstract
Unlabelled Image
Keywords
Pandemic
Emerging environmental impacts
Perception
Social behaviours
Natural environment
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pmc1 Introduction
The rapid human population growth and the corresponding increased use of resources are causing huge challenges to ensure healthy human and ecological systems. In response to these grand challenges, since the early 2000s, numerous organizations and governmental institutions worldwide have conceived and promoted sustainable ecological transitions based on models of a circular economy with initiatives to support sustainable development. Examples of such initiatives are the “2005 World Summit on Social Development” based on sustainability development (UN General Assembly, 2005) and, likewise, the Sustainable Development Goals (SDGs) program, initiated in 2015 by the United Nations (https://www.eea.europa.eu/policy-documents/eu-biodiversity-strategy-for-2030-1). However, the COVID-19 pandemic, an unprecedented event in modern times, has affected the development of these sustainability programs (Zhang et al., 2020; Wang and Su, 2020). The pandemic has led to the prioritization of public health measures (lockdowns, vaccination programs) and economic recovery over the continued development and implementation of sustainability agendas (You et al., 2020; Cheval et al., 2020).
The COVID-19 restrictions, which governments imposed to limit social interactions and to prevent transmission of the disease through human physical proximity, have produced environmental effects that differ in duration (into short-term effects, lasting months, to long-term effects, lasting years), and direction (positive or negative effects; Helm, 2020; Institute for Global Environmental Strategies (IGES), 2020; Cheval et al., 2020; Sharifi and Khavarian-Garmsir, 2022). While many long-term effects remain to be clarified, lockdowns and reduced activity have produced negative short-term effects on employment rates (Garrido et al., 2020), tourism, commerce, and industry, with devastating effects on the global economy (Bashir et al., 2020; Cheval et al., 2020; Nilashi et al., 2020). Previous studies have highlighted the massive shift towards remote work (in particular during the initial peak of the pandemic) and hybrid forms of work (during later stages of the pandemic), which were associated with an overall reduction in the number of commuting trips, in particular during peak time, as well as modifications in the use of various modes of transport (Matson et al., 2022). Among other related changes in activities and travel, a substantial increase in the use of online shopping was observed (Young et al., 2020) while the use of active modes of transport (including walking and bicycling) experienced some temporary renaissance and increased popularity, even if many of the latter changes were only temporary and rather short-lived as the pandemic evolved (McElroy et al., 2022). From a psychosocial perspective, the pandemic has increased anxiety and stress levels, decreased well-being (Franceschini et al., 2020; Shailaja et al., 2020) and increased social disparities causing vulnerable groups to be disproportionately impacted (Sharifi, 2022). Positive short-term environmental impacts initially emerged, such as a noticeable improvement in environmental conditions, mostly linked to reduced road traffic and consequent decreases in noise and air pollution. In particular, reduced emissions from the industry sector and urban traffic led to notable reductions in NO2, SO2, and PM2.5 and PM10 emissions (Nilashi et al., 2019; Bates et al., 2020; Mousazadeh et al., 2021; Prakash et al., 2021; Querol et al., 2021).
Moreover, reduced human activity has led to water quality improvement (Lokhandwala and Gautam, 2020; Yunus et al., 2020) and increased wildlife activity in urban and peri-urban environments (Paital, 2020; Bates et al., 2021b). Research has confirmed these positive impacts of the COVID-19 pandemic, particularly during periods when lockdown measures were widely enforced (Zambrano-Monserrate et al., 2020; Cheval et al., 2020). Chibueze et al. (2020) called this positive impact “Endorsement of Green Recovery”, which is being widely recognized as having a positive influence on human health and well-being via the use of green spaces (Lal et al., 2020; Lutu et al., 2020; Malliet et al., 2020). However, the global COVID-19 pandemic has also generated new human habits and behaviours that may drive societal change, and consequently, new anthropogenic impacts with positive and negative outcomes (e.g., Klemeš et al., 2020; Rupani et al., 2020; Paital et al., 2020; Wang et al., 2022). The aforementioned literature has deeply studied these impacts, but the respondent's perception of these changes remains unclear and not extensively studied. Recent literature search (i.e. Web of Science; November 2022) revealed that the topic of perception has not been well studied (Sharifi, 2022). For instance, Büssing et al., 2020a, Büssing et al., 2020b studied the perceived changes of certain attitudes and Ruiu et al. (2022) studied how the COVID-19 pandemic has impacted the perception of Climate Change in the UK though these studies generally remain specific to certain contexts and geographical regions.. The public awareness about these impacts offers an opportunity to develop effective future policies to protect the environment (Mousazadeh et al., 2021; Soni and Mistur, 2022) and develop better urban planning (Sharifi, 2022).
Previous studies in India and China have analysed the impacts of restriction measures and COVID-19 pandemic management using a SWOT framework (Strengths (S), Weaknesses (W), Opportunities (O), and Threats (T)) (Thakur, 2021b; Zhou et al., 2021). However, this type of analysis has not been applied in other parts of the world, and studies on new habits due to the COVID-19 pandemic and respondent perception are scanty at global scale.
This study explores the public awareness about the effects of the COVID-19 pandemic on the environment and those novel human habits that arose during the pandemic, in an international context, and across a variety of cultures, sociodemographic conditions, and geographical locations. Our goals are to illuminate emerging patterns and differences in human activities and behaviours, and to suggest measures required for mitigating impacts of restrictive public health measures in the future by integrating urban governance strategies (Van der Hel, 2018; Sharifi and Khavarian-Garmsir, 2020). We focus on associations between these potential new habits and a variety of socio-demographic variables, including country of residence (in relation to the COVID-19 management measures), cultural and socioeconomic regimes, and social status. To achieve these objectives, we first look critically at the pandemic through internal strengths, weaknesses, external opportunities, and threats (in the SWOT framework). Afterwards, we analyse data collected with an international survey that administered among a large group of respondents across 37 countries eliciting their perceptions on i) waste management, energy saving and sustainable consumption, ii) travel behaviour and mobility, iii) gender and social inequalities, iv) perceptions about noise generation, v) perception about the environment and natural spaces, and vi) human perception towards the future and the pandemic. Additionally, we analysed attitudes towards travel by plane, purchasing behaviours, and visits to natural areas to contrast behaviours before and during the pandemic.
2 Material and methods
2.1 SWOT analysis and development of the survey
The research strategy was based on a mixed-method approach. We first conducted a SWOT analysis (Teddlie and Tashakkori, 2011; Appendix A) to detect societal and physical shifts as a result of the COVID-19 pandemic. “Strengths” were considered as intrinsic or direct improvements in environmental features, derived from the pandemic. “Weaknesses” were attributes that can undermine the achievement of the “Strengths”. Conversely, “Opportunities” included changes that could potentially, if left unchecked, contribute to environmental conservation and maintenance of natural services. “Threats” were features that might prevent the detection of opportunities. From the results of the SWOT analysis, we identified six groups of behavioural variables and designed an online survey with specific questions for each group designed to assess people's new lifestyle habits (behavioural variables) in the context of socio-demographic variables, including age, country, gender, parenthood, areas of knowledge, and employment situation.
The survey contained 34 questions with different structures including multiple response questions, open-ended text fields, qualitative (yes/no questions), and quantitative, several types of quantitative questions measured in form of frequency scales or levels of agreement with certain statements, among others (content of the survey is reported in Appendix B). The survey was administered online among participants who were over 18 years old from 37 countries. The respondents were recruited via a convenience sampling approach, through invitations sent out among professional organizations, academic networks, various listservs, and social media. Our aim was to include, at least, the European countries that had been most affected by the pandemic, according to the European Centre for Disease Prevention and Control (2021) and Johns Hopkins University (2021): France, Germany, Greece, Ireland, Italy, Portugal, Slovakia, and Spain. We complemented these target countries with India and Mexico, which are densely populated countries in the Northern Hemisphere and which, consequently, were highly affected by the COVID-19 pandemic (https://www.worldometers.info/coronavirus/). In total, we received completed surveys from 37 countries (Fig. 1 ).Fig. 1 Survey density map. Scale 1:140,000,000.
Fig. 1
The administration of the survey started with a 34-question online pilot survey in Spain (N = 300 respondents). The pilot survey, in Spanish, was modified, as needed, to improve comprehension and translated into four languages (English, Portuguese, Italian and French). Respondents completed the online survey after the first wave of the COVID-19 pandemic, from February to September 2021a. As a result of the recruitment process, a total of 2370 valid entries were received, including the first 300 from Spain that were used to refine our methodology.
2.2 Statistical analysis
We analysed the diversity of the survey participants in the aforementioned socio-demographic variables. To reduce bias, we included in the analyses data from those countries returning an adequate sample size for further processing (whereby responses comprised >0.55% of the total number of responses).
Pearson's χ 2 tests were used to detect whether the behavioural variables were associated with the demographic variables. Yates's correction was applied when tables were 2*2 or less (Camilli and Hopkins, 1978). The p-values were corrected according to Benajmini and Hochberg approach to control the Type I error rate by means of “stat” base package implemented in R software (Benjamini and Hochberg, 1995; R Core Team, 2021).
Three pairs of questions compared the behaviour of the respondents based on three main aspects before and during the pandemic (Q15–16 for travels by plane, Q22–23 for purchasing behaviour, and Q25–26 for the number of visits to natural areas). In the first step, the answers were categorized on a numeric scale, being 0 in the absence of that behaviour (i.e., “never” answer), 1 in the lowest frequency of that behaviour, and 3 or 4 in the highest frequency depending on the number of possible answers to that question. By doing so, the answers were ranged in a scale that allow determining how many steps the respondents changed in their habits during the pandemic. Then, paired Mann-Whitney-Wilcoxon tests were performed to compare all the responses concerning before and during the pandemic as a whole. This non-parametric test was chosen due to non-normal distributions (Kolmogorov-Smirnoff test with Lilliefors correction; α =0.05). In a second step, the intensity of these changes was calculated for each participant by subtracting the value during the pandemic from the value before it. Additionally, the intensity of the changes was also associated with demographic variables by creating three-dimensional figures (the third dimension using colour intensities) where the overall index ranged from −4 (weakest) to 4 (strongest). This intensity was associated with the socio-demographic variables in pairs to compare all the combinations of variables. Only combinations of socio-demographic factors with at least 20 responses were considered to avoid a bottleneck effect.
All statistical analyses were performed using R software, version 4.1.0.
3 Results
3.1 Socio-demographic information of the participants
Responses were homogeneously distributed in terms of age and knowledge areas (Fig. 2A and 2E). The countries with the most respondents were Spain, Greece, Portugal, and Mexico, followed by Slovakia, Italy, France, the UK, Germany, and Ireland (Fig. 2B). Most participants did not have children (66%; Fig. 2C), with a larger proportion of women participating in the survey than other genders (Fig. 2D), a feature that is common to many other surveys administered with similar approaches. Of all participants, over 90% declared they were employed, students, or a combination of both (Fig. 2F).Fig. 2 Percentage of responses grouped by socio-demographic variables: A. Age. B. Country. C. Parenthood. D. Gender. E. Knowledge area. F. Employment situation. DK/NA: I don't know / I don't want to answer/Not applicable. N = 2370.
Fig. 2
3.2 Knowledge about the behaviours relevant to the environment
Independently of the behavioural groups of questions, the survey results (Supplementary material 1: Figs. S1 to Fig. S26) were classified into the following SWOT categories:
3.2.1 Weaknesses
The increase in the consumption of hospital resources, the generation of clinical waste (e.g., test kits, masks), and the waste derived from packaging emerged as important concerns by respondents. Half of the respondents reported making use of at least one COVID-19 test (Q8: Fig. S1) since the beginning of the pandemic to the moment when the survey was done (50% did “between 2-5 tests” and “more than 5 tests”). Moreover, the use of disposable masks increased (Q9: Fig. S2); while 26% of the surveyed people showed that they used washable masks, >19% indicated using >20 disposable masks per month from the beginning of the pandemic. However, 36% of all participants indicated that they used the same quantity of disposable household products (plastic cutlery, disposable gloves) as before the pandemic, while 21% used more than prior to the pandemic onset, only 8% used less, 34% did not use these types of products, and 0.5% chose the Did not know / Not applicable category (Q10: Fig. S3). Respondents reported in response to questions on purchasing behaviour (sustainable consumption, Q22–23), an increase in online shopping since the beginning of the pandemic (i.e. an increase in e-shopping), where the frequency of choosing the categories “1 to 3 times a month” and “more than 3 times a month” increased by >10 percentage points (Fig. S14–15). Although the pandemic could provide an opportunity to promote technology for remote work, for those participants who continued going to physically commute to their workplace (Q14: Fig. S7), the majority (91%) indicated that they did not change their transport model with private vehicle use being prevalent. Additionally, more that 72% of respondents thought that the reduction of tourism by the lockdown restrictions had harmed the cities economically (Q28: Fig. S20).
3.2.2 Threats
We grouped threats into inequalities that were based on gender and social groups. Forty-eight percent of respondents believed that all sub-sections of the society have been equally affected by the pandemic (Q17: Fig. S10); however, 25% indicated that older people were most affected. Respondents strongly indicated that the urban population was most affected by the pandemic (78%; Q19: Fig. S12). Respondents indicated that the pandemic worsened gender inequality in the workplace, with 35% indicating no effect, while 28% and 25% indicated they “have perceived inequalities” or they “were with doubt”, respectively (Q18: Fig. S11).
3.2.3 Strengths
Strengths emerged in waste management, energy-saving, and sustainable consumption. Respondents noticed reduced food-related waste after decreasing purchased quantities and improving choices (Question-Q24: fig. S16). Only 18% of surveyed respondents indicated buying a greater quantity of products during the pandemic. Additionally, commitment to sustainable mobility and transport options emerged during the pandemic as work shifted to remote platforms and fewer respondents needed to physically commute to their workplace. Although around one-third of respondents (32%; Q13; Fig.S6) worked in person (physically) also during the pandemic, a similar percentage (29%) switched to remote work. The remaining (29%) used a mixed (hybrid) working model. Perceptions of noise generation (Q21; Fig. S13) were also impacted by lockdown measures. Almost half (47%) noticed noise reduction due to the pandemic, whereas 40% noticed no changes in environmental noise levels. Respondents' relationships with the environment and natural areas improved. A large majority of the respondents (95%; Q29: Fig. S21) attributed high value to natural spaces during the pandemic.
3.2.4 Opportunities
A high percentage (80%) indicated that “green jobs” (positions in agriculture, manufacturing, administrative, and service activities aimed at protecting and promoting the environment) could help solve this pandemic rather than jobs with poorer job security (Q30: Fig. S22), and 90% agreed that 2021a presented a good opportunity for their countries to shift to more sustainable policies (Q32: Fig. S24). However, only 45% of the respondetns thought that the environmental situation in their countries would improve in 2021a (Q31; Fig. S23). Finally, 77% strongly considered that the new habits created during the pandemic would last over time (Q34: Fig. S26).
3.3 Effects of socio-demographic aspects on the behavioural variables
Most of the behavioural variables varied significantly in response to the socio-demographic variables (Fig. 3 ). Effects of socio-demographic aspects by country, gender, age, employment situation, and parenthood on behaviours are plotted in Supplementary material 2.Fig. 3 Pearson's χ2 tests statistic values (colours) and significance levels obtained by comparing the responses to each question of the survey. N = 2370, significance levels are: p ≤ 0.05 (*), p ≤ 0.01 (**), p ≤ 0.001 (***). Yates correction was applied when needed (in tables of 2*2 dimensions) and p-values were corrected by means of Benjamini and Hochberg (1995) approach. Colour intensity (red) highlights higher χ2 statistic values representing greater differences between the expected and observed distribution of responses. See Appendix B for the question content. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3
Behaviours and life habits concerning waste management, energy saving, and sustainable consumption (Q8 to Q12 and Q22 to Q24) varied significantly depending on various socio-demographic variables (Fig. 3). Age and country were among the most influential aspects for waste management, energy saving, and sustainable consumption (p ≤ 0.001; χ2 = 100–1000). Respondents from Spain and Portugal strongly indicated the use of fewer COVID-19 tests, whereas people from Slovakia and Greece indicated a high testing rate: with more than five tests per person, on average, since the beginning of the pandemic (Q8; Supplementary material 2). In addition, younger respondents (people from 18 to 35 years old) took more tests. Less frequent use of face masks was detected in Mexico and Slovakia than in Spain, Portugal, and Greece, where a large number of face masks was used monthly (Q9; Supplementary material 2). Some respondents, especially younger ones, reported using washable masks. Greece stood out in the use of disposable products (Q10), as participants there indicated that they used the same amount before and during the pandemic. However, in Spain, a great number of surveyed respondents indicated that they did not use disposable products.
Shopping/consumption habits (Q24) were independent from employment situation (p ≤ 0.05; Fig. 3).
All of the socio-demographic groups reported that their travel behaviour (Q13 to Q16) was largely affected by the pandemic (p ≤ 0.05, p ≤ 0.01, and p ≤ 0.001; Fig. 3). How respondents travelled to work was the variable (Q14) that was most strongly affected by the country and employment situation (p ≤ 0.001, Fig. 3), showing greatest changes in Spain and Greece (Supplementary material 2; Q14). Most respondents indicated that they did not change their usual transportation modes due to the pandemic (p ≤ 0.001, Fig. 3). Of the responses reporting no effect of the pandemic on habitual modes of transport, the frequencies of transport modes still depend on employment status (private transportation: Supplementary material 2; Q14).
The perception of gender and social inequalities (Q17 to Q19) was strongly related to all socio-demographic aspects studied (p ≤ 0.01 and p ≤ 0.001; Fig. 3). Both varied widely by country, age, and gender. Although most respondents agreed that the pandemic had affected all sectors of the population equally, it is noteworthy that the older people were considered as the most affected by the pandemic from the perspective of respondents from Portugal and Spain (Supplementary material 2; Q17).
The perception of noise reduction observed during the pandemic was related to all the socio-demographic aspects included in the surveys (p ≤ 0.001; Fig. 3), except for gender and knowledge area. Mediterranean countries, including Spain, Greece, and Italy, as well as India, indicated the perception of a decrease in noise (Supplementary material 2; Q21). This decrease was less noticed by young people (18 to 25) compared to the rest of the surveyed population (Supplementary material 2; Q21).
Generally, the perception of the environment, nature (Q25 to Q31 and Q34), and the human perception towards the pandemic and the future (Q28, Q32 and Q33) showed significant effects (p ≤ 0.001, p ≤ 0.01 and p ≤ 0.05). The respondent's country of residence showed the greatest significant effect on the responses (χ2 = 100–1000, p ≤ 0.001; Fig. 3). Regarding visits to natural spaces during the pandemic (Supplementary material 2; Q26), Greeks and Slovaks indicated a greater use of natural spaces with respect to the other respondents. Specifically, the questions about the improvement of the situation for 2021a (Q31), were the least affected by the socio-demographic aspects studied but highly affected by the country. The respondent's country was the most influential aspect in the opinion that COVID-19 has benefited to the environment (Q27), and Spaniards and Greeks more strongly indicated benefits of the pandemic (Supplementary material 2; Q27).
Human perception towards the pandemic was significantly affected by most of the socio-demographic aspects we studied (p ≤ 0.05; Fig. 3). In particular, social perspective varied noticeably among the knowledge areas with the lowest p-value for the importance of the tourism reduction in cities (Q28).
3.4 Comparison of the situation before and during the lockdowns
3.4.1 Quantitative changes in travels by plane, consumption habits and visits to natural areas
Our quantitative assessments suggest that travels by plane and the number of visits to natural and/or semi-natural spaces significantly decreased due to the pandemic (p ≤ 0.001), while online shopping increased (Fig. 4 ).Fig. 4 Comparison between the number of visits to natural areas (nature; Q25–26), purchasing behaviour (shop; Q22–23), and travel by plane (travel; Q15–16) before and during the pandemic. Overall results on the left plot, and results detailed per responses on the right. N = 2370, p ≤ 0.001 (***) by paired Mann-Whitney-Wilcoxon tests.
Fig. 4
3.4.2 Interaction between qualitative demographic variables and changes in travel by plane, consumption habits, and in the number of visits to natural areas
Supplementary material 3–5 shows how respondents changed some habits (number of airplane trips, purchasing behaviours, and number of visits to natural areas) associated with the qualitative demographic variables, due to the COVID-19 outbreak.a) Intensity of changes in travel by plane (frequency of airplane travels)
Travel frequency was reduced in two categories in most cases and one category in some cases (Supplementary material 3).
In Mediterranean countries, the airplane trips among people under 65 years old were particularly reduced in Greece and Spain (Supplementary material 3, Fig. Sa). Italy showed the same change for respondents between 18 and 35, and Portugal showed this change for people between 26 and 65. Mexico only showed a reduction in airplane trips for people between 36 and 50.
Overall, for all studied countries, the factor of parental situation concerning age did not seem to affect the reduction in the travelling frequency by plane, while the employment situation and field of knowledge did (Supplementary material 3 Fig. Sc). Unemployed people between 36 and 50 showed a smaller change in their travel frequency than the surveyed students and employed people, with students under 25 showing less change. People aged 51–65 involved in arts and humanities disciplines showed a lower decrease in their trips than those in other knowledge areas. Conversely, people in the health sciences field showed a higher reduction in their travel frequency.
Respondents involved in “arts and humanities” from Portugal and Mexico reported a smaller reduction in travel frequency, and Mexican respondents in “engineering, architecture and health sciences” showed a lower reduction than respondents in sciences and social sciences and law (Supplementary material 3, Fig. Si).b) Intensity of changes in consumption habits
In all of the cases studied, respondents increased their purchases in at least one level of intensity (Supplementary material 4).
Regarding the age of the respondents, the greatest changes were observed among 25–50 years old age groups, while the lowest was among younger age groups. Specific interactions with the country were observed in Greece, Portugal, and Mexico, where habitants in the 18–35 age class showed the lowest increase in their purchasing (Supplementary material 4, Fig. Sa). Only women aged 36 to 50 showed an increase in their purchasing frequency in comparison with the rest of the age classes and genders (Supplementary material 4, Fig. Sb). According to parenthood, only people aged 26 to 50 with children increased their purchasing habits compared to respondents without children (Supplementary material 4, Fig. Sc). Concerning employment status, active workers (“employed” and “student and employed”) intensified their consumption during the pandemic, compared with unemployed people (Supplementary material 4, Fig. Sd).
Concerning the country of residence, males from Portugal and Greece did not change their consumption, but females experienced a greater change. Mexican and Portuguese people with children were the ones showing the greatest changes in their consumption habits, while for Greece, no interaction between parenthood and country in purchasing behaviour was observed (Supplementary material 4, Fig Sg).
According to gender, overall females were the ones increasing their consumption compared to men. Also, parenthood status influenced shopping habits, with females with children being the only ones increasing their habits compared to females with no children (Supplementary material 4, Fig. Sj). Also, females with income (employed and student and employed) expressed a higher increase in purchases (Supplementary material 4, Fig. 7 k), particularly those in the knowledge area of “health sciences” (Supplementary material 4, Fig. Sl).c) Intensity of changes in the number of visits to natural areas
Despite an observed general reduction in visits to natural areas (Fig. 4), in most cases, this change was not as intense as changes in travel frequency (Supplementary material 5).
With respect to age, the most noticeable change was observed among Mexicans aged 18–25 and 51–65 who reported a decrease in the number of visits to natural areas, and the same change was experienced by young Portuguese (Supplementary material 5, Fig. Sa).
With respect to country of residence, respondents identifying as women from Portugal and Mexico reported a greater reduction in their number of visits to natural areas in comparison with men (Supplementary material 5, Fig. Sf). Regarding parenthood and country interaction, Portuguese with children showed a lower reduction in their visits to natural areas than Portuguese without children, and no interaction between parenthood and country was detected in Mexico, Spain, and Greece (Supplementary material 5, Fig. Sg). Mexican and Portuguese belonging to the categories Student and Employed and Student showed a notable reduction in this habit (Supplementary material 5, Fig. 8 h). People from Portugal and Mexico involved in “health sciences” and those Mexicans related to other Sciences disciplines showed a drastic reduction in their number of visits to natural areas (Supplementary material 5, Fig. Si).
Noticeable interactions were not detected with visits to natural areas for respondents representing different genders, parenthood status, employment situation, and knowledge area (Supplementary material 5, Fig. Sj-o).
4 Discussion
4.1 New perceptions and attitudes of the population due to the COVID-19 pandemic
The most alarming consequence of the pandemic, from an environmental point of view, was the unprecedented large amount of waste generation (medical and nonmedical) which has long-term consequences and unsustainable environmental impacts (Zhang et al., 2020; Klemeš et al., 2020; Rupani et al., 2020; Wang and Su, 2020). This situation was more acute in those countries that had already included the reduction of single-use products in their sustainable agendas before the pandemic, e.g., countries of the European Union, China, Canada, United Kingdom, etc. (Shams et al., 2020; Liu et al., 2020; UNCTAD, 2022, Benson et al., 2021). Although this fact has been previously reported, it is paradoxical as the perception of the population sometimes does not coincide with reality since most of the respondents declared to have used fewer single-use products during the pandemic. This can be used by governments to implement new measures to decrease the use of these products. In the same way, although our participants perceived that their purchasing behaviours were the same, the resurgence of e-commerce has negative impacts through the production of waste products, and competition with local commerce, leading to a reduction in local incomes (Cruz-Cárdenas et al., 2021). Respondents perceived the reduction in tourism traffic as another key weakness. However, an opportunity which emerged was to development of sustainable transport infrastructure with associated economic benefits: most respondents also believed that their countries should have focused on more sustainable jobs, e.g., green jobs to solve this pandemic. The United Nations has argued that green jobs are “the only way to go” (https://www.un.org/en/). The independent WWF agrees, indicating that new nature-based policies are vital (Lieuw-Kie-Song and Pérez Cirera, 2020).
Conversely, reduced amount of physical commuting have encouraged new working habits that may positively impact the environment if maintained in the long term (Crowley et al., 2012), which could be a potential strength. Previous studies have indicated that working remotely, working from a home-office, and telecommuting are part of a more productive work model that also improves work-life balance (at least for some workers) and can contribute to reduce transport flows(Hunter, 2019; OECD Policy Responses to Coronavirus (COVID-19), 2020; Morikawa, 2020). The reduced number of commuting trips mean less traffic congestion and air pollution, in particular during peak times, since the transpor sector is the largest contributor to urban air pollution (Hunter, 2019). However, about one third of respondents still commuted to a workplace (until September 2021a), and the majority of respondents indicated that they did not change their transportation mode due to the pandemic, with private vehicle use still being prevalent. There is also a potential that remote and hybrid work schedule, in the long run, might hurt public transport ridership, as this is usually designed in particular to serve commuting trips during peak times on major commuting corridors. Not surprisingly, in many larger US cities, public transport ridership continued to remain below pre-pandemic levels as workers resumed activities, with the demand for car travel rebounding much faster than that for public transport (Soza-Parra et al., 2022). Our results confirm a consistent excessive use of private vehicles even during the pandemic (Gkiotsalitis and Cats, 2020; Thombre and Agarwal, 2021) indicating that people make their travel choices based on different criteria, such as time, cost, convenience, safety and reliability (Sharifi, 2021a). Again, the role of governments in providing a sustainable transportation network is key in promoting this change of habit into more sustainable transportation modes. While some studies have pointed to the relative increase in popularity of active modes of travel (e.g. walking and cycling) during the pandemic, many of these changes proved to be only short-lived (McElroy et al., 2022). In this sense, several countries (e.g., Spain, USA) have regulated and updated labour laws to adapt to the pandemic towards promoting more remote or hybrid works, posing anopportunity for positive environmental impacts (Galanti et al., 2021). Applications of smart city solutions and technologies could offer new opportunities for reducing mobility even when the COVID-19 pandemic ends (Sharifi and Khavarian-Garmsir, 2020; Sharifi, 2022).
Many survey participants detected reduced environmental noise levels (strength) during the pandemic, as also reported by Zambrano-Monserrate et al. (2020) and Somani et al. (2020). Even so, it is important to note that after the lockdown many actions such as hotel business, traffic, and leisure activities, have moved outdoors due to the pandemic, potentially resulting in a new threat to the urban environment such as greater noise levels. Indeed, this flux of outdoor visitors may present a new threat to nature.
As most survey respondents perceived, strict lockdowns reduced air pollution, improved air quality, and decreased noise levels, which had an important positive environmental impact (Prakash et al., 2021). However, these short-term positive impacts were strictly derived from the lockdown restrictions on human travels and they disappeared as soon restrictions were lifted (i.e. Nilashi et al., 2019; March et al., 2021; Millefiori et al., 2021). This positive perception by the respondents may constitute an opportunity and should motivate governments to implement new measures to decrease pollution (chemical and noise) in the environment; in fact, respondents considered (in Q32) that now is the time to act due to the shock situation promoted by the pandemic. Governments should also be encouraged to implement new public policies to reduce pollution and face global change, simply because multiple threats such as the pandemic can interact with other drivers to global change and reduce the trajectory towards more sustainable futures (Garrido-Cumbrera et al., 2021; IPCC, 2021; Bates et al., 2021b; Nahm et al., 2022).
Another noteworthy aspect is the importance that has been attributed to natural spaces. Our results showed that the short-term positive environmental effects of the COVID-19 pandemic have been noticed by the population because our respondents indicated that COVID-19 has benefited the environment (Q27). According to our survey, most people are now aware that environmental changes are possible if the population alter their habits. This constitutes an opportunity to promote new politics to achieve more sustainable and greener cities following the concept of “Endorsement of Green Recovery” (Bashir et al., 2020; Kumar et al., 2020; Lal et al., 2020; Lutu et al., 2020).
4.2 Effects of socio-demographic aspects on behavioural variables
The effect of the country detected on waste management (i.e., number of COVID-19 tests used, number of used masks, or number of disposable products used) reflected the results of the government restrictions enacted to deal with the COVID-19 pandemic, along with cultural . For example, in Greece, many tests were conducted during the exact time of the current study for travellers who wished to enter the country, regardless of their vaccination status (https://travel.gov.gr/, last access 20 January 2022). It should be noted that the timing of the survey is crucial, as the use of COVID-19 tests has likely increased since we took the survey. It is important to consider that Peng et al. (2021a) calculated the excess generated of municipal mixed plastic waste (MMPW) during the pandemic as 4.4 million to 15.1 million tonnes, indicating an excess of waste from the use of masks, tests, etc. This excess of waste is considered as a new and important emerging negative impact in this situation that should not go unnoticed.
Although many respondents indicated that they used washable masks (Q9), a large number of responses were obtained in the category of “more than 20 disposable masks” per month, demonstrating that masks are one of the next waste problems, as some works have already indicated (Elvis and Zhiyong, 2021). In addition, the greater use of washable masks was detected in countries with lower income, such as Mexico and Slovakia, indicating that the use of masks is maybe more related to socioeconomic variables than environmental attitudes. Moreover, the higher use of washable masks was detected among young people and could be related to the lower income of this segment of the population with younger people being more likely to use less effective masks.
The low use of single-use products reported by survey respondents stands out and contrasts with published reports that single-use products were used more often during the COVID-19 pandemic (Klemeš et al., 2020; Rupani et al., 2020). This may be explained by the fact that these studies have considered masks as one of these products, and we placed the use of masks in a separate section of the survey to distinguish them from the other sources of single-use products. Moreover, some governments have regulated the prices of masks, in particular, controlling prices for KF94 surgical masks (e.g. Melkadze, 2022; Dae-Yong, 2021), which led to a price reduction for disposable masks; hence, their consumption has increased. However, this occurred after the time of the survey, and for that reason, we could not detect the possible effect of the reduction in prices regulated by governments (country) on the use of masks.
Participants perceived that their purchasing behaviours were the same during lockdown periods, while our results show that online shopping has modestly increased due to the pandemic effect with significant differences between countries (Supplementary material 1; Q24). For instance, respondents from Spain and Portugal have increased their e-commerce more than others with a lower Consumer Price Index (CPI), such as Mexico (https://en.www.inegi.org.mx/temas/ppc/). Nevertheless, countries with lower purchasing power, such as Greece, also increased their online purchases, demonstrating that habits have changed due to the pandemic, independent of purchasing habits or gross national income. The increase in online shopping was relevant among young people, highlighting an emerging tendency for younger generations to consider. Online shopping is one of the most relevant online activities, making important contributions to the global economy (Cai and Cude, 2008; Steinfield et al., 1999). But a disadvantage related to e-commerce activity is the creation of impulsive consumers, with important consequences to the environment (considered to be a negative behaviour) (Beatty and Ferrell, 1998).
As for mobility and sustainable transport, Spain and Greece stand out as the countries with the greatest number of people working physically and travelling to their workplace despite pandemic restrictions. Spanish and Greek respondents indicated that they mostly use private transport. In addition, the use of public transportation is restricted to that specific country or even restricted to a particular city. It seems that the employment situation affects the way people get to the workplace observing a higher use of private vehicles by employed people (people with higher purchasing power). Hence, governments in Spain and Greece ought to support employees more in order to improve access to reliable and efficient public transport.
Concerning gender and social inequalities, the effect of the interactions among different countries, ages, and genders, gives a clear indication that policies are very important. In most surveyed countries, most people stated that older respondents were the most affected by the pandemic. In contrast to these opinions, a recent report from United Nations Foundation (2020) argued that domestic violence spiked during this “shadow pandemic”, as girls and women sheltered in place with their abusers, women lost jobs, and the world's nurses (a female-dominated profession) shouldered tremendous risks and burdens, and the unpaid care work mostly provided by girls and women. Even so, participants who identified as either male or female claimed to be more affected than their respective counterparts (Supplementary material 1; Q17).
Although most socio-demographic aspects influenced the perception of noise generation, the role of the country of residence and its cultural aspects emerged as being significant. The findings obtained by Garrido-Cumbrera et al. (2021a) suggested that the positive impacts on the natural environment, including noise reduction, as a result of the lockdown were better received by the populations of Spain and Ireland. In Mediterranean countries such as Spain, Greece, and Italy, the noise level is high due to most people living in flats, and a high percentage of their household expenditures are devoted to restaurant services (Eurostat, 2018). For this reason, lockdowns made the noise reduction more noticeable in these countries.
People with scientific backgrounds might better understand the environmental situation and social responsibility during the pandemic and in the future. Having a scientific background could therefore be an influential factor, although it showed a lower effect than expected. But socio-demographic aspects do have a clear effect on perceptions that COVID-19 positively affected the environment. This aspect was also detected by Garrido-Cumbrera et al. (2021), who considered the pandemic to be an unprecedented opportunity to raise awareness of the effects of human activity on nature and to reduce pollution in the long term.
The perception that “the pandemic has had a positive effect on the environment in general” (Supplementary material 1; Q27) was especially high among Spaniards, although they did not expect the positive effects to last; this perception also prevails among people from other countries. However, the negative effects of the pandemic may be longer-term, and neither the negative effects or their consequences seem to be perceived by the public (Cheval et al., 2020; Rume and Islam, 2020; Garrido-Cumbrera et al., 2021; Leal et al., 2021a; Peng et al., 2021).
Human perception towards the future and towards the pandemic were mainly affected by the country under consideration. All countries detected an impact due to reduced tourism (Supplementary material 1; Q28). Respondents from countries with a high dependence on tourism, such as Spain, Portugal, and Greece, indicated an important negative impact due to reduced tourism during the pandemic. However, this did not extend to the respondents from Italy, despite tourism being one of the most important industries for the country's economy (https://www.oecd-ilibrary.org/sites/3d4192c2-en/index.html?itemId=/content/component/3d4192c2-en). This can be explained by the high importance granted to health during the pandemic.
4.3 Comparison of the situations before and after the lockdowns
In general, concerning travel behaviour, most people reported a reduction in their trips due to the restrictions' governments imposed to minimize social and physical interactions. However, this reduction can be considered only in the short term, as it does not necessarily imply a persistent change in people's travel habits. The effects of country of residence on the changes in travel behaviour for the surveyed Mediterranean countries (Spain, Greece, and Italy) were similar, but countries such as India and Mexico did not show changes. Generally, people from India and Mexico spent little money on travelling like generally happen: only people aged between 36 and 50 years reduced their trips, possibly related to business or work. Unemployed people between the ages of 36 and 50 showed less change than the rest of those surveyed, indicating that employed people had travelled more than the rest due to greater purchasing power but were more affected by the pandemic.
Online shopping also varied by country and among demographic groups. Mouratidis and Papagiannakis (2021) analysed online shopping habits in Greece and detected a modest increase in this habit, and we detected similar behaviour in our results from Portugal and Mexico. Dittmar et al. (2004) associated women's online buying with barriers (social–experiential factors) and facilitators (efficiency, identity-related concerns) grounded in their attitudes towards conventional buying, but other works indicated that women liked to shop more than men (Vijaya, Aparanjini and Lahari, 2017). Obviously, people with children showed an increase in their online purchasing habits due to the need for child-care products and additional restrictions when shopping.
Although many recent studies during the pandemic argued for the possible existence of the phenomenon of the “Endorsement of Green Recovery” and an increase in the appreciation of urban green spaces (Lal et al., 2020; Lutu et al., 2020; Zhu and Xu, 2020; Ugolini et al., 2020), our results were in contrast to this sentiment due to the observed reduction in the visits to natural areas. Respondents did not significantly increase their contact with nature and drastically reduced their visits to natural or seminatural spaces, which implies a different approach and adoption of attitudes that do not support acquaintance with or promotion of the environment (Kanelli et al., 2021). Again, the perception of the respondents did not coincide with the reported frequency of visits to green areas. This fact may be due to the timing of the survey dissemination: most of the countries surveyed had mobility restrictions, so visiting natural areas was not within people's reach. Another possible explanation, as Maltagliati et al. (2021) also indicated, is that the closure of leisure and entertainment facilities has caused many people to reduce their (already normally limited) physical activity in outdoor natural environments. Some authors such as Cheval et al. (2020) evaluated the current situation produced by COVID-19 as an opportunity to improve the natural environment, with Zhu and Xu (2020) demonstrating a positive relationship among green spaces, health, and well-being, and Garrido-Cumbrera (2021a) showing an increased appreciation for urban green spaces during the first wave of the COVID-19 pandemic. Indeed, is important to understand the main factors influencing people's attitudes towards biodiversity-friendly greenspace management. Understanding how the different social and cultural background variables aid the better design and management of biodiversity-friendly greenspaces, is thus critical for successful biodiversity conservation in cities and natural areas (Fischer et al., 2018a, Fischer et al., 2018b).
4.4 Limitations of the study
The study was limited to people who had direct access to the internet or were approachable by email. The ability to use English was important for countries where the survey was not translated to the official language, such as Greece and Slovakia, even though we do not expect this to yield a considerable bias. While efforts were made to recruit a large enough sample of respondents, and with varied sociodemographic, and the sample distributions are not far from those of the populations of the countries of interest, the use of non-probability-based sampling, and convenience sampling in particular, somewhat limits the ability to obtain more representative results to the entire population. Many people had a higher level of education, and may not represent a complete sample of the whole country. Although the sample size of our study was large, we obtained relatively more responses from countries such as Spain, Greece, Portugal, and Mexico. We expect that this, to an extent, might have also been reflected in the awareness, attitude, and perceived environment of the included respondents.
5 Conclusion
The results of our study provide insights into the individuals' perception of the effects of the COVID-19 pandemic on the environment, confirming the social vision towards improvements in environmental quality. The novelty of this work relies on being able to capture a mismatch between individual perceptions and the reported data by the literature related to visits to natural areas, generation of waste, etc. Specifically, the observed changes in perceptions and/or attitudes during the COVID-19 pandemic represent an opportunity to improve the environmental quality of many countries worldwide and to transition towards greater respect for the environment. Others, however could constitute a threat in the achievement of the principles of sustainable development.
The increase in COVID-related waste, along with the increase in online shopping, is producing an increase in consumption that results in increasingly unsustainable resource use and waste production (somehow exacerbating existing unsustainable patterns from before the pandemic). This increase in waste in combination with the development of new economic models can be unsustainable for small businesses and represent activities that could have irreversible negative consequences for our planet in terms of waste production.
While this pandemic has had significant negative health and economic consequences worldwide, our findings demonstrate new human habits and behaviours that may negatively impact the environment in the near future if government policies and decision makers do not address them at national and international levels. We further identify emerging perceptions about the environment and ecosystems, and the consideration of respondents about the need to implement new and more sustainable jobs. Such perceptions represent a unique window of opportunity to reinforce environmental protection policies which respect our cities and environmental spaces, but also promote positive human interactions with green spaces. In addition, the increased remote working patterns, new technologies and subsequent reduction in the use of transport (though the latter change has already largely reversed, at the time of writing of this paper) could provide an opportunity to reduce greenhouse gas emissions that is urgently needed to protect life as we know it on Earth.
Despite this study was elaborated with responses from some of the most affected countries by the pandemic, slight variations in the results could be expected in other countries. Therefore, future research should attempt to include a broader geographical coverage to check for possible differences in the results.
Credit authorship contribution statement
NHT: Conceptualization, Methodology, Validation, Visualization, Writing – original draft. AP: Conceptualization, Statistical analysis, Writing – review & editing. SR: Conceptualization and Formal analysis. AED: Writing – review & editing and Supervision. Rest of the co-authors: Writing – review & editing, and international survey administration.
Funding
Language proofing and editing funded by UMass Lowell.
Uncited references
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Alon et al., 2020
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Asian Development Bank, 2020
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Bates et al., 2021a
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Thakur, 2021a
Verma and Prakash, 2020
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Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Appendix A Supplementary data
Supplementary Material 1
Fig. S1 to Fig. S26. Results obtained from the survey from question number 8 to question number 34.
Supplementary material 2. Detailed responses derived from questions 8 to 33 by country, by gender and by age, by employment situation and by parenthood.
Supplementary material 3. Intensity of changes in travel by plane (frequency of airplane travels).
Supplementary material 4. Intensity of changes in consumption habits.
Supplementary material 5. Intensity of changes in the number of visits to natural areas.
Supplementary Material 1
Data availability
Data will be made available on request.
Acknowledgements
A. Picornell was supported by a postdoctoral grant financed by the Consejería de Transformación Económica, Industria, Conocimiento y Universidades (Junta de Andalucía, POSTDOC_21_00056).
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.eiar.2022.107013.
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| 0 | PMC9744709 | NO-CC CODE | 2022-12-15 00:01:54 | no | Environ Impact Assess Rev. 2022 Dec 13;:107013 | utf-8 | Environ Impact Assess Rev | 2,022 | 10.1016/j.eiar.2022.107013 | oa_other |
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Eur J Pediatr
Eur J Pediatr
European Journal of Pediatrics
0340-6199
1432-1076
Springer Berlin Heidelberg Berlin/Heidelberg
4754
10.1007/s00431-022-04754-8
Research
Children’s views on artificial intelligence and digital twins for the daily management of their asthma: a mixed-method study
Gonsard Apolline [email protected]
1
AbouTaam Rola [email protected]
1
Prévost Blandine [email protected]
2
Roy Charlotte [email protected]
1
Hadchouel Alice [email protected]
13
Nathan Nadia [email protected]
2
Taytard Jessica [email protected]
24
Pirojoc Alexandra [email protected]
5
Delacourt Christophe [email protected]
13
Wanin Stéphanie [email protected]
6
http://orcid.org/0000-0002-7324-4992
Drummond David [email protected]
137
1 grid.50550.35 0000 0001 2175 4109 Department of Pediatric Pulmonology and Allergology, University Hospital Necker-Enfants Malades, AP-HP, 149 Rue de Sèvres, 75015 Paris, France
2 grid.413776.0 0000 0004 1937 1098 Department of Pediatric Pulmonology, University Hospital Armand Trousseau, AP-HP Paris, France
3 grid.508487.6 0000 0004 7885 7602 Université Paris Cité, Paris, France
4 grid.418241.a 0000 0000 9373 1902 UMRS1158 Neurophysiologie Respiratoire Expérimentale Et Clinique, Sorbonne Université, INSERM, Paris, France
5 Paris Cité Necker–Cochin Clinical Research Unit, Paris, France
6 grid.413776.0 0000 0004 1937 1098 Department of Pediatric Allergology, University Hospital Armand Trousseau, APHP, Paris, France
7 grid.417925.c Inserm UMR 1138, Centre de Recherche Des Cordeliers, HeKA Team, 75006 Paris, France
Communicated by Peter de Winter
13 12 2022
112
15 10 2022
30 11 2022
5 12 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
New technologies enable the creation of digital twin systems (DTS) combining continuous data collection from children’s home and artificial intelligence (AI)-based recommendations to adapt their care in real time. The objective was to assess whether children and adolescents with asthma would be ready to use such DTS. A mixed-method study was conducted with 104 asthma patients aged 8 to 17 years. The potential advantages and disadvantages associated with AI and the use of DTS were collected in semi-structured interviews. Children were then asked whether they would agree to use a DTS for the daily management of their asthma. The strength of their decision was assessed as well as the factors determining their choice. The main advantages of DTS identified by children were the possibility to be (i) supported in managing their asthma (ii) from home and (iii) in real time. Technical issues and the risk of loss of humanity were the main drawbacks reported. Half of the children (56%) were willing to use a DTS for the daily management of their asthma if it was as effective as current care, and up to 93% if it was more effective. Those with the best computer skills were more likely to choose the DTS, while those who placed a high value on the physician–patient relationship were less likely to do so.
Conclusions: The majority of children were ready to use a DTS for the management of their asthma, particularly if it was more effective than current care. The results of this study support the development of DTS for childhood asthma and the evaluation of their effectiveness in clinical trials. What is Known:
• New technologies enable the creation of digital twin systems (DTS) for children with asthma.
• Acceptance of these DTSs by children with asthma is unknown.
What is New:
• Half of the children (56%) were willing to use a DTS for the daily management of their asthma if it was as effective as current care, and up to 93% if it was more effective.
•Children identified the ability to be supported from home and in real time as the main benefits of DTS.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00431-022-04754-8.
Keywords
Telemonitoring
Digital twins
Paediatrics
Internet of things
Automated decision system
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pmcIntroduction
During the twentieth century, the practice of medicine was transformed by the multiplication of data sources allowing physicians to refine their diagnosis and optimise the management of their patients’ disease [1]. The growing amount of data has two consequences in the first half of the twenty-first century: (i) the multiplication of computational models processing patients’ health data to propose a diagnosis, make a prognosis, and/or recommend a treatment rather than another, grouped under the term “artificial intelligence” (AI) [1, 2]; (ii) the possibility of obtaining, using the internet of things (IoT), a comprehensive representation of the patient’s health status in real time, i.e. a live digital replica of the patient, more commonly known as a “digital twin” (DT) [3, 4]. The combination of AI in DTs could lead to digital twin systems (DTS): DTS comprise a physical element—the patient, a digital element—the patient’s DT, and 2-way interactions between the physical and digital elements: sensors transform the patient’s signal into the patient’s DT, and software processes them to act on the patient’s management through recommendations to the physician or automated adaptations [5]. Compared to existing mobile applications, DTS integrate multiple data sources to provide as complete an assessment of the patient as possible, collect most of the data in real time, and automatically adjust management when possible and alert medical teams when not.
Such DTS are particularly interesting in childhood asthma [6]. Despite effective treatments, clear guidelines, and the efforts from physicians, children, and their families, two-thirds of children with asthma continue to experience frequent asthma attacks resulting in decreased quality of life [7]. A personalised, real-time management of childhood asthma could help prevent asthma attacks in children and obtain better asthma control [8]. New connected objects (connected inhalers, connected smartwatches, etc.) and environmental databases (pollutants, pollens, weather conditions) now make it possible to passively and continuously collect objective and quantitative data on essential determinants of asthma control (adherence to controller treatment, environment, etc.). In the near future, this data can be processed by AI techniques to provide real-time recommendations to children, their families, and healthcare professionals.
While these DTS look attractive from a medical point of view, it is essential to collect the point of view of children and their families before developing such systems. In a survey conducted in France in 2020 before the COVID-19 pandemic, 54% of the 295 parents interviewed were ready to use such systems for the management of their child’s asthma, with socially advantaged parents being more willing to use them [9]. However, we are not aware of similar studies in children with asthma, who will be the first to be affected by this new type of management.
The primary objective of this study was to describe the children’s perception of AI and to assess whether they would accept/prefer a DTS for the management of their asthma compared to their current management by a physician only. Secondary objectives were to identify factors associated with a preference for the use of a DTS among the children interviewed, to collect their opinions on the potential advantages and disadvantages of DTS for the management of their asthma, and to investigate the correlation between the children’s and their parents’ responses.
Methods
Study design and population
A mixed-method study was conducted from June 2021 to May 2022 in three departments of paediatric pulmonology in two hospitals in Paris, France. Children and adolescents aged between 8 and 17 years with a physician-diagnosis of asthma were proposed to participate in a semi-structured interview, and their accompanying parents were invited to complete a survey. All participants provided informed consent. The study was approved by the ethics committee CERAPHP.CENTRE (Comité d'éthique de la recherche APHP Centre-2021-03-04).
The study was conducted in two stages. First, children were asked about their perception of AI in the management of their asthma and then about their perception of DTS in the management of their asthma. In both cases, we used a mixed method with a sequential design: qualitative and then quantitative.
Conduct of the semi-structured interviews
Development of the semi-structured interview guide followed the 5-step process presented in the systematic methodologic review by Kallio et al. [10]. Two of the authors (DD and AG) wrote the first version of the topic guide, which was then tested in three ways: internally (between the authors), with experts in the field (a psychologist and a data scientist from the ethics committee), and after reformulation following comments from these experts, with two children (8 and 11 years old) and a teenager (13 years old) with asthma (field testing). The final guide is presented in the supplemental material (Table S1).
All interviews were conducted face-to-face by the same investigator (AG), who had no prior relation with the children included. After introducing herself and obtaining the consent of the child and his/her parents, the investigator started by asking general questions to the child (age, school level, etc.). Then, the first open questions focused on AI: children were asked about their knowledge of AI and their views on how AI could help in the management of asthma in general. A closed question related to the place of AI in medical decisions regarding their health was associated (quantitative data).
At this stage of the interview, children were given an explanation about DTs integrating AI, using a demonstrator of a DTS interface modifying the asthma treatment of the child based on his/her responses to a short questionnaire equivalent to the Global Initiative for Asthma questionnaire (Fig. 1). Following these explanations, open questions were used to collect the children’s views on the potential advantages and disadvantages of using such a DTS for their daily asthma management. Then, the investigator collected quantitative data using closed questions related to their agreement (or not) to use a DTS for the daily management of their asthma. For this question, children were first asked if they would agree to use a DTS (yes or no). Then, in order to estimate their degree of preference for asthma management by the DTS over their current management by the physician only, they were asked to choose between the two types of management in 5 situations: an imaginary scenario of asthma management by the physician limiting the use of emergency treatment to 10 times per year and an imaginary scenario of asthma management by the DTS limiting the use of emergency treatment to 7, 8, 9, 10, or 11 times per year for each situation, respectively. These situations correspond to differences in effectiveness of + 30%, + 20%, + 10%, 0%, and − 10% for DTS-based management compared to physician-based management. The situation in which participants chose DTS over physician management defined their “strength of preference for DTS”, from 0 (refusal of DTS in all cases) to 5 (choice of DTS even when its effectiveness is 10% lower than that of physician management).Fig. 1 Animation created for the study to show children what the interface of the digital twin system might look like (https://scratch.mit.edu/projects/721368471)
Additional questions were asked about potential explanatory variables of their degree of preference for the DTS. The choice of the variables was based on a review of the literature, and included children’s characteristics (age, gender, school level), asthma severity (assessed using the GINA medication step), perceived importance of the physician–patient relationship, perceived knowledge of AI, concerns about data collection and use, and declared computer skills using scoring systems developed in our previous study [9] and presented in the supplementary material (Table S1).
Finally, to ensure that children understood all the questions related to AI and DTS and provided meaningful answers, the last question of the interview asked children to explain the DTS integrating AI. A custom score ranging from 1 (no understanding) to 4 (ability to explain the DTS in details) was used.
Parental survey
In parallel to the interviews with children, accompanying parents were asked to complete a short survey on their characteristics and on their degree of preference for their child’s asthma to be managed by the DTS compared to their current management by the physician.
Statistical analysis
For the qualitative part, a grounded theory approach was used to develop the codebook. Interviews were transcribed verbatim. Two investigators (AG and DD) independently coded the first 12 interviews, and codes were refined until consensus was reached. The subsequent interviews were then coded using the codebook in blocks of 12, and codes were revised after each turn. Although no new code appeared after the 79th interview (thematic saturation achieved), the investigators coded the remaining interviews because 104 dyads needed to be included for the quantitative analysis. Following an inductive approach, the codes were grouped into categories that were themselves grouped into major themes by AG and DD. Themes were reviewed until no new themes could be identified, tested by looking for confirming and disconfirming cases, and finally sent to all the authors for validation. In terms of researcher characteristics and reflexivity, AG is a junior paediatric pulmonologist, and DD is a senior one, both following children with asthma. However, AG had no previous experience of AI and DTS applications in childhood asthma, whereas DD is developing several research projects linked with these topics and anticipated both the potential advantages and risks of DTS for children [5]. Thus, the analyses were conducted by two researchers with different backgrounds, reducing the risk of a biased analysis of the children’s responses. Inter-rater reliability (IRR) was calculated using Cohen’s κ coefficient.
For the quantitative part, categorical variables were reported as proportions and percentage, and continuous variables were summarised by means and standard deviations (SD). The correlation between the degree of acceptance of a DTS by children and their parents (from the same dyad) was assessed by the Spearman coefficient. To identify the potential causal determinants of agreement to use DTS among children and conduct the appropriate statistical analysis, we used a directed acyclic graph (DAG) [11]. DAGs are an increasingly popular approach for identifying confounding variables that require conditioning when estimating causal effects, decreasing the risk of bias due to over adjustment [12]. We designed the DAG using the freely available software DAGitty v3.0 (http://www.dagitty.net/dags.html) [13] and identified potential determinants of DTS acceptance and their links based on a review of the literature (Supplementary material). The resulting DAG is presented in Fig. 2.Fig. 2 Directed acyclic graph used to identify the total effect of each variable on the agreement to use the digital twin system
From the DAG, the variables needed to estimate the total effect of each determinant were identified using d-separation rules automatically calculated by the DAGitty software. For each determinant, a specific ordinal logistic regression model was used with the corresponding set of adjustment variables.
Analyses were performed with R software (4.1.2), using the MASS package [14].
With 9 predefined potential explanatory variables, and a minimal number of 10 events per variable, 90 interviews needed to be completed to run the ordinal logistic regression model. We estimated that 15% of the parent’s surveys may be incomplete and aimed to include 104 parent–child dyads.
Results
Of the 107 parent–child dyads approached, 104 agreed to participate in the study. Five dyads whose child showed no understanding of the concept of DTS and AI at the end of the study despite the explanations given were excluded from the analysis. Finally, 99 children and their 95 parents (four siblings) were included in the analysis (flow chart in Figure S1). The characteristics of these children and their parents are presented in Tables 1 and S2, respectively. For the qualitative analysis, there were 506 text units coded with 43 different codes. The IRR between the two coders (AG and DD) was κ = 0.98. The mean number of different codes per interview was 5.1.Table 1 Children characteristics
Characteristic Total n = 99
Age (years)—mean (SD) 12.3 (2.8)
Male gender—n (%) 65 (66%)
School level—n (%)
Elementary school 31 (31%)
Middle school 43 (43%)
High school 25 (25%)
Asthma severity (GINA medication step)—n (%)
Step 1 12 (12%)
Step 2 10 (10%)
Step 3 55 (56%)
Step 4 9 (9%)
Step 5 13 (13%)
Perceived importance of the physician–patient relationship (/10)—mean (SD) 7.8 (2.0)
Computer skills (/5)—mean (SD) 3.7 (0.9)
Knowledge of AI (/5)—mean (SD) 2.5 (1.0)
Agreement to the use and process of personal data (/4)—mean (SD) 3.2 (1.0)
AI artificial intelligence, GINA Global Initiative for Asthma, SD standard deviation
Children’ views on artificial intelligence for asthma
The level of understanding of artificial intelligence among participants at the beginning of the study was variable. Quotes from four patients reflect this heterogeneity: “I don’t know at all”; “It’s a robot that is intelligent”; “You have something on your phone, you give him a name, and you can ask it some question like -what is the weather- and it’s going to answer you”; “AI is a computer intelligence that can think by itself, it’s not programmed to tell you this and this, it can think by itself”. Older age was associated with higher knowledge of AI, while, surprisingly, higher parental education level was associated with lower knowledge of AI (Table S3).
When asked about their views on how AI could help manage asthma, 52% of children had no idea. For the remainder, the main themes were that AI could help with the daily management of asthma (by improving adherence, monitoring symptoms, adjusting treatments, providing advice, or predicting asthma attacks), with the development of new solutions for asthma management (new devices/treatments), decrease waiting times for appointments and automate the order of asthma treatments (Table 2).Table 2 Frequency of codes related to opinion on how AI could help in asthma management
Code Representative quotation (translated from French) n = 99
n (%)
No idea I#60 “I have no idea, I don’t know” 51 (52%)
AI is of no interest I#24 “It cannot do anything, it’s just an artificial intelligence” 1 (1%)
AI to help with daily asthma management 41 (41%)
By improving adherence I#18 “Maybe to tell me that I've forgotten to take my medication or to remember to buy this” 21 (21%)
By monitoring asthma control I#21 “To measure asthma”; I#37 “To try to see the state of your asthma, like when we do the PFT”; I#42 “It sleeps right next to me, it tells me when I'm wheezing, when I'm having an asthma attack” 14 (14%)
By regularly adjusting asthma management I#1 “On a daily basis, it could tell me what I need”; I#3 “By recording the asthma data and proposing medication solutions, by doing regular tests”; I#43 “Perhaps by observing whether there is a treatment that might be necessary depending on the daily activity, the sports we play, etc.” 12 (12%)
By providing advice and answers I#25 “By giving advice for example, I#30 “If I ask questions about my asthma, it will answer to my question” 8 (8%)
By predicting asthma attacks I#95 “Something that can predict, based on environmental data, whether you're going to have an asthma attack” 2 (2%)
By replacing an appointment I#58 “Simply to replace an appointment” 2 (2%)
AI to help develop new solutions for asthma management I#11 “It can help to build machines for asthma like inhalers”; I#37 “It can try to find a treatment that can cure asthma” 6 (6%)
AI as a logistical aid 3 (3%)
By optimising appointments I#11 “It could help to reduce waiting times” 2 (2%)
By ordering asthma treatments I#40 “To order some products” 1(1%)
Categories are not mutually exclusive
AI artificial intelligence, I# interview number, PFT pulmonary function test
Children's views on the place of artificial intelligence in medical decisions affecting them
When asked to determine the respective positions of their doctor (human intelligence) and an AI for medical decisions concerning them, 61 children (62%) responded that these decisions should rely only on their physician or essentially on their physician assisted sometimes/often by an AI (Fig. 3). Only 3 (3%) supported the idea of medical decisions based on fully autonomous AI.Fig. 3 Children’s views on the place of the doctor and artificial intelligence in medical decisions about themselves. AI artificial intelligence
Children’s views on digital twin systems for the daily management of their asthma
The potential advantages and disadvantages of DTS identified by the children are presented in Table 3 and summarised below. As the number of respondents was 99, only the percentages are reported, as the number of children is almost identical. Older children (13–17 years old) identified more advantages and disadvantages of using a DTS than younger children (8–12 years old, Table S4).Table 3 Frequency of codes relating to the advantages, disadvantages, and concerns of using DTS
Code Representative quotations (translated from French) n = 99
n (%)
Potential advantages
No idea of any advantage I#21 « I didn’t find any.» 14 (14%)
Remote asthma management 47 (47%)
Decreased number of travels I#6 “We wouldn't have to make the route; we wouldn't have to wake up early this morning” 36 (36%)
Decreased number of visits (follow-up/emergency) I#40 “Fewer visits to the doctor in a year” 7 (7%)
Flexibility of adjustments in time and space I#95 “You can do it whenever you want and where you want” 5 (5%)
Decreased missed school days I#30 “I don’t miss any day of school” 4 (4%)
Virtual doctor at home I#22 “There is a sort of doctor in our home” 2 (2%)
Assistance with daily asthma management 27 (27%)
Adjustment of medication I#1 “If we decide to decrease the treatment and I start to have symptoms, it could tell me if I should increase it (the treatment) or wait a little longer” 12 (12%)
Adherence support I#12 “It could send parents < your child hasn't taken their medication > and it could be taken more often” 11 (11%)
Integration of environmental factors I#15 “It could tell us what we want to know, the allergies, the viruses that are circulating around us”; I#58 “Just to have the air quality” 7 (7%)
Support for the management of asthma attacks I#25 “It could be practical in case of an asthma attack, to know what to do” 3 (3%)
Personalised management I#14 “If we have this application, we can change my treatment depending on what I do” 2 (2%)
Management in real time 26 (26%)
Immediacy, rapidity of the system I#10 “I would say the rapidity” 10 (10%)
Continuous health monitoring I#22 “It looks after my health very often” 10 (10%)
Real-time physician alert I#52 “And if I have an asthma attack, it notifies the doctor directly” 8 (8%)
Better performance than physicians I#4 “It would never be wrong somehow if it's well programmed”; I#13 “It’s going to be smarter”; I#49 “There are things that the artificial intelligence sees that the doctor may not” 9 (9%)
Decreased dependence on the physician 8 (8%)
Visit to the physician only if necessary I#101 “That way I don't have to go to the physician for my asthma when I don't have anything, it will warn me and tell me when my asthma is unwell and then I will go to the physician” 6 (6%)
Autonomy from the physician I#14 “If we have this application, we can change my treatment without having to go to the doctor” 2 (2%)
Potential disadvantages and concerns
No idea of any disadvantage I#7 “No disadvantage” 43 (43%)
No concern I#6 “No, no concern” 54 (55%)
Technical issues related to the embedded AI 52 (53%)
Risk of bug resulting from programming error I#3 “It might get confused and take a basic treatment that might work, but by mistake or miscalculation might forget a detail that could ruin everything”; I#88 “Maybe the AI will bug and tell me to take a medication that I shouldn’t take” 38 (38%)
Risk of a bug resulting from a system failure, virus, or hacking I#11 “It would be nice, but it would be a shame if it broke down”; I#16 “If it crashes sometimes, can this software have viruses inside or should we install an antivirus application?”; I#42 “It can be hacked”; I#67 “Yes, as it’s digitised, it can still crash, if there’s an internet outage, if it’s running over the internet, if the servers are too overloaded, it can crash too” 17 (17%)
Risk of bug (without precision) I#28 “Yes because sometimes it can bug and do weird stuff” 7 (7%)
Loss of humanity 24 (24%)
Difficulty in trusting the embedded AI I#5 “I wouldn't be 100% reassured because an app can't be trusted 100%” 15 (15%)
Human supervision required I#4 “I still think decisions should be validated by a physician” 7 (7%)
Loss of human touch I#58 “There will always be a small difference between having a real consultation and a program, there is something physical that you don’t have” 6 (6%)
Lower performance than physicians 18 (18%)
Physicians are better at handling the unexpected I#10 “I would prefer a human because the human could see other symptoms that are not known to the app”.; I#14 “I think the doctor is better, the robot is programmed to know this, this, this, and may not look for the right thing” 15 (15%)
System unable to replace the physician I#2 “It can be a help, but it can’t be in place of the doctor” 5 (5%)
Uselessness of the system I#33 “I think it’s going to be useless” 3 (3%)
Risks related to the personal data needed to run the DT system I#10 “It can be an invasion of my privacy in terms of health, it takes data, and we don’t really know what the software does with it”; I#16 “Are we sure that the robot could keep the information confidential, that it wouldn’t leak? Imagine there is your address, and someone takes it” 11 (11%)
Risks related to the connected objects required 5 (5%)
Risk of physical harm I#67 “Considering that being exposed to waves is not recommended, if you have to carry it with you all the time, it can have an impact on your health in the long term” 3 (3%)
Risk of fragility I#12 “The disadvantage is that if it's not protected enough it breaks in the pocket” 2 (2%)
Negative impact of the DTS on the development of autonomy I#62 “Well then, if you're too dependent on the application, that means you're not responsible, you're not able to take care of yourself” 3 (3%)
Categories are not mutually exclusive
AI artificial intelligence, I# interview no
The majority of children (87%) reported the advantages of using a DTS. The possibility of remote management of their asthma was the dominant theme (47%). It included the advantages of fewer travels, fewer medical visits, and fewer missed school days. The second main theme was the assistance provided by the DTS in the daily management of asthma (27%), including automated medication adjustment, support to improve adherence and manage asthma attacks, personalised management based on the child’s actions, and the integration of environmental factors into asthma management. The continuous health monitoring offered by the DTS allowing real-time management with immediate alerts from the physician in case of deterioration was the third theme (26%). In summary, the main benefits of the DTS identified by the children were that they could be supported in the daily management of their asthma (i) from home and (ii) in real time.
Children had more difficulty identifying the disadvantages of using a DTS with only 57% providing an example. The main disadvantage identified was the risk of bugs (53%), whether caused by a programming error (38%) or an external cause (virus, hacking) (17%). Then, the loss of humanity was the second main theme (24%): children shared their difficulties in trusting the embedded AI (15%), some asked for human supervision of all decisions (7%), and others regretted the loss of human contact (6%). Several respondents thought that the DTS would perform worse than their physician (18%), with their physician being better able to deal with symptoms and unexpected events than the embedded AI (15%).
Children’s acceptance of a digital twin system for their daily asthma management
Eighty-five percent of children agreed to use a system equivalent to the DTS presented during the interview. To assess their strength of preference for a DTS over their current physician-based management, we asked them to choose between the usual follow-up by their physician and the follow-up by the DTS (Fig. 4). Seven percent never chose the DTS, even when its hypothetical ability to control asthma was 30% better than that of the physician alone. If the DTS was said to be equally effective as the physician, 56% of participants were willing to use it, and this rate increased to 93% if the DTS was said to be 30% more effective than the physician. Even when the DTS was considered 10% less effective than the physician, 23% of children preferred this new type of care. These results were not different between children (8–12 years old) and adolescents (13–17 years old) (p = 0.6).Fig. 4 Respondent’s strength of preference for a digital twin system-based management of childhood asthma compared to physician-based management, using varying levels of effectiveness in achieving asthma control. DTS digital twin system
Parent’s acceptance of a digital twin system for the daily management of their children's asthma
Parents were more reluctant than their children to use a DTS, with 31% saying they would never choose the DTS. However, 43% were willing to use the DTS if it was as effective as the physician, and up to 69% if the DTS was said to be 30% better than the physician’s usual management (Fig. 4). There was no significant correlation between the children’s and their parents’ responses to this question (Spearman’s rho coefficient = 0.17; p = 0.10).
Analysis of factors associated with children’s acceptance of a digital twin system
In the multivariate analysis, children were more prone to choose the DTS-based management if they had high computer skills and less prone to choose the DTS-based management if they valued the physician–patient relationship (Table 4).Table 4 Analysis of factors associated with acceptance of a DTS by children
Variable Adjusted for Odds ratio Confidence interval
Age 1.03 0.91–1.17
Sex (male) 1.56 0.76–3.25
School level Age, parent’s education level
Elementary school 1 (ref) Reference
Middle school 1.13 0.32–4.06
High school 1.21 0.16–9.95
Parent’s education level
No degree 1 (ref) Reference
High school degree 0.42 0.14–1.21
Undergraduate and graduate degree 1.05 0.30–2.81
Agreement to the use of personal data Age, sex, computer skills, AI knowledge, parent’s academic level 1.19 0.80–1.78
Asthma severity (GINA Step) Age, sex
Step 1 (reference) 1 (ref) Reference
Step 2 and 3 1.88 0.77–4.60
Step 4 and 5 2.10 0.73–6.16
Importance of the physician–patient relationship Age, sex 0.82 0.68–0.98
Computer skills Age, sex, school level Parent’s academic level, 2.01 1.26–3.27
Knowledge of AI Age, sex, computer skills, Agreement about the use of personal data, parent’s academic level 1.40 0.93–2.13
AI artificial intelligence
Discussion
The main finding of this study was that half of the children were willing to use a DTS for the daily management of their asthma if it was as effective as current care, and up to 93% if it was more effective. Children reported that the ability to be supported in managing their asthma from home and in real time was the main benefit of the DTS. They also identified risks related to technical problems that might occur, as well as the risk of loss of humanity.
This study supports the idea that children’s views should be taken into account when considering changes in their care at the societal level: discussions were rich, and the advantages and disadvantages of the potential use of DTSs identified by children were similar to those reported by adults regarding the use of AI in medical settings [15]. The understanding of the topic discussed was also good, with only five children unable to simply re-explain the concept of AI and DTS at the end of the interview.
One of the original features of our study is that we compared children’s attitudes towards DTS with those of their parents. We found that parents were less prone to use DTSs than children. However, within the same family, we did not find a correlation between the child’s response and the parents’ response when asked to choose between a DTS and a physician-based management.
There are several hypotheses to explain why children are more prone to use DTS than their parents. A first hypothesis is that children are less aware of the risks associated with the use of a DTS than their parents. A study conducted by UNICEF on the perception of AI by adolescents aged 14–16 [16] showed that the majority of them had little or no understanding of the risks of AI. In our study, when children expressed concerns about DTS, they were similar to those reported by adults [15], but raised less frequently. Acceptance of DTS may be higher among children because they do not perceive their risks as much as adults.
A second hypothesis is that younger people are more used to new technologies and more comfortable with their use, which would explain why they are also more prone to use a DTS. This hypothesis is supported by the results of our study, which identified that a higher level of computer skills predicted a higher strength of preference for the DTS. Being comfortable with the technology might make it easier to see how a DTS like the one presented would work and to not remain in fear of the unknown.
The third hypothesis is that of a profound digital transformation of society. Whereas the previous generation was used to face-to-face consultations, the “digital-native” generation has been raised in an environment of screens, rapid home deliveries, and instant answers from search engines and now virtual assistants. In our study, the main advantages of the DTS identified were that their asthma could be managed (i) from home and (ii) in real time. It is possible that this new generation is ready for a complete paradigm shift in the management of chronic diseases, which would be managed remotely and in real time by connected physicians closer to health engineers than to the image of the family physician.
This change in mentality seems to have been largely reinforced by the COVID-19 pandemic: our team had conducted a similar study [9] among 300 parents of asthmatic children in France between September 2019 and February 2020, during which 45% of them had declared that they would never agree to use a DTS. In our study, only 31% of parents said they would never use a DTS. Between the two studies, there was the COVID-19 pandemic, which forced patients to become familiar with the use of telemonitoring and telecare and spread and established its use among all generations [17, 18].
Nevertheless, the physician–patient relationship remains important for the children and adolescents interviewed. Those who were most attached to this relationship were less likely to choose DTS management. For the majority of respondents, as for the majority of adults [9, 15], AI and DTS remain an additional tool that shall remain under the supervision of their physician.
This study has several limitations. Patients were recruited from two Parisian university hospitals, and the extrinsic validity of our results to the general population of children with asthma remains unknown. In addition, participants were asked about hypothetical scenarios, and it is difficult to say whether their answers would be transposable if they were offered to use a real DTS. Finally, we only proposed a model of DTS that supports remote self-management and did not address the case of DTs with other applications such as personalising patient education.
In conclusion, half of the participating children were ready to use a DTS if it was as effective as usual management by the physician, and this proportion increased to 9 out of 10 children when the DTS was associated with at least 20% better asthma control compared to usual management by the physician. The results of this study support the development of DTS for childhood asthma and open up a new field of research. Future studies will need to determine how best to involve children in the design of DTS, and how to evaluate such systems taking into account both the medical and economic dimensions, as well as the societal and environmental consequences of their implementation.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 151 KB)
Author contribution
Apolline Gonsard and David Drummond contributed to the study conception and design. All authors participated in data collection. Apolline Gonsard and David Drummond analysed the results and wrote the first draft of the manuscript. All authors commented on previous versions of the manuscript, read, and approved the final manuscript.
Availability of data and material
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Code availability
Not applicable.
Declarations
Competing interests
The authors declare no competing interests.
Ethics approval
The study was approved by the ethics committee CERAPHP.CENTRE (Comité d'éthique de la recherche APHP Centre—2021–03-04).
Consent to participate
Informed consent was obtained from all individual participants included in the study.
Consent for publication
Not applicable.
Conflict of interest
The authors declare no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
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8. Guilleminault L et al (2017) Personalised medicine in asthma: from curative to preventive medicine. Eur Respir J 26
9. Abdoul C Parents’ views on artificial intelligence for the daily management of childhood asthma: a survey J Allergy Clin Immunol Pract 2021 9 1728 1730.e3 10.1016/j.jaip.2020.11.048 33290917
10. Kallio H Pietilä A-M Johnson M Kangasniemi M Systematic methodological review: developing a framework for a qualitative semi-structured interview guide J Adv Nurs 2016 72 2954 2965 10.1111/jan.13031 27221824
11. Lederer DJ et al (2019) Control of confounding and reporting of results in causal inference studies. Guidance for authors from editors of respiratory, sleep, and critical care journals. Ann Am Thorac Soc 16:22–28
12. Diemer EW Hudson JI Javaras KN More (adjustment) is not always better: how directed acyclic graphs can help researchers decide which covariates to include in models for the causal relationship between an exposure and an outcome in observational research Psychother Psychosom 2021 90 289 298 10.1159/000517104 34252900
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15. Young AT Amara D Bhattacharya A Wei ML Patient and general public attitudes towards clinical artificial intelligence: a mixed methods systematic review The Lancet Digital Health 2021 3 e599 e611 10.1016/S2589-7500(21)00132-1 34446266
16. United Nations Children’s Fund (UNICEF) (2021) Adolescent perspectives on artificial intelligence. https://www.unicef.org/globalinsight/sites/unicef.org.globalinsight/files/2021-02/UNICEF_AI_AdolescentPerspectives_20210222.pdf
17. Karimi M et al (2022) National survey trends in telehealth use in 2021: disparities in utilization and audio vs. video services. 15
18. Predmore ZS Roth E Breslau J Fischer SH Uscher-Pines L Assessment of patient preferences for telehealth in post–COVID-19 pandemic health care JAMA Netw Open 2021 4 e2136405 10.1001/jamanetworkopen.2021.36405 34851400
| 36512148 | PMC9745267 | NO-CC CODE | 2022-12-15 00:02:23 | no | Eur J Pediatr. 2022 Dec 13;:1-12 | utf-8 | Eur J Pediatr | 2,022 | 10.1007/s00431-022-04754-8 | oa_other |
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Pediatr Cardiol
Pediatr Cardiol
Pediatric Cardiology
0172-0643
1432-1971
Springer US New York
3071
10.1007/s00246-022-03071-z
Article
Implementation of a Regional Oxygen Saturation Thought Algorithm and Association with Clinical Outcomes in Pediatric Patients Following Cardiac Surgery
http://orcid.org/0000-0002-6175-8435
Spaeder Michael C. [email protected]
12
Keller Jacqueline M. 3
Sawda Christine N. 4
Surma Victoria J. 4
Platter Erin N. 1
White Douglas N. 3
Smith Clyde J. 15
Harmon William G. 1
1 grid.27755.32 0000 0000 9136 933X Division of Pediatric Critical Care, University of Virginia School of Medicine, Box 800386, Charlottesville, VA 22908 USA
2 grid.27755.32 0000 0000 9136 933X Center for Advanced Medical Analytics, University of Virginia School of Medicine, Charlottesville, VA USA
3 grid.412998.f 0000 0004 0434 0379 Pediatric Intensive Care Unit, University of Virginia Children’s Hospital, Charlottesville, VA USA
4 grid.239560.b 0000 0004 0482 1586 Division of Cardiology, Children’s National Hospital, Washington, DC USA
5 grid.27755.32 0000 0000 9136 933X Division of Pediatric Cardiology, University of Virginia School of Medicine, Charlottesville, VA USA
13 12 2022
16
6 5 2022
5 12 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Near infrared spectroscopy is routinely used in the noninvasive monitoring of cerebral and somatic regional oxygen saturation (rSO2) in pediatric patients following surgery for congenital heart disease. We sought to evaluate the association of a bedside rSO2 thought algorithm with clinical outcomes in a cohort of pediatric patients following cardiac surgery. This was a single-center retrospective cohort study of patients admitted following cardiac surgery over a 42-month period. The intervention was the implementation of an rSO2 thought algorithm, the primary goal of which was to supply bedside providers with a thought aide to help identify, and guide response to, changes in rSO2 in post-operative cardiac surgical patients. Surgical cases were stratified into two 18-month periods of observation, pre- and post-intervention allowing for a 6-month washout period during implementation of the thought algorithm. Clinical outcomes were compared between pre- and post-intervention periods. There were 434 surgical cases during the period of study. We observed a 27% relative risk reduction in our standardized mortality rate (0.61 to 0.48, p = 0.01) between the pre- and post-intervention periods. We did not observe differences in other post-operative clinical outcomes such as ventilator free days or post-operative ICU length of stay. Providing frontline clinical staff with education and tools, such as a bedside rSO2 thought algorithm, may aide in the earlier detection of imbalance between oxygen delivery and consumption and may contribute to improved patient outcomes.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00246-022-03071-z.
Keywords
Spectroscopy
Near infrared
Heart defects
Congenital
Cardiac surgical procedures
Infant
Newborn
Child
Critical care
==== Body
pmcIntroduction
Near infrared spectroscopy (NIRS) is routinely used in the noninvasive monitoring of cerebral and somatic regional oxygen saturation (rSO2) in pediatric patients following surgery for congenital heart disease [1–3]. Monitoring of cerebral and somatic rSO2 can provide clinicians with insights into regional oxygen delivery and consumption following cardiac surgery [3–8]. Multiple studies have demonstrated associations between rSO2 values obtained following cardiac surgery in pediatric patients and postoperative outcomes such as mortality, ventilator free days, and low cardiac output syndrome [9–12].
For many practitioners, cerebral and somatic rSO2 are viewed as routinely monitored vital signs not unlike mean arterial pressure or arterial oxygen saturation in postoperative cardiac surgical patients. While clear target ranges and treatment approaches to abnormal values are established for several monitored values (e.g., mean arterial pressure) following cardiac surgery, this practice has not fully been extended to rSO2 monitoring [13]. We sought to evaluate the association of a bedside rSO2 thought algorithm with clinical outcomes in a cohort of pediatric patients following cardiac surgery.
Materials and Methods
We conducted a retrospective cohort study of patients admitted following cardiac surgery to the pediatric intensive care unit (PICU) between October 1, 2017, and March 31, 2021, at the University of Virginia Children’s Hospital, an academic, tertiary-care center. The Institutional Review Board for Human Subjects Research at the University of Virginia School of Medicine (Protocol #19035) approved this study. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [14].
We included patients less than or equal to 18 years of age that underwent cardiac surgery with cardiopulmonary bypass (CPB). Additionally, we included patients that underwent cardiac surgery without CPB for the following procedures: pulmonary artery banding, systemic to pulmonary shunting (e.g., Blalock-Taussig-Thomas shunt), and coarctation of the aorta repair.
Multiple surgeries in an individual patient over the course of the study were considered independent surgical cases if they occurred during separate hospitalizations. In the operating room, cerebral and somatic oximetry sensors were placed on the forehead and right flank below the costovertebral angle overlying the right kidney, respectively. Values of cerebral and somatic rSO2 were continuously monitored in the PICU using the INVOS™ oximeter (Medtronic, Minneapolis, MN). Duration of post-operative rSO2 monitoring was at the discretion of the clinical team.
A multidisciplinary group of PICU providers developed the thought algorithm (Supplementary Fig. 1) through consensus agreement. The primary goal of the implementation was to supply bedside providers with a thought aide to help identify, and guide response to, changes in rSO2 in post-operative cardiac surgical patients. The primary bedside nurse was instructed to complete the thought algorithm upon admission to the PICU following cardiac surgery and after initiation stabilization and resuscitation of the patient within the first hour following admission from the Operating Room. Completion of the thought algorithm included establishing baseline cerebral and somatic rSO2 values based on the individual patient’s physiology as well as thresholds that might suggest significant changes in oxygen delivery or oxygen consumption. Orientation to the thought algorithm as well as background education on rSO2 monitoring was provided to PICU staff (nurses, house staff, respiratory therapists, advanced practice providers, and attending physicians) through a variety of mechanisms (e.g., online education modules, in-person lectures) over a two-month period prior to implementation in June 2019. Our primary objective was to assess differences in clinical outcomes over two 18-month periods before and after thought algorithm implementation. We designated the pre-intervention period as October 2017 to March 2019, and the post-intervention period as October 2019 to March 2021, allowing for a six-month washout period from April 2019 to September 2019. During the period of study, there were no changes in the cardiac surgical or pediatric critical care faculty or in the provision of post-operative care of patients following cardiac surgery.
We collected patient and clinical characteristics including age at time of surgery, CPB and cross clamp times, cardiac diagnosis, surgical procedure, delayed chest closure, use of extracorporeal life support, and postoperative ventilator free days (VFD) and PICU length of stay. Postoperative VFDs was defined as the number of days of invasive mechanical ventilation following surgery to postoperative Day 28, with patients who died before Day 28 assigned zero. For the first 48 h following surgery, peak lactate was collected, and peak vasoactive inotropic score was calculated [15]. The Society of Thoracic Surgeons—European Association for Cardiothoracic Surgery Heart Surgery (STAT) mortality categories were assigned to each surgical procedure [16]. Standardized mortality ratios were calculated for the pre-intervention and post-intervention periods using the Society of Thoracic Surgeon Congenital Heart Surgery Database Mortality Risk Model [17].
We performed a sensitivity analysis on the subset of neonates (< 30 days of age) that underwent cardiac surgery with cardiopulmonary bypass to compare several NIRS-derived measures between time periods. Values of cerebral and somatic rSO2 (crSO2 and srSO2, respectively) were continuously captured using the INVOS™ oximeter over the first 48 h following surgery and averaged over 1-min intervals. In addition to average crSO2 and srSO2, we calculated crSO2 and srSO2 desaturation indices defined as the duration of time over the first 48 h following surgery that crSO2 and srSO2 were below 50% [12]. Variability of crSO2 and srSO2 were calculated using the root mean of successive squared differences [18].
Distribution of continuous variables was assessed using the Wilk-Shapiro test for normality. Continuous variables were compared using Student’s T test, Wilcoxon rank sum testing, or linear regression as appropriate. Categorical variables were compared using chi-square test or Fisher’s exact testing as appropriate. Multivariable regression analysis was performed to adjust for confounders. Type I error was set at 0.05. All calculations were performed using STATA/IC 12.1 (STATA Corporation, College Station, TX).
Results
There were 434 surgical cases included in the study with a median patient age at the time of surgery of 3 months (interquartile range 9 days–18 months). The demographic and clinical characteristics of the included patients are listed in Table 1. The distribution of surgical cases over the three time periods was: pre-intervention: 218 cases (50%); wash-out: 91 cases (21%); and post-intervention: 125 cases (29%).Table 1 Patient and clinical characteristics
Characteristic Number (%) or median (IQR) (n = 434)
Age (months) 3 (9 days-18 months)
Female sex 199 (46%)
STAT mortality category
STAT 1 74 (17%)
STAT 2 79 (18%)
STAT 3 67 (16%)
STAT 4 169 (39%)
STAT 5 45 (10%)
CPB time (mins) 152 (94—195)
Cross clamp time (mins) 83 (40–128)
Delayed chest closure 64 (15%)
Extracorporeal life support 15 (3%)
Post-operative PICU LOS (days) 6 (3–11)
Ventilator free days 26 (23–28)
Mortality 13 (3%)
CPB cardiopulmonary bypass, IQR interquartile range, LOS length of stay, PICU pediatric intensive care unit, STAT Society of Thoracic Surgeons—European Association for Cardiothoracic Surgery
Patient and clinical characteristics were compared between the pre-intervention and post-intervention periods (Table 2). Patients in the post-intervention period were younger at the time of surgery than patients in the pre-intervention period (median 1 month vs 3 months, p = 0.03). Patients in the post-intervention period were more likely to have delayed sternal closure (20% vs 11%, p = 0.03). We did not observe differences in peak lactate or VIS in the first 48 h following surgery, VFDs, or post-operative PICU length of stay between the study periods.Table 2 Comparison of patient and clinical characteristics between study periods
Characteristic Pre-intervention period
No. (%) or median (IQR) (n = 218) Post-intervention period
No. (%) or median (IQR) (n = 125) p-value
Age (months) 3 (11 days-18 months) 1 (8 days-5 months) 0.03
Female sex 93 (43%) 62 (50%) 0.21
STAT mortality category 0.11
STAT 1 38 (18%) 16 (13%)
STAT 2 41 (19%) 15 (12%)
STAT 3 33 (15%) 21 (17%)
STAT 4 90 (41%) 55 (44%)
STAT 5 16 (7%) 18 (14%)
CPB time (mins) 157 (94–198) 148 (109–176) 0.43
Cross clamp time (mins) 84 (41–133) 79 (39–117) 0.23
Delayed chest closure 25 (11%) 25 (20%) 0.03
Extracorporeal life support 5 (2%) 6 (5%) 0.21
Peak VIS 8 (7–10) 8 (6–10) 0.76
Peak lactate (mmol/dL) 2.1 (1.6–2.9) 2.3 (1.8–3) 0.09
Post-operative PICU LOS (days) 6 (4–12) 7 (4–11.5) 0.44
Ventilator free days 25.5 (23–27) 25 (22.5–27) 0.28
Mortality 7 (3.2%) 4 (3.2%) 1.0
Standardized mortality rate 0.61 (95% CI 0.16–1.06) 0.48 (95% CI 0.01–0.95) 0.01
CI confidence interval, CPB cardiopulmonary bypass, IQR interquartile range, LOS length of stay, PICU pediatric intensive care unit, STAT Society of Thoracic Surgeons—European Association for Cardiothoracic Surgery, VIS vasoactive inotropic score
The observed mortality rate was identical for both study periods (3.2%). Delayed sternal closure, use of extracorporeal life support and peak lactate were all associated with observed mortality (p = 0.003, p < 0.001, and p = 0.025, respectively). Expected mortality was increased in the post-intervention period (p = 0.012). Controlling for significant confounders, study period, delayed sternal closure and peak lactate were all associated with expected mortality (p = 0.037, p < 0.001, and p = 0.009, respectively). The standardized mortality ratio for the pre-intervention period was 0.61 (95% CI 0.16–1.06) and for the post-intervention period was 0.48 (95% CI 0.01–0.95) (p = 0.01). This difference represents a 27% relative risk reduction in standardized mortality in the post-intervention period.
We included 125 neonates (68 pre-intervention, 57 post-intervention) in the NIRS-based measures sensitivity analysis. We did not observe differences in average crSO2, crSO2 or srSO2 variability, or crSO2 or srSO2 desaturation indices. Adjusting for single ventricle physiology, neonates in the post-intervention period had increased average srSO2 values over the first 48 h following surgery (p = 0.045) as compared to the pre-intervention period. Among neonates with single ventricle physiology, the average srSO2 value increased from 70 to 75% following the intervention.
Discussion
Following the implementation of a bedside rSO2 thought algorithm for pediatric patients following cardiac surgery, we observed a 27% decrease in our standardized mortality rate. We did not observe differences in other post-operative clinical outcomes such as peak VIS or lactate, ventilator free days, or post-operative ICU length of stay. In the cohort of neonates with single ventricle physiology, we did observe an increase in the average srSO2 value following the intervention.
While there are several studies demonstrating the association of rSO2 measures with both invasively measured parameters (e.g., central venous oxygen saturation) and clinical states (e.g., low cardiac output syndrome), there is a paucity of data to support the role rSO2 monitoring plays in impacting clinical outcomes [3–6, 10]. A recently published systematic review and meta-analysis by Hansen et al. included 25 randomized clinical trials involving 2606 adult and pediatric patients randomized to either cerebral rSO2 monitoring or no monitoring [19]. The Authors noted a high risk of bias in reported trials and concluded that the effects on clinical care with access to cerebral rSO2 monitoring versus clinical care without access to cerebral rSO2 monitoring remains uncertain [19].
From a practical standpoint, there are well-defined assessment and treatment algorithms for abnormalities in routine vital signs such as hypotension or hypoxemia. Inherent in this process is the care team’s ability to understand the physiologic property that is being measured by any given vital sign and possess a shared understanding of what that value represents. With rSO2 the interpretation of values may require a more nuanced approach. This characteristic may help explain why the use of NIRS monitoring is still viewed primarily as a trending tool by many practitioners [13]. Irrespective of how the end-user incorporates rSO2 measures into clinical decision making, NIRS is routinely used in the PICU following cardiac surgery, contributing to a lack of equipoise for the conduct of a randomized controlled trial in this population.
Our approach in this study was modeled on the work of Woods-Hill et al. who designed a novel framework to improve blood culture utilization in the PICU [20]. As one of the participating PICU’s in the Woods-Hill study, our team learned the importance of stakeholder involvement in the creation of the algorithm and practical education of the end-users which we integrated into our study approach [20]. We recognized that several processes would be necessary for successful adoption of the rSO2 thought algorithm, including understanding the physiology monitored by rSO2 and the science behind the thought algorithm and suggested clinical pathways [21]. Anecdotally, following our educational efforts and implementation of the thought algorithm, we observed increased attention to, and reporting of, rSO2 values by bedside providers in patients following cardiac surgery.
Our most interesting finding was the decrease in our standardized mortality ratio for the post-intervention period. In a cohort of healthy children who underwent acute normovolemic hemodilution, Fontana et al. demonstrated that significant drops in rSO2 occurred well before changes in lactate were observed [22]. We hypothesize that the monitoring of rSO2 and informed responses to changes to rSO2 contributed to the earlier detection of imbalance of oxygen homeostasis allowing for intervention and improved outcomes. While we did not observe a statistically significant difference in surgical complexity between periods, we did note a 21% increase in the rates of STAT 4 and STAT 5 cases in the post-intervention period which may contribute to the lack of differences observed in post-operative ventilator free days and post-operative PICU length of stay.
We did observe that patients in the post-intervention period were younger and more likely to have delayed sternal closure as compared to the pre-intervention period. We surmise that these differences were highly influenced by the COVID-19 pandemic, the early stages of which occurred during the post-intervention period and was characterized by routine postponement of non-urgent and elective cardiac surgical procedures. Additionally, the pandemic effect likely drove the increase in expected mortality in the post-intervention period. While we did not see an increase in observed mortality with the increase in expected mortality, caution is warranted when evaluating the impact of our intervention on mortality outcomes.
Our study has several limitations, most notably the single-center design and the semi-passive nature of our intervention. While end-users were provided with education on both the principles of rSO2 monitoring and the thought algorithm, we did not mandate or protocolize clinical responses to changes in rSO2 values nor did we attempt to assess knowledge retention over time. It should be acknowledged that our intervention may simply have led to an overall increased level of clinical engagement at the bedside in the post-intervention period, irrespective of rSO2 monitoring. A potential next step would be to randomize patients to a protocolized response versus standard of care. Randomizing to rSO2 monitoring or no monitoring seems impractical in the current practice environment for children following cardiac surgery.
Monitoring of rSO2 in children following cardiac surgery has become routine. Providing frontline clinical staff with education and tools, such as a bedside rSO2 thought algorithm, may aide in the earlier detection of imbalance between oxygen delivery and consumption and may contribute to improved patient outcomes. Future studies aimed at evaluating specific therapeutic response strategies are needed.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (TIFF 9124 kb)
Author contributions
MS conceived the study design, performed all data analyses and wrote the main manuscript text. MS, JK, EP, DW, CS and WH developed the thought algorithm. MS and JK led the thought algorithm education effort and clinical implementation. MS, CS and VS performed data collection and abstraction. All authors reviewed the manuscript.
Funding
None declared.
Declarations
Conflict of interest
None declared.
All work was performed at the University of Virginia Children’s Hospital and the University of Virginia School of Medicine, Charlottesville, VA.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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14. von Elm EAD Egger M Pocock SJ Gøtzsche PC Vandenbroucke JP STROBE Initiative: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies Ann Intern Med 2007 147 573 577 10.7326/0003-4819-147-8-200710160-00010 17938396
15. Gaies MG Gurney JG Yen AH Napoli ML Gajarski RJ Ohye RG Charpie JR Hirsch JC Vasoactive-inotropic score as a predictor of morbidity and mortality in infants after cardiopulmonary bypass Pediatr Crit Care Med 2010 11 2 234 238 10.1097/PCC.0b013e3181b806fc 19794327
16. Surgery SoTS-EAfC (2020) Appendix C: The Society of Thoracic Surgeons - European Association for Cardio-Thoracic Surgery Congenital Heart Surgery Mortality Categories (STAT Mortality Categories)
17. O'Brien SM Jacobs JP Pasquali SK Gaynor JW Karamlou T Welke KF Filardo G Han JM Kim S Shahian DM The society of thoracic surgeons congenital heart surgery database mortality risk model: part 1-statistical methodology Ann Thorac Surg 2015 100 3 1054 1062 10.1016/j.athoracsur.2015.07.014 26245502
18. Spaeder MC Surma VJ Cerebral regional oxygen saturation variability in neonates following cardiac surgery Pediatr Res 2021 90 4 815 818 10.1038/s41390-020-01171-1 32967003
19. Hansen ML Hyttel-Sorensen S Jakobsen JC Gluud C Kooi EMW Mintzer J de Boode WP Fumagalli M Alarcon A Alderliesten T Cerebral near-infrared spectroscopy monitoring (NIRS) in children and adults: a systematic review with meta-analysis Pediatr Res 2022 10.1038/s41390-022-01995-z
20. Woods-Hill CZ Lee L Xie A King AF Voskertchian A Klaus SA Smith MM Miller MR Colantuoni EA Fackler JC Dissemination of a novel framework to improve blood culture use in pediatric critical care Pediatr Qual Saf 2018 3 5 e112 10.1097/pq9.0000000000000112 30584639
21. Keim-Malpass J Kitzmiller RR Skeeles-Worley A Lindberg C Clark MT Tai R Calland JF Sullivan K Randall Moorman J Anderson RA Advancing continuous predictive analytics monitoring: moving from implementation to clinical action in a learning health system Crit Care Nurs Clin N Am 2018 30 2 273 287 10.1016/j.cnc.2018.02.009
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| 36512036 | PMC9745270 | NO-CC CODE | 2022-12-15 00:02:23 | no | Pediatr Cardiol. 2022 Dec 13;:1-6 | utf-8 | Pediatr Cardiol | 2,022 | 10.1007/s00246-022-03071-z | oa_other |
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J Bioeth Inq
J Bioeth Inq
Journal of Bioethical Inquiry
1176-7529
1872-4353
Springer Nature Singapore Singapore
10217
10.1007/s11673-022-10217-4
Original Research
Should Cash Subsidy Be Offered to Family Caregivers for the Elderly? The Case of Hong Kong
Fan Ruiping [email protected]
Yung Lawrence Y. Y. [email protected]
grid.35030.35 0000 0004 1792 6846 Department of Public and International Affairs City University of Hong Kong, Tat Chee Road Kowloon Tong, Hong Kong, SAR China
13 12 2022
113
20 7 2021
10 6 2022
© Journal of Bioethical Inquiry Pty Ltd. 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Hong Kong’s Covid-19 epidemic circumstances have given us a valuable opportunity to reflect on Hong Kong’s elderly care policies. This essay argues that Hong Kong should learn from the West and provide a subsidy to family caregivers for proper elderly care. We rebut the social and moralistic reasons for not introducing such a subsidy in Hong Kong. We indicate that providing cash subsidy to family caregivers does not monetize or tarnish Confucian filial obligation to take care of elderly people, but enable adult children from low-income families to undertake this obligation effectively. In addition, we contend that providing such a subsidy would not significantly affect the job market in Hong Kong and that incurred financial and manpower costs for monitoring family care are controllable.
Keywords
Elderly care
Subsidy for family caregivers
Institutional care
Family care
Confucianism
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The COVID-19 pandemic has posed enormous challenges to the normal operation of elderly care in every society. According to the U.S. Center for Disease Control and Prevention, older adults are at highest risk for severe illness and death with COVID-19, since the risk for severe illness with coronavirus increases with age. It is noted that “8 out of 10 COVID-19 deaths reported in the U.S. have been in adults 65 years old and older” (CDC 2021). In particular, nursing homes are a precarious situation, as more than one-third of COVID-19 deaths reported in the United States are linked to nursing homes (New York Times 2021). Indeed, the safety and security of institutional care for the elderly has been put in jeopardy in almost every developed region since the outbreak. For example, in Sweden, as of November 2020, nearly half of the more than 6,400 COVID-19 deaths were nursing home residents (Reuters 2020). In Spain, as of February 2021, 29,408 elderly persons living in care homes had died due to the virus (El PAIS 2021). Evidently, elderly people residing in nursing homes and other elderly-care institutions are most vulnerable to COVID-19.
Hong Kong seemed exceptional. Until the fifth wave of the epidemic in early 2022, there had not been any big COVID-19 outbreaks among Hong Kong’s residential care homes and there had not been many confirmed cases among their residents. This success had been achieved through the stringent anti-COVID-19 control measures implemented in each elderly residential institution, including the banning of visits by any non-staff personnel, such as family members (Chow 2021). These measures, however, had generated other severe adverse consequences for older people living in the institutions, such as depression, social isolation, loneliness, decline in physical and cognitive function, and increase in dependency, since many services other than direct care had been suspended (Woo 2020). Although the institutions attempted to tackle such undesirable consequences through alternative methods made available by digital technologies (such as providing interaction with family members facilitated by mobile devices using WhatsApp video calls and transfer of images), the outcome was not satisfactory. It was reported that a “loneliness epidemic” had struck elderly residents, and some of them suffered severe mental problems because they had no chance of meeting their family members for many months (Sun 2021).
In contrast, elderly people staying in their own homes were living in a privileged situation. Although they were also restricted by general anti-COVID-19 measures, such as wearing a facial mask and keeping social distance, they were accompanied by their family members, being able to roughly maintain their habitual manner of life. Evidently, during the COVID-19 epidemic, Hong Kong’s family care for the elderly had not encountered a dilemma that its institutional care had to face: on the one hand, if visits by family members were allowed, infection would be increased so that the security of elderly residents would be compromised; on the other hand, if no visit by family members was allowed, security would be enhanced but elderly loneliness and depression would be inflicted.
It might be argued that the stringent management measures were worthwhile because we had a situation of competing values and had to make trade-offs to protect elderly lives. Unfortunately, due to the occurrence of the highly contagious Omicron variant, even the stringent measures taken to combat COVID outbreaks had to fail. Hong Kong’s so-called fifth wave of COVID epidemic occurred in early 2022. As of 28 March 2022, it had claimed 7,207 lives in Hong Kong: 96 per cent of the death toll was aged sixty or above, and 56 per cent of them were linked to residential elderly institutions (Hong Kong Government 2022). Details aside, the latter figure indicates that Hong Kong’s residential elderly institutions, no matter how stringent their control measures, failed to do better than family care in protecting the lives of elderly people in the COVID pandemic.
This situation suggests that institutional care for elderly people is by no means a preferable option to ageing in place in protecting elderly lives in the pandemic. Indeed, Hong Kong’s anti-COVID circumstances give us a new opportunity to reflect on its elderly-care policy regarding institutional care in comparison with family care. In fact, the government of Hong Kong has long proclaimed the policy of “ageing in place” for older citizens. Its underlying principle has been officially announced as “ageing in place as the core, institutional care as back-up” (居家安老為主，院舍照顧為後援) (Elderly Commission 2017, 14). However, the government has seemed only to give lip service to this principle, without implementing necessary financial and social measures to carry it out. Indeed, the government has invested little in community care services and failed to support family caregivers in order for the elderly to age in place. Instead, the government has heavily funded elderly institutional settings, ending up with the highest elderly institutionalization rate among all countries and regions in the world—approximately 7 per cent of its elderly people (aged sixty-five and older) were living in long term institutional care settings in 2020 (Census and Statistics Department 2022; Social Welfare Department 2022; Woo 2020) (see section II for details).
In this paper we will argue that the government of Hong Kong should offer a cash subsidy to family caregivers to facilitate elderly people continuing to live in their own homes if they so wish. In our view, such a subsidy is much needed. It should be offered for at least three general reasons: it is consistent with the governmental elderly-care principle to support ageing in place, it is a good policy to be learned from the West (as it has operated in a number of Western countries), and it is made even more appealing by Hong Kong’s anti-pandemic circumstances in which elderly residents in institutions suffered not only more psychological stress but also a slightly higher death risk than those ageing at home. By the last point, we do not mean to argue that institutional care is only problematic during the pandemic whereas it is preferable over family care in ordinary circumstances. Instead, it is our view that institutional care for the elderly in Hong Kong is by no means preferable over family care in any circumstances in relation to our policy concerns.1
Before we proceed, it is necessary to clarify two relevant points. First, we do not assume that elderly persons cared for at home are always better off than those cared for in institutions. We fully understand that some elderly individuals need institutional care and prefer such care, and there is nothing wrong in the government supporting institutional care. We also do not think that there is anything wrong for Hong Kong to have the highest elderly institutionalization rate in the world. What we think is problematic is that the government has failed to offer adequate support to community care and to family caregivers, whereas it has funded institutional care enormously. This imbalanced configuration of support is particularly problematic when many elderly people receiving institutional care in Hong Kong actually prefer family care if they have a choice. For example, a survey conducted in 2009 found that 73.5 per cent of the 435 respondents who were receiving long term care services in Hong Kong agreed or strongly agreed that they preferred to receive care at home rather than at a residential institution (Elderly Commission 2009, 24). Without assuming that family care is always better than institutional care for every elderly individual, we hold that it is appropriate that the government to offer financial support for elderly care so that elderly preferences can legitimately be satisfied. Offering cash subsidies to family caregivers is one such way.
Moreover, at the outset it is worth noting that although our discussion is only focused on the Hong Kong regulatory context and moral tradition, it also has broad import for other societies, just as many papers addressing Western regulatory contexts and moral traditions have broad import for other places.2 Cross-cultural learning through a specific focus is beneficial. In the case of Hong Kong, we hold that providing cash subsidies to family caregivers has the potential of assisting those elders preferring home care over institutional care to be able to stay home for their elderly lives. We will also argue that there need not be a conflict between a Confucian moral obligation to care for one’s elders and receiving governmental financial support in order to care for them. Instead, such subsidies can effectively help low-income families to discharge elderly-care responsibilities.
II
In fact, a dozen years ago, a proposal to provide cash subsidies to family caregivers was raised in the government-established Hong Kong Elderly Commission but eventually rejected. Specifically, in 2011, the Commission published a formal report (hereafter the Report) thoroughly addressing the elderly care issues facing the city. The Report has disclosed several crucial features of Hong Kong’s elderly care, and these features, in our view, have remained the same up to the present. In short, in our view, there has not been any essential change in Hong Kong’s elderly care policy since the publication of the Report, and neither has there been any serious challenge made to the conclusions or arguments of the Report, such as its rejection of cash subsidy to family caregivers.
As indicated in the report, in 2008 Hong Kong already had the highest institutionalization rate of elderly people (6.8 per cent) in the world when compared to other countries or regions, such as South Korea (1.1 per cent), mainland China (1.73 per cent), Taiwan (1.9 per cent), Japan (2.9 per cent), Singapore (2.9 per cent), Germany (3.7 per cent), United States (3.9 per cent), Ireland (4.0 per cent), United Kingdom (4.2 per cent), Norway (5.5 per cent), Sweden (5.9 per cent), Switzerland (6.4 per cent), and Netherlands (6.7 per cent) (Elderly Commission 2011, 94). Unaffordable housing price and the lack of household space in Hong Kong may have made ageing in place difficult for the elderly, but these have not been the major factors leading to this highest institutionalization rate. As the report admits, among the major factors that pushed up the institutionalization rate were the inadequacy of subsidized community care services (CCS) and the huge amount of the government welfare support to residential care services (RCS) (see below). RCS are provided by the institutional care homes primarily run by non-government organizations or private operators. In contrast, CCS are provided by both governmental and social agents, including homecare, day-care centres, and social centres for the elderly, but do not provide residential services.
Crucially, residential elderly care in Hong Kong is highly subsidized by the government. For example, government expenditure on subsidized RCS in the 2010-2011 financial year amounted to HK$2549 million (providing 24,746 residential places), while the expenditure on CCS was only HK$381 million (covering 7089 serving places only) (Elderly Commission 2011, 5, 76). The government provides financial support to institutional care in two ways. First, it provides direct subvention to non-government organizations as operators of RCS for elderly people to live in. Moreover, the government offers social security payment through its major welfare programme titled “Comprehensive Social Security Assistance” (CSSA) to the elderly opting for private residential care homes, so that they may use the assistance fund for RCS and thereby live in a private elderly care institution. In this way, the government indirectly provides the elderly with RCS. As a result, as the report admits, “there has been a tendency for older people (or their family members) to opt for RCS instead of CCS,” because not only are there not many CCS resources available for them to use, but they are provided with funding for moving to RCS (Elderly Commission 2011, 43). Indeed, private residential care homes provide about 70 per cent of the total supply of beds in Hong Kong’s institutional care, and a substantial portion of their users are the recipients of the CSSA funding (Elderly Commission 2011, 44). Accordingly, the high institutionalization rate of the elderly and the imbalance between residential care service and community care service expenditures and places have been largely due to the enormous government financial support to institutional care instead of community care.
Ironically, the “ageing in place” policy principle was already set by the government as early as in 1977 (Elderly Commission 2011, 50 –51). The Elderly Commission rightly claims that this principle should be upheld in order to avoid premature or unnecessary institutionalization (Elderly Commission 2011, 41). Indeed, this principle is in line with the wishes of the elderly in Hong Kong. As mentioned before, many elders living in institutions would prefer to live in their own homes given the choice (Elderly Commission 2009, 24). The same preference seems to be held by most elderly individuals in all societies. For example, a survey conducted in the United States in 2004 found that more than 90 per cent of American people aged sixty-five and older wanted to remain in their homes as long as possible (AARP 2012, 48). Such findings align with understandings of basic human nature in which the elderly are generally more comfortable living with their families or continuing to live in a familiar environment than moving to a strange elderly institution. Given the reality of the Hong Kong government’s high financial aid to institutional care and low support to community services, we have reason to suspect that there indeed exists significant “premature or unnecessary institutionalization” in the sense that low-income elderly people have been motivated by governmental financial funds to move to institutional care against their preferences for overall good care.
The Report aimed to advise the government on introducing more flexible modes of financing subsidized community care services. In particular, the Report makes recommendations on three aspects of long-term care provision to strengthen CCS in Hong Kong, namely (i) improving the service provision of subsidized CCS and increasing the service volume, (ii) improving the financial mode, and (iii) creating an environment for further development of CCS (Elderly Commission 2011, 11-38). To improve the financial mode, the Report suggests introducing CCS vouchers based on affordability, shared responsibility, and equitable allocation of resources. It also considers the proposal of “providing cash subsidy to family caregivers so to compensate for their employment income forgone due to caring,” making family caregivers a financially viable option to help their elders to fulfil their preferences to age in place. In our view, such a proposal should have been adoptable and justifiable. Unfortunately, the proposal was turned down in the Report.
The Report marshals three reasons why it should be rejected (Elderly Commission 2011, 277-278). The first is on so-called “social and moralistic grounds”:It should be reckoned that in Hong Kong there are still the traditional Chinese cultural norms that emphasize the family’s responsibility of taking care of older family members. There might be the concern that the provision of cash subsidy to family members for taking care of their frail older family members might be construed as monetizing and thus tarnishing such traditional virtue
The second reason has to do with the macro-economic implications and the labour market in particular. The Report refers to the experience of the United States to support its concern: “the provision of cash subsidy to family caregivers may turn out to be a disincentive for people to join the workforce and thus would affect the labour market” (Elderly Commission 2011, 277).
Finally, the Report states that “the institution of monitoring mechanisms would inevitably incur financial and manpower costs, which ultimately would increase the financial burden of public services.” Therefore, the Report concludes that “given that there are still controversies as to the desirability and appropriateness of introducing carer subsidy to family carers, there is need to have prudent consideration on the various issues pertaining to such a suggestion” (Elderly Commission 2011, 278).
III
The so-called “prudent consideration” has been conducted for eleven years now but nothing has been done. In the remainder of this paper, we will rebut the above three reasons given in the Report. Our proposal is that the Hong Kong government should offer cash subsidy to family caregivers as a proper incentive for elderly care, even if it is true that families have a special moral obligation to take care of their elderly members, and recognizing that performing such obligation should not be paid in a salary competitive with other occupations in the market. We argue that the provision of such a cash subsidy to family caregivers would not significantly affect the job market in Hong Kong and that incurred financial and manpower costs for monitoring family care are controllable.
The social and moral grounds for rejecting cash subsidy to family caregivers as cited above seem to consist of two reasons: (i) the traditional Chinese cultural norms that emphasize the family’s responsibility for taking care of older family members are still present and functioning in contemporary Hong Kong society, and (ii) the provision of cash subsidy to family caregivers for taking care of their older family members might be construed as monetizing and thus tarnishing the traditional virtue of filial piety.
We think reason (i) cannot be drawn on to reject the provision of cash subsidy to family caregivers. It is true that most Hong Kong people are still committed to the traditional Confucian virtue of filial piety and taking care of their elderly parents and grandparents in physical, psychological, and/or financial ways. They still believe that they bear a moral responsibility to do so. However, we think the vitality of such family responsibility in Hong Kong society precisely calls for providing financial subsidy to family caregivers in low-income families, because they need the economic support in order to fulfil the responsibility. A caring role under this responsibility is very demanding and the care of family members may come at a significant cost in lost income and employment opportunities. Of course, upper and middle-income families have resources to hire domestic helpers to do the caring work. According to Hong Kong government statistics, the number of households employing domestic helpers increased from 212,500 in 2000 (about 10.1 per cent of all households) to 355,700 in 2019/20 (13.4 per cent) (Census and Statistics 2021). However, low-income families cannot afford to hire domestic helpers. It is not that they reject the cultural norm of filial piety and the practice of looking after their elder members who wish to live in their own home rather than move to an institution, but that they are unable to do so without necessary economic subsidies. In addition, they cannot enjoy tax allowances as middle and upper-income families can (see section IV).
In fact, various forms of income support to family caregivers can be found in countries like Australia, Canada, Ireland, Sweden, the United Kingdom, and the United States. For example, in Canada, the Newfoundland and Labrador’s Paid Family Caregiving Option was introduced in 2014 as a pilot scheme and was approved as a permanent option after evaluation. Under this scheme, subsidies to eligible elderly are provided so that they can pay a family member for approved home support (Newfoundland Labrador Health and Community Services 2015). In Australia, an income support payment called “Carer Payment” provides financial assistance to eligible carers who are unable to support themselves because of the demands of their daily care for someone who has a disability or serious illness or is frail aged (Australian Government 2021). It is subject to income and assets tests. If carers are in employment and their income level reaches the prescribed level, the payment will be reduced. If carers earn more than the upper level of the income test, the payment will stop. Carer Payment also covers non-relative carers and carers who do not live with the care receiver. In addition, a supplementary financial assistance called “Carer Allowance” provides income support to carers who provide daily care at home. Carer Allowance is not taxable or subject to income and assets tests. In 2007, there were 116,614 recipients of Carer Payment, and two-thirds of them were female and more than one third were aged between fifty and fifty-nine years. Only 13 per cent of the recipients had their payment reduced because their income from employment reached the prescribed level of income. There were 393,263 recipients of Carer Allowance in 2007. Over half of the recipients also received other income support payment such as Carer Payment or Age Pension, Parenting Payment, or Disability Support Pension (Australian Government 2008).
In the United Kingdom, a cash award scheme allows an eligible care receiver to opt for cash payment instead of care services so that one can pay their own family member to do the care (Carers UK 2014). The Carer’s Allowance covers non-relative carers and carers who do not live with the care receiver. The allowance is usually below the threshold for paying income tax, but carers who receive the allowance will have to pay tax if they have other sources of taxable income. In the United States, a care receiver can hire a family member (including spouse) as caregiver and pay for the care services received under the Cash and Counseling Program.3
There must be some people in these Western countries still believing and practicing their traditional norms (such as the Judeo-Christian Commandment of “honouring your father and mother”) and undertaking the family’s responsibility of looking after older family members. But the availability of such traditional Western norms has not negatively affected their governments’ decision in setting up subsidies to family caregivers. Accordingly, such Western policies are heuristic to Hong Kong. It is unreasonable to exaggerate “differences” between Western countries and Hong Kong in this regard. Even if more people in Hong Kong than in the West still uphold traditional virtues for the family responsibility, this should not be relevant to the legitimacy of providing a subsidy to family caregivers. For the crucial issue is that Hong Kong should provide such assistance in order to follow its principle of ageing in place as the core, even if families also have moral responsibility to take care of their elderly members. When low-income families are unable to discharge such a responsibility without subsidy, society is justified to provide it, as long as there is no other compelling reason against such provision.
IV
Some may take reason (ii) listed in the Report as constituting such a compelling reason. The central idea of reason (ii) seems to be that the exercise of virtue and cash subsidies for elderly care are incompatible. This idea implies that providing cash subsidies to family caregivers monetizes the traditional Confucian virtue of filial piety, thereby dulling or even destroying the exercise of virtue in Hong Kong society. Accordingly, it concludes that although Western liberal countries may provide such cash subsidies, Confucian Hong Kong should not.
Indeed, while contemporary liberal culture holds that adult children do not have a moral obligation to take care of their elderly parents because they have never agreed to be born in the world and discharge such obligation (English 1992; Daniels 1988), Confucian culture has long emphasized the virtue of filial piety (xiao), upholding such obligation as heavenly mandated or naturally given without the need of any contract to be made. Indeed, Confucian filial piety is not grounded in any man-made contract but is understood to be originated from the Way of Heaven —a manifestation of natural principles for worldly righteousness and for guiding proper human lives and relations (Legge 2010). In the Confucian view, most general and complete Confucian virtue is ren (benevolence), and ren is taken to be rooted in filial piety. Confucius points out in the Analects: “the gentleman devotes his efforts to the roots, for once the roots are established, the Way will grow therefrom. Filial piety and fraternal care are the root of ren” (Analects 1.2). In Confucian tradition, ren is primarily meant for “loving people” (Analects 12.22). However, ren as love does not advocate absolute egalitarian love, but rather differentiated and graded love; namely, that one should love one’s parents and immediate family members more than other people. As Mencius indicates, “one’s capacity of love is not naturally directed to everyone with equal intensity. Your affection for your brother’s baby is not like your affection for a neighbor’s baby, and is rightly so” (Mencius 3A5). Thus, Mencius sometimes stresses that ren is equivalent to loving one’s parents (Mencius 7A15). In the Confucian classic of filial piety, it is clearly stated that “those who do not love their parents but love others are violating virtue; those who do not respect their parents but respect others are violating the rites” (The Classic of Filial Piety 9).
Indeed, in the Confucian view, since everyone is born and grown in the family, love (as the function of the virtue of ren) must be started and learned from the family. Without being able to learn and practice the loving of one’s immediate family members, especially one’s parents, one will not be able to learn and practice the loving of other people. As a result, Confucianism stresses that love should be started from and cultivated in the family and be extended to other people outside the family. As Mencius states, “Treat with respect the elders in my family, and then extend that respect to include the elders in other families. Treat with tenderness the young in my family, and then extend that tenderness to include the young in other families” (Mencius 1A7); “A person of ren extends his love from those he loves to those he does not love” (Mencius 7B1).
It has been generally noticed that Confucian filial obligation towards one’s parents consists of three aspects of work: taking care of their physiological needs, taking care of their mental lives and making them happy, and taking care of their spirits after they die. Moreover, such work should be conducted and guided in terms of Confucian rituals or rites. As Confucius requires, “When your parents are alive, comply with the rites in serving them; when they die, comply with the rites in burying them and in offering sacrifices to them” (Analects 2.5). Finally, in the process of exercising the rituals and performing such work of care, adult children must adopt the important attitude of respect (jing) towards their parents: “those who are considered filial these days are those who are able to provide food to their parents. However, even dogs and horses are, in some way, provided with food. If one shows no respect, where is the difference?” (Analects 2.7).
This long-standing Confucian ethic of filial piety is still vibrant in Confucian-influenced East-Asian societies, including Hong Kong (Cheung and Chow 2006; Li 1997; Nie 2015; Qiu 2004; Yu 2007; Yung 2015). This ethic has significant policy implications. Scholars have argued that Confucian filial obligation should be adopted to formulate appropriate long-term care policies for elderly people in these societies, and such policies should be made in ways in which adult children are encouraged, facilitated, and assisted to exercise this virtue and take care of their elderly parents (Wang 1999; Chong et al. 2006; Chong and Liu 2016; Engelhardt 2007; Fan 2006 and 2007; Tao 2007; Chow and Ho 2014). As mentioned above, the Report acknowledges that the elderly in Hong Kong prefer to live in their own home rather than in an institution (Elderly Commission 2011, 43) and Confucian filial obligation and respect would require adult children to give assistance to their elderly parents for them to live in their own home if they so wish. When low-income families do not have finance or space to hire a domestic helper to meet this need, the only option would be for an adult child or other relative to stay with the elderly and offer needed care. But this child or relative would need a subsidy to support them in order to do so. Should the government offer such subsidy? Does it, if offered, monetize the virtue of filial piety as reason (ii) charges?
We think this charge is untenable. Properly provided cash subsidies to family caregivers cannot change the moral nature of the obligation under the virtue of filial piety. No doubt, “monetizing” is often a derogatory term. When one says “monetizing something,” it is usually meant that one wants to make money from it, or that one wants to express its nature in terms of money or currency when one should not. However, when cash subsidy is properly set at an amount lower than the market price of similar work for an adult child or relative to care for one’s parent or an elderly relative at home, he or she would hardly be motivated by a “money-making” intention to undertake the care work under such subsidy arrangement, because such an intention would be satisfied much better by doing something else in the market. Moreover, caring for the elderly is by no means an easy or interesting task. It engages tedious routine work and requires the spirit of love, care and dedication as well as enthusiastic and constant efforts. Provision of a small amount of cash subsidy to family caregivers by no means changes the expression of the moral nature of such work into that of money or currency.
Finally, although there is no such subsidy offered currently in Hong Kong, the government offers tax allowances under the Additional Dependent Parent and Dependent Grandparent Allowance policy to encourage adult children to give financial assistance to their parents or grandparents. Under this policy, eligible taxpayers can claim the basic Dependent Parent and Dependent Grandparent Allowance for each dependent parent or grandparent (Inland Revenue 2022). Moreover, adult children who live with their dependent parent or grandparent can claim the Additional Dependent Parent and Dependent Grandparent Allowance, which is the same amount as the basic Dependent Parent and Dependent Grandparent Allowance. As a result, an eligible adult child who lives with a dependent parent or grandparent can claim twice more allowance than another person who does not live with his or her dependent parent or grandparent. In 2018, the total labour force in Hong Kong was 3.98 million and only 47 per cent of the working population were required to pay salaries tax (Inland Revenue 2019). Such tax papers must belong to middle- and upper-class people in Hong Kong. Although we cannot find a formal figure about how many taxpayers claim such allowances, we trust that the figure is big. Obviously, such allowances do not benefit two million low-income employees nor other unemployed people. If such tax allowances do not monetize the virtue of filial piety on the part of middle- and upper-class children (as we believe they do not, because such children could still gain more money for themselves if they do not offer financial assistance to their parents or grandparents), cash subsidy to family caregivers for the low-income group does not either.
Indeed, teachers, social workers, and civil servants (including policemen and firefighters) are all paid for their work. The monetary reward does not compromise the moral obligation borne by such work. Although familial obligation is a special moral obligation that does not arise from a contract for profit, society should offer a subsidy to family caregivers as a proper support and incentive for low-income families to be able to discharge the obligation. It can be construed as playing the same function as the above-mentioned tax allowance for middle- and upper-income families to support their parents and grandparents. As long as such subsidy is set at a lower rate than the salary of a relevant job in the market, it can help to ensure that the primary motive of a family caregiver is filial piety, love, and respect for their elders, rather than making money.
Nevertheless, some may contend that even if cash subsidy does not monetize the virtue of filial piety, it may still tarnish the virtue in other ways, as the Report seems to suggest. First, they may argue, isn’t it likely that providing cash subsidy would generate free riders so as to corrode the virtue? That is, some adult children may apply for the cash subsidy to gain the “available” money, but they will not actually do the work of taking care of their elderly members (just as they have no interest to do any useful work in the market to support themselves, either). In this way, they may conclude, the society would have paid the financial cost for these individuals in vain while the virtue of filial piety is corrupted. Of course, we cannot exclude the possibility that there will be, no matter how few, such free riders in Hong Kong society, just as any financial arrangement may have to face this problem. However, the possible damage of such free-rider behaviour on the virtue of filial piety can be prevented or reduced through appropriate designment, management, and supervision of cash subsidy provisions in the society. In this regard, Hong Kong should learn from the experiences of other countries in adopting certain checks and balances applicable to the provision of carer cash subsidy. For example, in Australia, fraudulent carer’s payments can be reported to the police and will be investigated as welfare fraud (Australian Government 2021). In Ireland, fraudulent carer’s payments will be investigated and, if persecuted, will lead to sentencing and compensation to the state (Heylin 2021).
In addition, the virtue of filial piety may be dulled in another way in the eyes of objectors. In Chinese society, it is admirable and honourable to offer good care to one’s elderly parents and grandparents without seeking any financial benefit. It is also claimed that in traditional societies only honorary but not economic incentives were offered to reward the virtue of filial piety. Thus, the objectors may conclude, if certain cash subsidies are offered to family caregivers, the honourable meaning of care work would be discounted, and family caregivers may even be seen as conducting the work for the sake of money rather than love or virtue, so that they will fear ill-reputation and thereby will not apply for such subsidies. As a result, the subsidy policy will not encourage suitable children or relatives to become family caregivers, thus the traditional virtue will be ill-served and even stained.
We do not think this is likely to happen. First, it is a misunderstanding that traditional Confucian societies offered only honorary incentives but not economic or financial ones to encourage filial piety. True, Confucian tradition upholds honouring elderly people in general ritual performance and praises those children who take good care of their older family members. But it is also true that governments offer economic facilities to families with older members. For example, in the Confucian classic of rites (Liji), it is recorded that Confucian sages not only used ceremonial rituals to nourish and entertain elderly persons, but also formulated assisting regulations to help families in taking care of their elders: for instance, if a family has an eighty year old, one of the sons would be free from all duties of government service; if a family has a ninety year old, all family members would be free from such duties (Liji 5). Throughout traditional Chinese dynasties, there have always been relevant statues and regulations that offer tax allowances or relieve governmental levies for families with elderly members (Tang and Chan 2014, 68–94). In short, people in traditional Confucian societies have never held that giving certain economic or financial support to families for looking after their elderly members would discount the honourable meaning of their care work so as to stain the virtue of filial piety.
Moreover, contemporary societies differ from traditional agricultural ones in the delivery of elderly care. In traditional societies, families conducted agricultural work and lived near the farm to do the work. If governments refrained from levying their young members from the family, they could care for their elders while conducting their work, without suffering work–care imbalance. Accordingly, relieving families from governmental levies would be an enormous help in traditional society. In contrast, the employment setting of contemporary society is much more demanding on employees, who will normally have to commute to work on fixed time schedules, and overtime work is a commonplace. As a result, the incompatibility between work requirements and family obligations becomes the root of many social problems, including parental neglect or poor parent–child relationships.4 Accordingly, offering cash subsidies to low-income families for elderly care in contemporary society is in a sense analogical to relieving governmental levies from families in traditional society: one is thereby able to stay home and take care of one’s elderly parents or grandparents. With such subsidies, some individuals from low-income families would be able to take care of their elderly relatives at home, without having to work in the market for an income. They will still be honoured rather than ill-reputed because they will be understood as giving up a better salary for taking care of their elders at home. The honourable meaning of their care work cannot be depreciated.
V
In addition to the worries about the erosion of the virtue of filial piety, the Report mentions two other negative implications that may likely be generated by the provision of cash subsidy, one for the labor market, and other for the public finance. This section will briefly tackle these issues and indicate that they do not constitute sound reasons against providing cash subsidies to family caregivers in Hong Kong.
The Report states that the provision of a cash subsidy to family caregivers may encourage people to become family caregivers and thereby withhold or withdraw from the labor market. Therefore, such provision, it is argued, would turn out to be a disincentive for people to join the workforce and thus would negatively affect the labor market. We think this worry is ungrounded. First, the subsidies should only be given to those caregivers who are from low-income families, not to any from middle- or upper-income families. Some may want to argue that such subsidies should extend to middle-income families to incentivize more individuals to stay at home and provide care for their elderly members. We do not think equity consideration supports such extension. Even if tax allowances are insufficient for the middle-income to provide home care, most of them are already capable of hiring domestic helpers to do the work at home. Providing support to low-income families is much more necessary and urgent.
Moreover, it is unlikely that many individuals from low-income families would prefer to become full-time family caregivers primarily for the sake of the money offered by such subsidies, since the money from such a subsidy would be lower than a salary one may obtain from the market. In addition, full-time, intensive caregiving for an elderly family member is a highly time-consuming and emotionally draining work. Such subsidies would only attract those individuals who are virtuously willing to take care of their elderly relatives at home for a minimal income support. Finally, providing cash subsidies to low-income family caregivers would not significantly affect the job market because ever-increasing automatization and the use of robots in the workplace have begun to replace more and more low-skill workers. Unemployment would inevitably grow when individuals cannot migrate from low-skill work to mid-skill or high-skill work. Although the government should offer unemployment aid, new training and reskilling programmes for such individuals, providing them the opportunity to become family caregivers through subsidies would also be a valuable way to assist them while improving the elderly care of the society.5
The Report fears that providing cash subsidies would incur financial and manpower costs, which ultimately would increase the financial burden of public services. We think this depends on how subsidy provisions are designed and monitored. First, a means-test mechanism must be enforced. As a necessary condition for becoming a family caregiver to receive a subsidy, a qualified person must be from a low-income family. Moreover, the amount of such subsidy should not be more than the amount of the welfare fund (namely CSSA in Hong Kong) that an older adult has received or is going to apply for institutional elderly care. In the financial year 2017–2018, the government spent as much as HK$257.6 million in CSSA for elderly people to pay for their institutional care (Hong Kong Government 2019). Such huge amount of payment in CSSA can be significantly reduced if cash subsidies to family caregivers are adopted. They will be saved and used instead for family care, without increasing total governmental budget. Accordingly, in the long run, the provision of such cash subsidy will not be a significant drain on public resources, as the demand for residential care services funded directly or indirectly by the government will not be significantly increased since more elders will live with their families and be cared for by family caregivers. Furthermore, regarding concern about the bureaucracy and manpower that would be required to monitor the wellbeing of the elderly at home, although we cannot contend that no such costs would be incurred, we trust that they would not be uncontrollable. As the government has already managed and monitored the operation of CSSA payment for elderly care in the current system, available civil servants from welfare departments and social workers could also serve to manage and monitor family caregivers for the care of the elderly at home. At the end of the day, even if the society would have to increase a bit more management costs than now by ensuring the accountability of the means-test administration and the monitoring of care quality in operating such subsidies family care, it remains worth doing because it can help meet elderly preferences, avoid unnecessary or premature institutionalization, and fulfil the governmental principle of “ageing in place.”
If anyone charges us for showing little understanding of and concern with the burden, risk, and plight of the family caregivers, most of whom come from a low-income background in Hong Kong, that would be a misunderstanding. We certainly advocate that more assistance be offered to support family caregivers in Hong Kong, including setting up governmental programmes designed for their education and skills training, environmental modification, care management, counselling, and respite care as offered in many other societies, although we do not have space to address them in this essay. But these measures by no means contradict our suggestion that monetary subsidies be offered to them in the first place. The reality is that many of them are already offering care for their elderly family members while living in financial difficulty but receiving no subsidy at all. That is why many have to apply for a special welfare fund (such as CSSA for institutional care) to send their elders to an institution against their preferences.
Would a subsidy as proposed lead to an exploitation of the poor but an unjust benefit to the rich? Some might be concerned that under such subsidies, the poor would have to care for their elders at home, being paid below market rate for the work, while it takes away the opportunity to compete for more well-paying positions that may alleviate poverty. At the same time, the objectors would add, the well-off hire domestic helpers to take care of the elderly in their home, not being burdened with caring for their elders, and continue to have the opportunity to be economically active. We think this is also a misunderstanding. First, no matter whether such a subsidy is offered to the poor, the rich remains living the way as they do. Thus, it is nonsensical to believe that providing such a subsidy would unjustly benefit the rich. Moreover, we recommend that the government continue to offer CSSA for institutional care. This means low-income families can continue to apply for it if they so wish. Thus, the proposed subsidy provides an additional option to gain funding for those who wish to take care of their elders at home. To offer such an additional option to the poor cannot constitute an unjust exploitation of them, because they have freedom not to choose it. Indeed, by providing such a subsidy, no person from a low-income family would be forced upon the caring work presently done by institutions, because everyone would have as much freedom to go to the market to improve their economic situation as before.
VI
Hong Kong is an ageing society. Its elderly people (aged 65 and older) made up 19.1 percent of its 7.5 million population in 2020 (Census and Statistics Department 2022). The COVID-19 pandemic has given us a valuable opportunity to reflect on Hong Kong’s elderly care policies. To facilitate ageing in place, the government should provide some form of income support to the family caregivers who are unable to support themselves because of the demands of their caring roles. This paper argues that the provision of a cash subsidy to family caregivers to meet their living expenses is a morally justifiable policy option to pursue ageing in place, thus avoiding unnecessary or premature institutionalization of the elderly when most of them prefer to live in their own home. We should learn from Western experiences in offering such a subsidy.
We rebut the social and moralistic reasons for not introducing cash subsidy to family caregivers. Confucianism upholds an adult child’s moral obligation to take care of their elderly parents, and this obligation includes giving necessary assistance to their parents in order to realize their wish for ageing in place. To provide cash subsidy to family caregivers does not monetize or tarnish this moral obligation. Instead, it can enable adult children from low-income families to take care of their older family members at home if they so wish. Of course, we do not mean to suggest that no other social or communitarian services be needed at the same time for improving elderly care in Hong Kong. Neither have we explored detailed policy measures regarding which relatives are qualified to be family caregivers, how much a subsidy should be offered, and how it should be offered. These will require additional research.
Declarations
The authors declared that the paper did not involve the use of animal or human subjects.
1 Most institutionalized elders in Hong Kong are financially supported by the government, but they live in private institutions (see section II). The care quality of such institutions varies from one to another. Poor management, low-quality care, and even abuse cases in some institutions have been reported; see, e.g., a newspaper report from December 2, 2020, at http://www.takungpao.com.hk/news/232109/2020/1202/527155.html. Lacking sufficient comparative studies, this paper does not make any general assumption that elderly people in institutions are better off—or not— than those ageing in their own homes.
2 Indeed, as one of this journal’s anonymous reviewers on an earlier draft of this paper rightly notes, much of our argument and conclusion are applicable to a broader audience, while our effective rebuttal to the idea (that receiving financial support to care for one’s elders is incompatible with the Confucian virtue of filial piety) is of specific value to improving the situation of Hong Kong for elderly care.
3 The Cash and Counseling Program is administered by the National Resource Center for Participant-Directed Services (NRCPDS). The programme began in fifteen states and then expanded to at least forty-three states. It is also referred to as Consumer Direction, Participant Direction and Self Direction Care. See http://www.payingforseniorcare.com/longtermcare/resources/cash-and-counseling-program.html.
Moreover, recent studies have shown that the supply of unpaid family caregivers in the United States will become limited, and paid caregivers will be needed to take up the slack (Osterman 2018).
4 Hong Kong passed the Family Status Discrimination Ordinance in 1997 to protect people from discrimination on the basis of family status. This Ordinance applies to seven different areas: employment, education, provision of goods, facilities or services, disposal or management of premises, eligibility to vote for and to be elected or appointed to advisory bodies, participation in clubs, and activities of government. See https://www.elegislation.gov.hk/hk/cap527!en. We see this ordinance as necessary but not sufficient for the sake of proper elderly care. Providing cash subsidy to family caregivers is particularly necessary.
5 The Report suggests that the experience of the United States in family caregiving has macro-economic implications, especially on the labour market (Report, Paragraph 277). However, a recent American report (based on a systematic national research project) concludes that such implications are generally neutral: “Nearly one-third of family caregivers, and nearly one-half of family caregivers who provide intensive care without help from others, are ages 65 and older, and thus unlikely to work if they did not serve as family caregivers. The available empirical evidence suggests that relatively few younger caregivers would increase their labor supply much if they did not provide care.” Meanwhile, this document emphasizes that “Family caregivers provide invaluable assistance to older adults with disabilities, improving the quality of their lives and allowing many to live independently and delay or avoid expensive nursing facility care” (U.S. Department of Health and Human Services 2020).
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| 36512152 | PMC9745271 | NO-CC CODE | 2022-12-15 00:02:24 | no | J Bioeth Inq. 2022 Dec 13;:1-13 | utf-8 | J Bioeth Inq | 2,022 | 10.1007/s11673-022-10217-4 | oa_other |
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Bull Environ Contam Toxicol
Bull Environ Contam Toxicol
Bulletin of Environmental Contamination and Toxicology
0007-4861
1432-0800
Springer US New York
3638
10.1007/s00128-022-03638-9
Article
Suspended Particulate Matter Analysis of Pre and During Covid Lockdown Using Google Earth Engine Cloud Computing: A Case Study of Ukai Reservoir
Paul Arnab 1
K.S. Vignesh [email protected]
2
Sood Atisha 2
Bhaumik Swastika 3
Singh Kunwar Abhishek 3
Sethupathi Sumathi 4
Chanda Arunima 5
1 grid.466780.b 0000 0001 2225 2071 Indian Institute of Remote Sensing (IIRS), ISRO, 248001 Dehradun, Uttarakhand India
2 School of Public Health, SRMIST, 603203 Chennai, Tamil Nadu India
3 grid.429017.9 0000 0001 0153 2859 Indian Institute of Technology (IIT), 721302 Kharagpur, West Bengal India
4 grid.412261.2 0000 0004 1798 283X Universiti Tunku Abdul Rahman, Kampar, Perak Malaysia
5 grid.411818.5 0000 0004 0498 8255 Jamia Millia Islamia, 110025 New Delhi, Delhi India
13 12 2022
2023
110 1 730 9 2021
14 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Presence of suspended particulate matter (SPM) in a waterbody or a river can be caused by multiple parameters such as other pollutants by the discharge of poorly maintained sewage, siltation, sedimentation, flood and even bacteria. In this study, remote sensing techniques were used to understand the effects of pandemic-induced lockdown on the SPM concentration in the lower Tapi reservoir or Ukai reservoir. The estimation was done using Landsat-8 OLI (Operational Land Imager) having radiometric resolution (12-bit) and a spatial resolution of 30 m. The Google Earth Engine (GEE) cloud computing platform was used in this study to generate the products. The GEE is a semi-automated workflow system using a robust approach designed for scientific analysis and visualization of geospatial datasets. An algorithm was deployed, and a time-series (2013–2020) analysis was done for the study area. It was found that the average mean value of SPM in Tapi River during 2020 is lowest than the last seven years at the same time.
Keywords
SPM
Covid
Remote sensing
Landsat 8
GEE
issue-copyright-statement© Springer Science+Business Media, LLC, part of Springer Nature 2023
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pmcIntroduction
Rivers are the dominant source of fresh water, even though water covers 70% of the earth’s surface. The river waters are subjected to a high rate of pollution owing to the disposal of domestic sewage and industrial effluents and so on. Furthermore, climate change, increasing population and other anthropogenic factors have escalated the freshwater crisis. Water Resources Management is the immediate need to optimize the available natural water flows. Artificial reservoirs are constructed for various purposes like irrigation, power generation, flood control, etc. Rivers carry pollutants and sediments and eventually deposit them in reservoirs. Sedimentation is an essential factor that threatens the sustainability and longevity of reservoirs. It reduces the storage capacity of the reservoir. Besides, water quality is an important parameter that needs to be evaluated from time to time for sustainability for aquatic organisms and human beings. Various parameters determine the water quality, such as DO, BOD, COD, pH, turbidity, ammonia, etc. DO or dissolved oxygen is a very important measure of water quality as it impacts the phytoplankton health, algal growth sustainabilty (Gorde and Jadhav 2013). Biochemical oxygen demand or BOD is the measure of the amount of biodegradable organic material present in the water. COD or chemical oxygen demand is the amount of oxygen required to oxidise all the substances (even biologically decomposed) in is the water (Chandra, 2012) and a very useful tool for contamination monitoring. pH is a very well known parameter for water quality. Any water sample below or above pH 7 is a indication of water contamination.
Turbidity measures the amount of total suspended organic and inorganic materials in water (Giardino et al., 2017). It is an optical property and has a relationship with the reflectance in water bodies (Sravanthi et al., 2013). Several studies (Garg et al., 2017, Doxaran et al., 2002) have reported an increase in reflectance in the visible region (red region) with an increase in turbidity. Apart from anthropogenic processes, several natural processes also like floods and erosion, influence the amount of suspended sediments in the water column. The suspended sediments reduce the penetration of sunlight which lowers the primary productivity. Toxic metals and organic matter can get associated with suspended sediments causing eutrophication and water pollution (Point et al., 2007; Stoichev et al., 2004). Thus, turbidity can be used as an indicator of water quality. Suspended particulate matter (SPM) is one of the key water quality parameters for assessing the pollution of a waterbody. SPM causes a range of aquatic discomforts and plethora of environmental damage (Dersch, 1986) including problems such as benthic concealing, irritation of fish gills and hindrance of light for photosynthesis etc. (Davies-Colley, 2002). The presence of SPM in a waterbody or a river can be caused by multiple reasons such as other pollutants by the discharge of poorly maintained sewage, siltation, sedimentation, flood and even bacteria.
Before the advancement of remote sensing, early literatures used secchi disks to measure the water transparency. It was very time and cost-consuming as well as the extension of coverage was very restricted. Remote sensing methods made it easier for the researchers to overcome all these hurdles by establishing the relationship between water-leaving reflectance and turbidity (SPM) (Curran et al., 1987). It has been well-established that with increasing turbidity, reflectance is also increasing. Doxaran et al. (Doxaran et al., 2002) showed that the reflectance from 400 to 1000 nm increases with turbidity. Wei et al. (Wei et al., 2021)the inferred in SPM study that the ascending order of the reflectance is proportional with the increasing turbidity. This kind of empirical algorithms are used in multiple successful studies using linear, log-linear and exponential relationship between the satellite images and reflectance (Yunus et al., 2020; Nechad et al., 2010; Doxaran et al., 2002; Tassan, 1994). A wide range of satellite sensor data has been used to estimate aquatic turbidity or Total Suspended Matter (TSM) globally such as SeaWiFS,Resources ats, VIIRS, Landsat, Resourcesat-2, and recently launched Sentinel − 3 satellites (Wei et al., 2021; Chander et al., 2018; Doxaran et al., 2002; Tassan, 1994). This study has used the Landsat 8 data to analyse and assess the SPM algorithm.
The new decadeof 2020 saw the outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or COVID-19, although it was initially reported in December 2019 in the Wuhan province of China. The first case in India was reported on 30th January 2020. It started spreading at a rapid rate, being highly transmissible. In March 2020, the World Health Organisation (WHO) declared COVID-19 a pandemic (Gupta et al., 2021; Sood et al., 2020b). In order to combat the contagion of the deadly virus, unprecedented measures were taken (Sood et al., 2020a). A nationwide 21-day lockdown was initially imposed from 25th March 2020, which got extended until the end of May, and subsequently unlock started from June. All industrial, transportation, and anthropogenic activities were restricted to some extent. For the past few decades, anthropogenic activities have been one of the primary sources of pollution in various compartments of the Environment (Barwal et al., 2020; Gao et al., 2018). A positive effect of the lockdown on the Environment in terms of improvement in air quality (Gautam et al., 2020; Lokhandwala and Gautam, 2020, Chauhan and Singh, 2020; Collivignarelli et al., 2020; Dantas et al., 2020; ) and water quality (Braga et al., 2020, Garg et al., 2020, Yunus et al., 2020, Lotliker et al., 2020, Mishra et al., 2020, Chakraborty et al., 2021) was reported. According to Sun et al. 2021, high-frequency remote sensing assessment of Wuhan lake, China has shown a steep 16% decline in mean turbidity. Tripathi et al., 2021 have shown that near Patna, Bihar where the discharge of industries and sewage is highest has a witnessed rapid decrease of sedimant concentration in the lockdown period. An extensive study (Kumar et al., 2021) has been done on the Ganga river with Sentinel-2 satellite data. Multiple points over the entire course of the river for Chl-a, CDOM, and TSM is taken. The study revealed that the Covid-19 lockdown has a very vivid effect on the water quality and hence quite assuredly inoftion over the different water bodies may have impactful results overall.
During the lockdown period, field data could not be collected, so remote sensing techniques were used to determine the changes in the Environment. The parameters which represent water quality are chromophoric dissolved organic matter (CDOM), suspended particulate matter (SPM), and Chlorophyll-a (Chl-a). In this study, remote sensing techniques were used to understand the effects of pandemic-induced lockdown on the suspended particulate matter (SPM) concentration in the lower Tapi reservoir or Ukai reservoir. The estimation was done using Landsat-8 OLI (Operational Land Imager) having radiometric resolution (12-bit) and a spatial resolution of 30 m. The Google Earth Engine (GEE) cloud computing platform was used in this study to generate the products. The GEE (cloud computing platform) is a semi-automated workflow system using a robust approach designed for scientific analysis and visualization of geospatial datasets. There is a massive data catalog made up of Earth-observing remote sensing and imagery many other environmental, geophysical, and socio-economic datasets (Gorelicks et al., 2017). An algorithm was deployed, and a time-series (2013–2020) analysis was done for the study area. GEE has proven to be an important tool for policymakers and researchers through plethora of standpoints. Enormous data storage with versatile data types (social, demographic, DEM, climate data) (Mutanga 2019). The applications of the GEE cloud computing platform cover the gargantuan spectrum of scientific and sociological arrays such as vegetation mapping (Poortinga et al. 2018), landcover mapping (Lee et al., 2018), agricultural applications (Aguilar et al., 2018), earth and meteorological observation (Sproles et al., 2018), disaster management (Lobo et al. 2018). In summary, the possibility of handling, monitoring, mapping huge data, and automating programs for operational level becomes easier with GEE and this has turned out to be a huge upgrade for combatting environmental problem. The list of studies have been launched globally to compare the status of air, ,water, soil and other sociological, economical and industrial standpoint before and after Covid-19 (Shami et al. 2021). Very few, among the aforesaid literatures rarely targeted the sediment problems and status of any river choked by the pollutants in the previous years (Sun et al. 2021) in India (Kumar et al., 2021; Tripathi 2021) that too with a different approach such as cloud platform workframe.
In this study, the main focus is finding the intensity of sediment deterioration of an extremely polluted river of India during the shut down phase of the nearby industrial plants during the 1st phase of Covid-19 lockdown. Our another aim is to establish the GEE as an impactful tool for the assessment of pre and during covid situation for the environmental managers, scholars and researchers for there respective studies.
Study Area and Data
Location Description: Ukai Reservoir
Tapi is a major river in Western India, and Ukai is the largest reservoir in Gujarat. It was constructed in 1972 for the purpose of irrigation, flood protection, power generation, and fisheries development. Ujjania et al., 2015, reported the higher suspended particulate matter as an indicator of pollution in the Ukai reservoir. The major source of suspended particulate matter is organic material from anthropogenic activities like fishing, domestic sewage, agricultural practices. The high amount of suspended load is most likely to cause flooding. During the lockdown period, as there was a reduction in anthropogenic activities, a reduction in suspended particulate matter is hypothesized.
The study area (Fig. 1) is Ukai reservoir in Southern Gujarat, India. The reservoir is situated on the Tapi River and is around 90 km from the Surat city in Gujarat. It is located between longitudes 73°32’25”-78°36’30"E and latitudes 20°5’0”-22°52’30"N and has a catchment area of 62,225 km2. The Tapi river originates from Multai (Madhya Pradesh), then flows through Maharashtra and then into Gujarat and joins the Arabian Sea in the Gulf of Cambay. It can be divided into three zones viz. Upper Tapi basin, Middle Tapi Basin, and Lower Tapi Basin (LTB). The portion between Ukai Dam to the Arabian Sea is considered as LTB and it is estimated to be 122 km.
Fig. 1 Study area location map
Data and Tools Used
The data used here is Landsat 8 OLI images with 30 m resolution and they are exported from the GEE platform after applying median composite and SPM algorithm over the images. Descriptions are given in the Table 1. Total 77 Landsat 8 (OLI) images were acquired (Path/Row: 147/45, 147/46, 148/45) (Fig. 2). All the images are level 2, collection 2 images from the GEE catalogue, meaning the images are radiometrically calibrated and atmospherically corrected surface reflectance derived data.
Table 1 Dataset used for the study
Dataset Description Properties Source
USGS earth explorer Landsat 8 Path/Row: 147/45, 147/46, 148/45 30 m Google Earth Engine (GEE)catalogue
Random GPS points 12 points (6 each on northern and southern sides) Lat and Long Google Earth
Fig. 2 Number of images of 2013 to 2020 divided into 3 row and path
The tool mainly used is GEE for fundamental image processing for the SPM concentration mapping and for map-making purposes ArcMap is used. Descriptions of the tools are given in the Table 2. The success of this study lies in the approach of GEE for retrieving the SPM images which is a sustainable method for the researchers and policy-makers without using any software or downloading unnecessary large data.
Table 2 Tools used for the study
S.No. Software Version Description
1 GEE - Cloud-based platform for remote sensing application enabled with JavaScript API
2 ArcMap 10.1 Used for Map generation
Methodology
Retrieving the Median Images of Each Year
The purpose of current study is to develop an automated framework using Google Earth Engine to evaluate the time series analysis of SPM in the Ukai dam, India from 2013 to 2020, specifically on the month of April 1st to June 7th of each year (lockdown period). Total 77 Landsat 8 (OLI) images were acquired (Path/Row: 147/45, 147/46, 148/45) (Fig: 1). All the images are level 2, collection 2 images from the GEE catalogue, meaning the images are radiometrically calibrated and atmospherically corrected surface reflectance derived data. The single median image of each year has been taken and SPM algorithm equation is applied on all of them. None of the images of the 3 path and rows were fully covering the reservoir so median composite approach is taken. It is to be noted that median is taken instead of mean to reduce the impact of outliers.
The first approach is to filter out the Landsat-8 data according to geometry, cloud cover year and months. Utilized functions are filterBounds()- to filter out the images lying over the study area. filterMetadata(name, operator, value)- to filter out the images that has more than 5% of cloud cover. filter(ee.Filter.calendarRange(startyear, endyear, ‘year’)- to fetch the data from 2013 to 2020. filter(ee.Filter.calendarRange(startmonth, endmonth, ‘month’)- to pick the data only for the desired month. These commads over the Landsat – 8 data brought total 77 images of 2013 to 2020 of the months April to June specifically. Clip() is used to extract the desired reservoir from the whole imageries. Select (band name)- we only need the red band so this function we automatically take the red band of the Landsat-8.
The next part creates a loop that will stack the the images according to the year as a median composite. Function that are used here, map(funtion{})- to operate desired function over the maps. Median()- processing the images a single median images without outliers and artifacts. This will return the 8 median images from the collection. After that SPM algorithm is applied in the median images which is explained in the Sect. 3.3.
Detection of Red Band Reflection Change
It has been accounted for in the writing and demonstrated that, because of the adjustment of suspended sediments of the water, the variation in the spectral reflectance in visible region of the spectrum are critical (Brezonik et al., 2005; Liedeke et al., 1995; Ritchie et al., 1976). Writing proposes that even a single band, whenever picked appropriately, can give a robust estimate of suspended sediments (Gholizadeh et al., 2016; Nechad et al., 2010; Pavelsky and Smith, 2009). It was proposed that a single red band can be utilized to gauge the suspended sediments in water (Shi and Wang, 2009; Hellweger et al., 2007; Miller and McKee, 2004). The single band concept was used where the reflectance increases with the increase in suspended sediment concentrations. In the present study red band is utilized for analyzing the change in spectral response due to varying suspended sediment concentration across the reservoir. The reflectance on each water pixel of each annual median images (2013–2020) was classified from high to low. It was viewed as the sediment concentration increases, the reflectance in the red band also increases and vice versa. In this manner, the pixels with high reflectance in red band are viewed as high suspended sediment concentration, while low reflectance as low suspended sediment concentration.
For measuring the reflectance values of red band over the northern and southern portion of the reservoir, ESRI’s Arc Map tool, Extract Multi Points Values to Points, is used. With the help of this tool the cell values that coincide spatially to a specified point feature class from one or more raster can be easily extracted and the value can be recorded as an attribute in the point feature class. In Table 3, the Global Positioning Syatem (GPS) points are listed, which were used to extract the reflectance values across the northern and southern regions of the reservoir.
Table 3 GPS Points over the northern and southern part of the Waterbody
S.No. Northern Region Southern Region
Longitude Latitude Longitude Latitude
1 73.841 21.421 73.641 21.235
2 73.862 21.437 73.627 21.258
3 73.82 21.415 73.697 21.217
4 73.889 21.445 73.697 21.253
5 73.889 21.461 73.703 21.201
6 73.824 21.388 73.673 21.23
SPM Algorithm
Previous study of Nandita et al., 2015 showed that the in-situ measurement of average value of SPM in Ukai dam ranges between 70 and 300 mg/L around all the seasons in 2014 (Nandita et al., 2015). Nechad et al., 2010 suggested a single band empirical model for the assessment of SPM in any waterbody. With the support of previous study it is safe to assume that the applying Nechad et al., 2010 empirical method will retrieve the SPM concentration data efficiently (RMS value < 10 mg/L).
The following equation of SPM concentration evaluation from the water-leaving reflectance value of the red-band is.
SPM = \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\frac{\varvec{A}\varvec{\rho }}{(1-\varvec{\rho })/\varvec{C}\varvec{\rho }}$$\end{document}
ρ is the water-leaving reflectance of red band of Landsat 8 satellite, Aρ and Cρ are the wavelength-dependent empirical co-efficients of the equation; Aρ = 289.29, Cρ = 0.1686. Parameters Cρ was standardised using standard inherent optical properties (IOPs). Aρ is calibrated using least-square regression model of in-situ data of turbidity and reflectance. After retrieving the median images of each year the above-mentioned SPM is applied to the median images of the corresponding year. This process salvaged the single band empirical model of retrieving surface water SPM for this paper.
In GEE, the whole process of applying the SPM equation starts with assigning the constatns to variables to simplify the visualisation. ee.Image.constant()- to assign variables of each component (co-efficients) of the equation. Image.expression()- assign the SPM equation or expression to each the median image.
Last thing was to downloading the images using Expression.image.toDrive() and save them in the drive. The entire methodlogy is explained in Fig. 3.
Fig. 3 Schematic diagram of the methodology used
Results
Yearly Trend of SPM in Ukai Dam
In this section the results and maps of the paper is discussed. Figure 4 shows the mean SPM value.
Fig. 4 Yearly graph of mean SPM in Ukai reservoir
of each year, 2020 has the lowest value of mean SPM. Image of 2013 and 2018 shows huge amount of SPM concentration. On contrary, 2014, 2016 and 2019 shows moderate account of SPM. The SPM concentration of 2020 is 7% less than the average of SPM concentration of last.
seven years (2013–2019) which very significant for a river with this much pollution. The mean rainfall data from the CHIRPS (Climate Hazards Group InfraRed Precipitation With Station Data) daily of the same exact period over the study area reveals that there no such linear relationship between rainfall and the turbidity. The Fig. 5 shows that in rainfall (mm) is pretty inconsistent with results availed from the SPM algorithm but it also requires further studies with the greater number of data points to find significant relationship between rainfall and turbidity.
Fig. 5 Mean rainfall from 1st April to 7th June of each year
The average SPM of the water body is generally between 66 and 70 mg/L in the month of March-June. SPM of the year 2018 shows the highest mean concentration of the SPM (70 mg/L). Figure 6 states that the changes in overall mean percentage of SPM in the reservoir than the previous year. The concentration increased from 2013 to 2015 and dropped in the year 2016. It again started to increase till 2018 and steeply dropped in 2020 mainly because of lockdown period all over India. All this graphs and maps suggest the decrease in SPM in 2020. Negative values shows the decrease in percentage of SPM concentration.
Fig. 6 Deviation of SPM concentration of each year than the previous one
Reflectance Value of Median Images Each
It has been observed that there was a significant variation in the reflectance of the red band. Higher the turbidity, higher will be red band reflectance and vice-versa (Tripathi 2021; Garg et al., 2020). Since the red band have generally less obstruction from the base and return backscattered energy from suspended particles for the most part. The reflectance over the northern portion of the reservoir was high than that of over the southern portion of the reservoir (Fig. 7a h). This is because of the high sediment concentration over the northern part that southern part. In 2020 (Fig. 7 h), it can be observed that change in reflectance of the red band across the reservoir is quite low than any other image (2013–2019) i.e. Figure 7a g, it might be possible because of the Covid-19 lockdown which results in shut down of industry and various anthropogenic activities resulting in lesser concentration of suspended sediments in the reservoir.
Fig. 7 Change in the reflectance values (especially of 5 h) all over the reservoir suggests that the change of red band reflectance is correlated with variation of SPM: (a) 2013, (b) 2014, (c) 2015, (d) 2016, (e) 2017, (f) 2018, (g) 2019, and (h) 2020
To verify that several points over north and south part of the reservoir were taken spatially and then reflectance value of each point were extracted. After that mean percentage reflectance were obtained for each image for the year 2013 to 2020. The percentage reflectance graph in the Fig. 8 showed that the change in reflectance of the red band in northern portion is significantly higher than that of southern portion of the reservoir. Thus, the concentration of suspended sediments is always high in the northern part because of the contractive shape of the catchment reservoir. In the year 2020 (Fig. 7 h), the percentage reflectance is significantly low in comparison to any other year which tells that the concentration of suspended sediment is less because of the lockdown effect across the country.
Fig. 8 Variation in the surface reflectance over thereservoir
SPM Concentration Maps
Figure 9 Suspended particulate matter (SPM) concentrations estimated for the Ukai Reservoir: (a) 2013, (b) 2014, (c) 2015, (d) 2016, (e) 2017, (f) 2018, (g) 2019, and (h) 2020. Last image of 2020 shows clear reduction of SPM.
Figure 9 (a-h) shows the images of SPM concentration (mg/L) over Ukai reservoir from 2013 to 2020. It is visually very prominent that the SPM on year 2020 has reduced drastically compared to the previous years. The Northern part of the reservoir has shown greater decrease of SPM as the northern inlet of the river carries water from the industrial area and due to complete closure of the factories on the banks of Tapi river, the water carried less pollutants which effectively lowered the SPM on the surface water. The SPM concentration of the southern part of the reservoir remained more or less unchanged. The explanation can be the width of the reservoir. The waterbody is distributed over a larger area so the SPM maintained uniformity and change is not vividly noticeable but the overall change in SPM is observed. The similar trend has been observed in Yunus et al., 2020. It took Vembanad lake of Kerala for the assessment of the SPM concentration using Landsat 8 images and found the same pattern of the variation in SPM all over the lake. The lake witnessed decreased SPM during the Covid-19 lockdown period compared to other years. Aswathy et al., 2021 applied same method over Astamudi Lake and saw almost 40% reduction of SPM compared to the average SPM of last 5 years. These studies establishes the findings of this paper as a concrete evidence of SPM variation with the lockdown period.
Fig. 9 Suspended particulate matter (SPM) concentrations estimated for the Ukai Reservoir: (a) 2013, (b) 2014, (c) 2015, (d) 2016, (e) 2017, (f) 2018, (g) 2019, and (h) 2020. Last image of 2020 shows clear reduction of SPM.
Conclusion
This paper has dealt with the effect of Covid-19 lockdown in Ukai reservoir of Tapi river using remotely sensed data and cloud-based platform Google Earth Engine. This study is effective in such a way that it did not need to download any of the 77 Landsat 8 images and it also did not required any software for any kind of image processing, editing or manipulating. A few lines of code created a flow of semi-automated data processing which delivered desirable result.
The research work has considered the one of the most polluted rivers of Gujarat to evaluate the influence of the global pandemic situation on SPM concentration. The study followed the algorithm of Nechad et al., 2010 but in an automated workflow which has provided satisfactorily good results. The satellite-based data of Tapi river have shown that the average mean value of SPM in 2020 is the lowest at the same period of time than the last seven years. This is mainly happened because of the closure of the industrial plants in the banks of the river and tourism industry. These results also suggest that the primary reason for the high SPM in the Tapi river are above mentioned pollution sources. The satellite data are very useful for change detection or trend analysis let it be water quality analysis or Land Use/ Land Cover classes. Here, this paper has used the Landsat 8 OLI data for the water quality investigation with the images taken by the satellite for the last 8 years (2013-2020).
Further study is required to be done using finer resolution (Sentinel- 2). There are many other pollutants effecting the water quality of the reservoir and algorithms and empirical models available (Goddijn-Murphy & Williamson, 2019; Choe et al., 2008) which can be helpful for understanding the detrimental situation of water quality of the study area. Overall, the study served the purpose of detecting the changes in SPM of the study area with the help of Google Earth Engine platform.
Acknowledgements
The authors would like thanks Mr. Ujaval Gandhi and team, Spatial Thoughts and Sachchidanand Singh, Chief Technology Officer, RBased Services Private Limited, Delhi for their help in using the GEE. The authors heartily thank Spatial Cube Private Limited, Kolkata for their help and guidance during the research.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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| 36512073 | PMC9745272 | NO-CC CODE | 2022-12-15 00:02:24 | no | Bull Environ Contam Toxicol. 2023 Dec 13; 110(1):7 | utf-8 | Bull Environ Contam Toxicol | 2,022 | 10.1007/s00128-022-03638-9 | oa_other |
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Zeitschrift Fur Gesundheitswissenschaften
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Original Article
Physical activity pattern before and during the COVID-19 pandemic and association with contextual variables of the pandemic in adults and older adults in southern Brazil
http://orcid.org/0000-0002-7780-3595
dos Santos Ferreira Viero Vanise [email protected]
12
Matias Thiago Sousa [email protected]
3
Alexandrino Eduardo Gauze [email protected]
1
Vieira Yohana Pereira [email protected]
1
Meller Fernanda Oliveira [email protected]
4
Schäfer Antônio Augusto [email protected]
4
Dumith Samuel Carvalho [email protected]
1
1 grid.411598.0 0000 0000 8540 6536 Postgraduate Program in Health Sciences, Universidade Federal do Rio Grande, Rio Grande, RS CEP: 96203-900 Brazil
2 Avenida Getúlio Dorneles Vargas, 1965, bairro Passo dos Fortes, Chapecó, Santa Catarina, SC CEP: 89805-001 Brazil
3 grid.411237.2 0000 0001 2188 7235 Department of Physical Education, Universidade Federal de Santa Catarina, Florianópolis, SC CEP: 88040-900 Brazil
4 grid.412291.d 0000 0001 1915 6046 Postgraduate Program in Collective Health, Universidade do Extremo Sul Catarinense, Criciúma, SC CEP: 88806-000 Brazil
13 12 2022
19
25 7 2022
30 11 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Aim
To compare the physical activity pattern before and during the COVID-19 pandemic and verify the association with contextual, behavioral, and health variables related to the pandemic in adults and older adults from southern Brazil.
Subject and methods
This is a panel-type, population-based study in Rio Grande-RS and Criciúma-SC, with 4290 individuals. The physical activity pattern (dependent variable) was measured using the International Physical Activity Questionnaire-IPAQ. In addition, contextual, behavioral, and health aspects related to the pandemic (independent variables) were assessed by questionnaires. Fisher’s exact test was used for bivariate analyses and Poisson regression with robust variance to calculate crude and adjusted prevalence, with their respective 95% confidence intervals.
Results
There was a 72% reduction in commuting physical activity and a 145% increase in physical inactivity when compared before and during the pandemic. Social distancing, excessive search for information about COVID-19, fear of the pandemic, and COVID-19 infection were all factors that contributed to the decline in physical activity during the pandemic. The home office was a protective factor for physical inactivity.
Conclusion
The COVID-19 pandemic has negatively affected the pattern of physical activity in the general population, except for those who switched to working from home.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10389-022-01789-x.
Keywords
Physical activity
Exercise
Health behavior
COVID-19
Pandemic
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pmcIntroduction
In response to the COVID-19 outbreak, governments in several countries implemented non-pharmacological public health interventions, such as containment strategies, to limit the spread of the virus, and prevent the population from being harmed by this virus (Garcia and Duarte 2020). Among these interventions, social distancing was presented as the most effective measure for preventing COVID-19 (Nussbaumer-Streit et al. 2020). For example, in Brazil, social distancing measures were promptly adopted by states and municipalities, such as encouraging remote work and implementing digital services, restricting the use of public transport, interrupting activities in schools and universities, and closing non-essential businesses and services (Garcia and Duarte 2020; Aquino et al. 2020).
Although necessary in times of a pandemic, these measures caused a significant change in daily life and affected the usual processes and routines, including physical activity (Wunsch et al. 2022).
Regular and adequate levels of physical activity are widely known to have beneficial effects on the immune system (Laddu et al. 2021) and to reduce the risks for many comorbidities such as obesity, diabetes mellitus, and coronary heart disease (Cleven et al. 2020), as well as depression (Schuch et al. 2018) and anxiety (Schuch et al. 2020). Furthermore, a recent meta-analysis concluded that physically active people had less chance of hospitalization and mortality from COVID-19 (Rahmati et al. 2022), and the regular practice of physical activity could be an important component for promoting, maintaining, and restoring mental health in the restrictive period (Matias et al. 2020; Marconcin et al. 2022).
Despite these benefits, recent systematic reviews with meta-analyses (Stockwell et al. 2021; Wunsch et al. 2022) found that the social restrictions imposed by the pandemic have reduced the population’s practice of physical activity and that psychological depreciation (Schuch et al. 2020) have also contributed to the decline of this behavior.
Although there is no doubt that the containment measures implemented to reduce the spread of COVID-19 have impacted the practice of physical activity by the population around the world, most studies evaluated the change in physical activity retrospectively (Ammar et al. 2020; Malta et al. 2020; Wilke et al. 2021; Caputo et al. 2021; Füzéki et al. 2021a, b). Prospective comparisons of this behavior “before” and “after” the pandemic are still scarce in the literature. In addition, it is crucial to analyze the effect of the pandemic on the different domains of physical activity and investigate what other contextual variables related to the pandemic (e.g., fear of infection, infodemic; home office) may be associated with the pattern of physical activity.
There are indications in the literature that more time at home during the pandemic (Knell et al. 2020) and physical symptoms of COVID-19 (Smith et al. 2020) negatively influenced physical activity behavior during the pandemic.
Method
Study design and location
To fill the knowledge gaps, the present study was carried out with the aim of comparing the pattern of physical activity before and during the COVID-19 pandemic and verifying the association with contextual, behavioral, and health variables related to the pandemic in adults and elderly adults in southern Brazil.
This is a panel-type study, which uses data from three cross-sectional studies, entitled “Health of the Rio Grande a population” and “Health of the adult and older population of Criciúma”, carried out in 2016 and 2019, respectively, and replicated in 2021, with the “Mental-COVID” survey, in order to compare the pattern of physical activity before and during the COVID-19 pandemic. “The studies “Health of the Rio Grande a population” and “Health of the adult and older population of Criciúma” aimed to evaluate the population’s health, and further methodological details about these studies can be found in other publications (Dumith et al. 2018; Saes-Silva et al. 2021). The Mental-COVID study sought to assess the impact of COVID-19 on the mental health of the adult and older population of these two municipalities in southern Brazil.
The municipality of Rio Grande is located in the southern region of the state of Rio Grande do Sul (RS) and Criciúma is located in the extreme south of the state of Santa Catarina (SC). The municipalities have similar characteristics in terms of population size and Human Development Index (HDI) (IBGE 2010).
Population and sample
The target population consisted of individuals aged 18 years or over, living in the urban areas of Rio Grande and Criciúma. Individuals who were institutionalized or who had physical and/or cognitive incapacity to answer the questionnaire were considered ineligible.
The samples of the three studies were obtained through a process of random sampling methods, which was carried out in two stages, based on data from the last Demographic Census of 2010 (IBGE 2010). The first stage included the census sectors, and the second stage, the households. In 2016, approximately 1600 eligible individuals were found, in the year 2019, approximately 1200 individuals, and in 2021, approximately 3000 individuals. All persons aged 18 years and over, residing in the selected households, were invited to participate in these studies.
The instrument, with an average completion duration of 30 minutes, was applied by previously trained interviewers. The interviews were carried out in front of the homes of those eligible, using a pre-coded and standardized questionnaire, mostly composed of closed questions. In the 2016 and 2019 studies, the interviews were applied through printed questionnaires. In 2021, the instrument was applied using tablets and was built using RedCap® software (acronym for Research Electronic Data Capture), followed by data transfer to the computer. Data collection took place between October 2020 and January 2021, with the interviewers wearing the appropriate Personal Protective Equipment-PPE.
Variables
The dependent variables of this study were: Some leisure-time physical activity (No/Yes); Some commuting physical activity (No/Yes); Leisure and commuting physical activity according to the recommendations of 150 minutes per week (World Health Organization 2010) (No/Yes); and Leisure and commuting physical inactivity (No/Yes). Those who responded that they did not perform physical activity on any days per week were considered inactive. These variables were evaluated using the leisure and commuting section of the International Physical Activity Questionnaire (IPAQ), long version, validated by Matsudo et al. (2012). The practice of physical activity in the week prior to the interview (in the previous seven days) was assessed through questions about weekly frequency and duration for walking (also for cycling in the commuting section) and the practice of moderate and vigorous physical activities.
The independent variables were: adherence to social distancing (No/Yes), search for information about the pandemic several times a day (No/Yes); started working remotely during the pandemic (No/Yes); has had symptoms of COVID-19 (No/Yes), has been infected with COVID-19 (No/Yes); and has had contact with someone infected with COVID-19 (No/Yes). These variables were obtained through self-report. In addition, fear of the pandemic was evaluated through the Fear of COVID-19 (FCV-19S) scale, adapted and validated for the Brazilian adult population by Medeiros et al. (2021).
Based on this scale, a score in quintiles was generated for this study, with the last quintile being isolated and considered the group with the greatest fear of being infected by the disease. Subsequently, the groups were dichotomized into “no” (from the first to the fourth quintile, group with less fear of COVID-19) and “yes” (last quintile, group with greater fear of COVID-19). Participants were also asked about the following symptoms of COVID-19: feverish sensation or fever ≥37.8°C, cough without phlegm, difficulty breathing, sore throat, muscle pain or more tiredness than normal, diarrhea, decreased taste, decreased sense of smell, tremors or chills, and headache. This variable was dichotomized into “no” (no symptoms) and “yes” (some symptoms).
To control for possible confounding factors, the following covariates were included in the analysis: sex (male/female), age group (collected in complete years and categorized as 18 to 39 years/40 to 59 years/60 years or more), schooling (elementary/secondary/higher), socioeconomic status (lowest – lowest socioeconomic level/intermediate/highest – highest socioeconomic level), stress (lowest stress level/intermediate/highest – highest stress level), and regular or poor perception of health (no/yes). Stress was assessed using the 14-item Perceived Stress Questionnaire (Siqueira Reis et al. 2010), with the score divided into tertiles.
In addition to the variables mentioned, the following were collected for exploration purposes: skin color, marital status, smoking, excessive alcohol consumption, BMI, health insurance, regular or poor sleep quality, depressive symptoms (Santos et al. 2013), feelings of sadness (Andrews and Withey 1976), arterial hypertension, diabetes mellitus, heart disease, and chronic back pain. These variables are detailed in Supplementary Table 1.
Statistical analysis
Univariate analysis was performed using absolute and relative frequencies to describe the characteristics of the sample. Bivariate analysis was performed to calculate the prevalence of the outcome according to the independent variable, using the Fisher’s exact test.
Multivariate analysis was performed using Poisson regression, which was used to calculate crude and adjusted prevalence ratios (PR) and their corresponding 95% confidence intervals (95%CI). The Wald ratio test for heterogeneity (dichotomous or nominal exposures) was used. The level of significance was set at 5% for two-tailed tests.
It is noteworthy that interaction was tested with the years of research, with statistical significance (p value <0.10) between all the aforementioned covariates.
All statistical procedures were performed using the Software for Statistics and Data Science (STATA), version 16.1 using the prefix svy, which considers the complexity of the sampling process and the effect of the study design. The figure was constructed using the Excel® program.
Results
A total of 2170 subjects participated in the study in the year 2021, with a response rate of 72%. Of these, the majority were female (59.7%), 31.2% were 60 years of age or older, and more than 70% of the population did not have higher education. Almost a quarter of individuals reported seeking information about the pandemic several times a day, 7.7% reported having switched to working remotely during the pandemic, more than 20% reported having had symptoms of COVID-19, and less than 10% had been infected by the disease (Table 1). The distribution of the sample in relation to demographic, socioeconomic, behavioral, and health variables before and during the pandemic was similar (see Supplementary Table 2).Table 1 Demographic, socioeconomic, health, and pandemic context characteristics of the sample (2021 assessment) (N = 2,170)
Variables N %
Sex
Male 875 40.3
Female 1295 59.7
Age group
18–39 729 33.6
40–59 763 35.2
60 or + 678 31.2
Schooling
Elementary 921 42.5
Secondary 692 31.9
Higher 555 25.6
Asset index (income tertiles)
1 (lowest) 719 34.7
2 (intermediate) 673 32.5
3 (highest) 680 32.8
Level of stress (tertiles)
1 (lowest) 760 35.3
2 (intermediate) 718 33.3
3 (highest) 676 31.4
Regular or poor perception of health
No 1624 74.9
Yes 545 25.1
Social distancing
No 1768 81.5
Yes 402 18.5
Infodemic
No 1692 78.0
Yes 478 22.0
Fear of the pandemic
No 1740 80.9
Yes 412 19.1
Switched to working remotely during the pandemic
No 2002 92.3
Yes 168 7.7
Symptoms of COVID-19
No 1667 76.9
Yes 500 23.1
Infection by COVID-19
No 2023 93.2
Yes 147 6.8
Had contact with infection
No 1617 74.5
Yes 553 25.5
N, Absolute frequency; %, Relative frequency
Figure 1 shows the comparison of the pattern of physical activity before and during the pandemic. It was found that commuting physical activity was 3.5 times higher before the pandemic and during the pandemic it decreased to 18.7%, representing a drop of 72.0%. Before the pandemic, almost half of the sample reached the recommendations of leisure and commuting physical activity for health (>=150min/week) and during the pandemic, only a quarter reported meeting the recommendations (>=150min/week). Approximately 24.4% of subjects reported being physically inactive before the pandemic, while during the pandemic almost 60% were classified as inactive. A change in the prevalence of leisure-time physical activity was also observed when analyzing before and during the pandemic; however, the percentage delta variation was smaller when compared to the other outcomes.Fig. 1 Comparison of the physical activity pattern before and during the COVID-19 pandemic in adults and older adults in the urban areas of Rio Grande, RS (2016/2021) and Criciúma, SC (2019/2021) (N = 4,290). LPA, Leisure Physical Activity; CPA, Commuting Physical Activity; LCPA, Leisure and Commuting Physical Activity; ∆, Delta Percentage= percentage difference in prevalence from before to during the pandemic
Regarding the changes from before to during the pandemic in associated factors, the reduction in leisure-time physical activity was greater for males, individuals aged 60 years or older, with less schooling and with a lower level of stress (Supplementary Table 3). The greatest reduction in commuting activity was observed for male individuals, with lower economic status, who perceived their health as fair or poor and had a low level of stress (Supplementary Table 4). Older, less educated, and low-income people who perceived their health as fair or poor reported greater reductions in leisure-time physical activity and commuting in line with health recommendations (>=150min/week) (Supplementary Table 5). Considering physical inactivity, the greatest increases were observed in individuals with a low level of stress, without depressive symptoms, and without feelings of sadness (Supplementary Table 6).
With respect to the association of demographic, socioeconomic, and health variables with pandemic variables, it can be observed that women adhered more to social distancing, had more infodemic behavior, and greater fear of the pandemic when compared to men. Individuals with higher levels of schooling adhered less to social distancing, had less infodemic behavior, and more COVID-19 infections, more contact with someone infected with the disease, and more remote work than individuals with lower levels of schooling. Those with the highest levels of stress had less infodemic behavior and greater fear of the pandemic, more symptoms of COVID-19, and more contact with someone infected with the disease than those with the lowest level of stress (Supplementary Table 7).
The prevalence of leisure-time physical activity during the pandemic was 17.0% (95%CI 13.6; 21.0) for those who adhered to social distancing versus 30.8% (95%CI 28.7; 33.0) for those who did not adhere. For commuting physical activity during the pandemic, the prevalence for those who sought information about the pandemic several times a day was 12.2% (95%CI 10.0; 15.5) versus 20.5% (95%CI 18 .6; 22.5) for those who did not seek information about the pandemic as often. Considering leisure and commuting physical activities according to health recommendations (>=150min/week), it was found that the prevalence for those who complied with social distancing was 14.8% (95%CI 11.6; 18.6) versus 26.9% (95% CI 24.9; 29.0) for those who did not comply. The prevalence of physical inactivity during the pandemic was 41.0% (95%CI 33.7; 48.7) for those who started working remotely during the pandemic versus 61.4% (95%CI 59.2; 63.5) for those who continued working as before (Table 2).Table 2 Adjusted analysis between pandemic variables and physical activity measures in adults and older adults in the urban areas of Rio Grande, RS (2021) and Criciúma, SC (2021) (N = 2170)
Variables LPA CPA LCPA Physical inactivity
% PR (95%CI)* % PR (95%CI)** % PR (95%CI)*** % PR (95%CI)***
Social distancing
No 30.8 1.00 18.8 1.00 26.9 1.00 57.3 1.00
Yes 17.0 0.78 (0.61; 1.00) 18.0 1.14 (0.87; 1.48) 14.8 0.77 (0.59; 1.01) 70.7 1.06 (0.96; 1.17)
Infodemic
No 28.9 1.00 20.5 1.00 25.0 1.00 57.8 1.00
Yes 25.9 0.93 (0.76; 1.15) 12.2 0.74 (0.55; 0.98) 23.4 0.99 (0.79; 1.25) 66.9 1.11 (1.01; 1.22)
Fear of the pandemic
No 29.4 1.00 18.3 1.00 26.0 1.00 58.7 1.00
Yes 22.6 0.93 (0.77; 1.12) 18.3 0.81 (0.63; 1.03) 17.3 0.78 (0.64; 0.96) 66.1 1.10 (1.01; 1.20)
Switched to working remotely during the pandemic
No 26.4 1.00 18.0 1.00 23.1 1.00 61.4 1.00
Yes 50.6 1.14 (0.95; 1.37) 26.8 1.37 (1.02; 1.84) 44.0 1.16 (0.92; 1.47) 41.0 0.87 (0.72; 1.04)
Symptoms of COVID-19
No 28.5 1.00 16.5 1.00 24.8 1.00 60.9 1.00
Yes 27.5 0.97 (0.80; 1.18) 25.7 1.55 (1.25; 1.92) 24.4 1.06 (0.85; 1.33) 56.2 0.89 (0.80; 0.99)
Infection by COVID-19
No 28.0 1.00 18.8 1.00 24.6 1.00 59.8 1.00
Yes 32.0 0.88 (0.63; 1.24) 16.3 0.42 (0.25; 0.69) 26.0 0.75 (0.49; 1.15) 60.3 1.34 (1.14; 1.58)
Had contact with infection
No 26.8 1.00 17.6 1.00 23.6 1.00 61.7 1.00
Yes 32.6 1.00 (0.84; 1.19) 21.7 1.29 (1.01; 1.65) 27.9 1.01 (0.84; 1.20) 54.3 0.92 (0.83; 1.03)
Bold entry indicate statistically significant associations
%, Prevalence, PR, Prevalence Ratio
*Adjusted PRs were calculated using Poisson regression, with robust adjustment for variance. The adjustment variables were: sex, age, education, asset index, stress, regular or poor perception of health, and commuting physical activity
**Adjusted PRs were calculated using Poisson regression, with robust adjustment for variance. The adjustment variables were: sex, age, education, asset index, stress, regular or poor perception of health and leisure-time physical activity
***Adjusted PRs were calculated using Poisson regression, with robust adjustment for variance. Adjustment variables were: sex, age, education, asset index, stress and regular or poor perception of health
During adjusting for possible confounding factors, it was observed that the probability of practicing physical activity during leisure time during the pandemic was lower in those who adhered to social distancing (PR = 0.78; 95%CI 0.61;1.00) when compared to those who did not. Regarding physical activity while commuting, the highest probability of practicing physical activity while commuting during the pandemic period was among those who started working remotely during the pandemic (PR = 1.37; 95%CI 1.02;1.84), who had symptoms of COVID-19 (PR = 1.55; 95%CI 1.25;1.92), and who had contact with someone infected with the disease (PR = 1.29; 95%CI 1.01;1.65) when compared to their peers. On the other hand, those who reported infodemic behavior and COVID-19 infection were 26% (95%CI 2 to 45%) and 58% (95%CI 31 to 75%), respectively, less likely to be active in commuting during the pandemic when compared to those who did not report infodemic behavior and who had the COVID-19 infection. As for the practice of physical activity during leisure time and commuting, according to health recommendations (>=150min/week), it was observed that the probability was 22% (95%CI 4 to 36%) lower in those who reported greater fear of the pandemic compared to those who were not so afraid. The highest probability of physical inactivity during the pandemic was for those who sought information about the pandemic several times a day (PR = 1.11; 95%CI 1.01;1.22), were more afraid of the pandemic (PR = 1.10; 95%CI 1.01;1.20), and had the COVID-19 infection (PR = 1.34; 95%CI 1.14;1.58) when compared to their peers. On the other hand, those who reported having symptoms of COVID-19 were 11% (95%CI 1 to 20%) less likely to be inactive when compared to those who had no symptoms of the disease (Table 2).
Discussion
This study compared the pattern of physical activity before and during the COVID-19 pandemic in adults and older adults and analyzed its association with contextual, behavioral, and health variables related to the pandemic in two municipalities in southern Brazil. The results showed that the pattern of physical activity underwent an unfavorable change during the pandemic period compared to the period before the restrictions, as found in other investigations that identified the effect of social isolation induced by the pandemic on physical activity behavior worldwide (Stockwell et al. 2021; Wunsch et al. 2022). These results were already expected since the “stay at home order,” together with working from home, and the ban on organized sports groups (Wunsch et al. 2022), probably influenced the reduction in this behavior during the pandemic.
It was found in our study that approximately one in four individuals were completely physically inactive before the pandemic, and during the pandemic period more than half became inactive. In the study by Silva et al. (2021), with 39,693 Brazilian adults, a 26% increase in physical inactivity was found during the pandemic. These data point to a worrying scenario, as in 2017, the World Health Organization developed a global plan called the “Global Action Plan on Physical Activity 2018–2030” (World Health Organization 2018) to prevent and control physical inactivity and promote physical activity. One of the goals of this plan was to reduce physical inactivity by 10% by 2025 and 15% by 2030 (World Health Organization 2010). However, instead of reducing the prevalence of physical inactivity, which before the pandemic was already high in adults (27.5%) (Guthold et al. 2018), the social distancing imposed by the pandemic influenced the even greater increase in its prevalence worldwide (Stockwell et al. 2021; Wunsch et al. 2022). Added to this is the fact that patients infected by COVID-19 who were physically inactive before infection had greater chances of hospitalization (OR = 2.26; 95%CI 1.81;2.83), admission to the intensive care unit (OR = 1.73; 95%CI 1.18;2.55), and death (OR = 2.49; 95%CI 1.33;4.67) as a result of this disease (Sallis et al. 2021).
In the current study it was observed that the greatest reduction in physical activity measures occurred in the commuting domain and not, as expected, in the leisure domain, which was also reported in studies carried out with the population of Italy (Füzéki et al. 2021a) and Germany Füzéki et al. 2021b), and can be explained by the closing of schools, universities, businesses, and non-essential commerce, as well as the worldwide adherence to the home office. Of all the physical activity measures evaluated in this study, leisure-time physical activity suffered the smallest decline during the pandemic when compared to the other measures, which could be attributed to the fact that individuals in population groups that were more active in this domain before the restrictions (such as individuals with higher education and higher income) continued to be more likely to practice leisure-time physical activities even with the restrictions imposed.
As verified in our findings, the virus infection that causes COVID-19 was not the only factor responsible for negatively influencing the behavior of physical activity, but the pandemic context, such as social distancing, the excessive search for information about COVID-19, and the greater degree of fear of the pandemic were also responsible for the decline in this behavior in the analyzed period. Social restrictions, as expected, reduced the probability of practicing physical leisure activities in the investigated population. This was also found in the study by Knell et al. (2020), in a sample of 1809 adults residing in the United States, indicating that those who spent more time at home were 1.06 times (95%CI 1.02; 1.09) more likely to report decreased physical activity. This may be linked to restrictions in access to parks and places conducive to sports and outdoor physical activities during the first waves of the pandemic (Wunsch et al. 2022).
In the current study, the excessive search for information about COVID-19 and a greater degree of fear of the pandemic were risk factors for total physical inactivity during the pandemic. These findings are in line with other studies that found that infodemic behavior and pandemic fear are associated with unfavorable health outcomes, such as anxiety, depression, stress, panic, fear, and tiredness (Rahman et al. 2020; Rocha et al. 2021) and increased risk behaviors (alcohol and smoking) (Rahman et al. 2020). In view of these convergences, it is suggested that the negative influence of the excessive search for information about COVID-19 and the greater fear of the pandemic were extended to behaviors related to physical activity in our study, as they may have been considered important barriers to the practice of physical activities during the pandemic period by the investigated population.
As found in our results, the study by Smith et al. (2020), carried out with 911 adults from England, Northern Ireland, Scotland, and Wales, to investigate the levels and correlates of physical activity during social distancing in a sample of UK adults, found that those who reported having physical symptoms of COVID-19 were less likely (OR = 0.31; 95%CI 0.21; 0.46) to be physically active during the pandemic. The direction of these associations was predictable, as this disease often causes physical complications such as fatigue, myalgia, arthralgia, reduced physical capacity, and declines in physical function, usual care, and daily activities (Shanbehzadeh et al. 2021), which can easily lead to greater unwillingness to practice physical activities.
While containment strategies may have introduced barriers to physical activity for some people, the requirement to work from home may actually have provided opportunities for physical activity for others, as seen in our study. These findings are consistent with another Brazilian population-based study carried out in two municipalities in Minas Gerais-Brazil, with a sample of 1750 individuals aged 18 years and over, which found that those who worked from home had reduced chances (OR = 0.45; 95%CI 0.24;0.85) and (OR = 0.51; 95%CI 0.29;0.88) of being physically inactive during leisure time, from March to August 2020 and October to December 2020, respectively (Moura et al. 2021).
Finally, this study must be interpreted considering its limitations and strengths. First, the cross-sectional design of the study does not allow a temporal relationship to be established, and thus may be subject to reverse causality bias. For example, it is not known whether those individuals who were infected with COVID-19 did not already have some debilitating physical condition that limited them in practicing physical activity before the outbreak of the pandemic, and the COVID-19 infection further aggravated this framework. Second, self-report of positive COVID-19 testing and physical activity measures may be subject to recall bias, as well as underdiagnosis, since the individual may have been infected but not aware of this.
As strengths, it should be noted that the present study was population-based and carried out in person, in the households of the interviewees. This is also a differential when compared to other studies on the subject that used online platforms, as the data collection method employed enabled the inclusion of individuals without internet access. In addition, it should be noted that our study differs from others in that we compared the pattern of physical activity before and during the pandemic with the same population and not retrospectively. Finally, we mention the fact that we evaluated different measures of physical activity (leisure physical activity, commuting physical activity, physical activity according to health recommendations (>=150min/week), and total physical inactivity) and that we identified the repercussions of the pandemic for each of these outcomes.
Information on the influence of the COVID-19 pandemic on physical activity pattern, as well as understanding how different contextual, behavioral, and health factors related to the pandemic influenced different measures of physical activity are valuable and can contribute to planning and targeting specific actions and strategies to improve each measure of physical activity behavior evaluated herein. We emphasize the importance of suggesting longitudinal studies to monitor this population, as well as interventions that promote the practice of physical activity, in order to mitigate the impacts of the pandemic on the present and future health of these individuals.
Conclusion
We concluded that the COVID-19 pandemic negatively affected the pattern of physical activity of the population studied. Commuting physical activity was the measure that suffered the biggest decline during the pandemic and not leisure activity as expected. Total physical inactivity almost tripled in the comparison of before and during the pandemic. Infection with the virus that causes COVID-19 was not the only factor that contributed to negatively altering physical activity behavior during the pandemic, as social distancing, fear of the pandemic, and the excessive search for information about COVID-19 were also factors responsible for this decline. Contrary to what was expected, work from home might be a protective factor for physical inactivity.
Supplementary information
ESM 1 (DOCX 80 kb)
Acknowledgements
SCD is a research productivity fellow from the National Council for Scientific and Technological Development (CNPQ). VSFV and YPV are social demand fellows from the Coordination for the Improvement of Higher Education Personnel (CAPES), case numbers 88887.605383/2021-00 and 88887.605391/2021-99, respectively.
Authors’ contribution
VSFV participated in the design of the manuscript, performed the analyses, participated in the writing of the manuscript. TSM, EGA, and YPV participated in the writing of the manuscript. TSM, FOM, and AAS critically reviewed the manuscript. SCD supervised the analyses, revised the final version of the article, and coordinated the study. All authors read and approved the final manuscript.
Funding
This study received financial support from the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul - FAPERGS, process number 20/2551-0000277-2.
Data availability
The data that support the findings of this study are available from the corresponding author upon request.
Code availability
Not applicable.
Declarations
Ethics approval and consent to participate
The studies are approved by the appropriate Research Ethics Committees (CEP) under the following opinion numbers: (no. FURG 20/2016 CAAE: 52939016.0.0000.5324; no. UNESC 3.084.521; no. FURG 4.055.737). All ethical principles established by the National Health Council in Resolution 466/12 were respected. Those who agreed to participate in the study informed this decision during reading and signing the Free and Informed Consent Form.
Consent to publication
Not applicable.
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Garcia LP Duarte E Intervenções não farmacológicas para o enfrentamento à epidemia da COVID-19 no Brasil Epidemiologia e Serviços de Saúde 2020 29 2 e2020222 10.5123/S1679-49742020000200009 32294756
Guthold R Stevens GA Riley LM Bull FC Worldwide trends in insufficient physical activity from 2001 to 2016: a pooled analysis of 358 population-based surveys with 1·9 million participants Lancet Glob Health 2018 6 10 e1077 e1086 10.1016/S2214-109X(18)30357-7 30193830
IBGE (2010) Instituto Brasileiro de Geografia e Estatística. Censo Demográfico. https://sidra.ibge.gov.br/pesquisa/censo-demografico/demografico-2010/inicial. Accessed 15 July 2022
Knell G Robertson MC Dooley EE Burford K Mendez KS Health behavior changes during COVID-19 pandemic and subsequent “stay-at-home” orders Int J Environ Res Public Health 2020 17 17 6268 10.3390/ijerph17176268 32872179
Laddu DR Lavie CJ Phillips SA Arena R Physical activity for immunity protection: inoculating populations with healthy living medicine in preparation for the next pandemic Prog Cardiovasc Dis 2021 64 102 104 10.1016/j.pcad.2020.04.006 32278694
Malta DC, Szwarcwald CL, Barros MBA, Gomes CS, Machado IE, de Souza Júnior PRB, Romero DE, Lima MG, Damacena GN, Pina MF, Freitas MIF, Werneck AO, da Silva DRP, Azevedo LO, Gracie R (2020) A pandemia da COVID-19 e as mudanças no estilo de vida dos brasileiros adultos: um estudo transversal, 2020. Epidemiologia e Serviços de Saúde 29(4). 10.1590/s1679-49742020000400026
Marconcin P Werneck AO Peralta M Ihle A Gouveia ÉR Ferrari G Sarmento H Marques A The association between physical activity and mental health during the first year of the COVID-19 pandemic: a systematic review BMC Public Health 2022 22 1 209 10.1186/s12889-022-12590-6 35101022
Matias T Dominski FH Marks DF Human needs in COVID-19 isolation J Health Psychol 2020 25 7 871 882 10.1177/1359105320925149 32375564
Matsudo S Araújo T Matsudo V Andrade D Andrade E Oliveira LC Braggion G Questionário Internacional de Atividade Física (IPAQ): Estudo de validade e reprodutibilidade no Brasil Rev Bras Ativ Fís Saúde 2012 6 2 5 18 10.12820/rbafs.v.6n2p5-18
Medeiros ED, Reis LM, Guimarães CLC, da Silva PGN, Monteiro RP, Coelho GLH, Guimarães CMC, Martins ERS, França LLA (2021) Psychometric properties of the Brazilian version of the fear of COVID-19 scale (FCV-19S). Curr Psychol. 10.1007/s12144-021-01476-2
Moura SS, Rocha AMS, Lourenção LG (2021) COVID-Inconfidentes : How did COVID-19 and home office influence the prevalence of leisure-time physical inactivity ? An analysis of before and during the pandemic. November, 1–23. 10.1186/s12889-022-14145-1
Nussbaumer-Streit B, Mayr V, Dobrescu AI, Chapman A, Persad E, Klerings I, Wagner G, Siebert U, Ledinger D, Zachariah C, Gartlehner G (2020) Quarantine alone or in combination with other public health measures to control COVID-19: a rapid review. Cochrane Database Syst Rev 2020(9). 10.1002/14651858.CD013574.pub2
Rahman MA Hoque N Alif SM Salehin M Islam SMS Banik B Sharif A Nazim NB Sultana F Cross W Factors associated with psychological distress, fear and coping strategies during the COVID-19 pandemic in Australia Glob Health 2020 16 1 95 10.1186/s12992-020-00624-w
Rahmati M, Shamsi MM, Khoramipour K, Malakoutinia F, Woo W, Park S, Yon DK, Lee SW, Shin JI, Smith L (2022) Baseline physical activity is associated with reduced mortality and disease outcomes in COVID-19: A systematic review and meta-analysis. Rev Med Virol. 10.1002/rmv.2349
Rocha YM, de Moura GA, Desidério GA, de Oliveira CH, Lourenço FD, de Figueiredo Nicolete LD (2021) The impact of fake news on social media and its influence on health during the COVID-19 pandemic: a systematic review. J Public Health. 10.1007/s10389-021-01658-z
Saes-Silva E Viero VSF Meller FO Schäfer AA Canena MV Saes MO Dumith SC Acute and chronic back pain in adults and elderly in southern Brazil Sci Med 2021 31 1 e39824 10.15448/1980-6108.2021.1.39824
Sallis R Young DR Tartof SY Sallis JF Sall J Li Q Smith GN Cohen DA Physical inactivity is associated with a higher risk for severe COVID-19 outcomes: a study in 48 440 adult patients Br J Sports Med 2021 55 19 1099 1105 10.1136/bjsports-2021-104080 33849909
Santos IS Tavares BF Munhoz TN Almeida LSP Silva NTB Tams BD Patella AM Matijasevich A Sensibilidade e especificidade do Patient Health Questionnaire-9 (PHQ-9) entre adultos da população geral Cadernos de Saúde Pública 2013 29 8 1533 1543 10.1590/0102-311X00144612 24005919
Schuch FB Vancampfort D Firth J Rosenbaum S Ward PB Silva ES Hallgren M Ponce De Leon A Dunn AL Deslandes AC Fleck MP Carvalho AF Stubbs B Physical activity and incident depression: a meta-analysis of prospective cohort studies Am J Psychiatr 2018 175 7 631 648 10.1176/appi.ajp.2018.17111194 29690792
Schuch FB Bulzing RA Meyer J Vancampfort D Firth J Stubbs B Grabovac I Willeit P Tavares VDO Calegaro VC Deenik J López-Sánchez GF Veronese N Caperchione CM Sadarangani KP Abufaraj M Tully MA Smith L Associations of moderate to vigorous physical activity and sedentary behavior with depressive and anxiety symptoms in self-isolating people during the COVID-19 pandemic: A cross-sectional survey in Brazil Psychiatry Res 2020 292 113339 10.1016/j.psychres.2020.113339 32745795
Shanbehzadeh S Tavahomi M Zanjari N Ebrahimi-Takamjani I Amiri-arimi S Physical and mental health complications post-COVID-19: scoping review J Psychosom Res 2021 147 May 110525 10.1016/j.jpsychores.2021.110525 34051516
Silva DRP, Werneck AO, Malta DC, de Souza Júnior PRB, Azevedo LO, Barros MBA, Szwarcwald CL (2021) Changes in the prevalence of physical inactivity and sedentary behavior during COVID-19 pandemic: a survey with 39,693 Brazilian adults. Cadernos de Saúde Pública 37(3). 10.1590/0102-311x00221920
Siqueira Reis R Ferreira Hino AA Romélio Rodriguez Añez C Perceived Stress Scale J Health Psychol 2010 15 1 107 114 10.1177/1359105309346343 20064889
Smith L Jacob L Butler L Schuch F Barnett Y Grabovac I Veronese N Caperchione C Lopez-Sanchez GF Meyer J Abufaraj M Yakkundi A Armstrong N Tully MA Prevalence and correlates of physical activity in a sample of UK adults observing social distancing during the COVID-19 pandemic BMJ Open Sport Exerc Med 2020 6 1 e000850 10.1136/bmjsem-2020-000850
Stockwell S Trott M Tully M Shin J Barnett Y Butler L McDermott D Schuch F Smith L Changes in physical activity and sedentary behaviours from before to during the COVID-19 pandemic lockdown: a systematic review BMJ Open Sport Exerc Med 2021 7 1 e000960 10.1136/bmjsem-2020-000960
Wilke J Mohr L Tenforde AS A pandemic within the pandemic? Physical activity levels substantially decreased in countries affected by COVID-19 Int J Environ Res Public Health 2021 18 5 2235 10.3390/ijerph18052235 33668262
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Wunsch K Kienberger K Niessner C Changes in physical activity patterns due to the Covid-19 pandemic: a systematic review and meta-analysis Int J Environ Res Public Health 2022 19 4 2250 10.3390/ijerph19042250 35206434
| 0 | PMC9745273 | NO-CC CODE | 2022-12-15 00:02:24 | no | Z Gesundh Wiss. 2022 Dec 13;:1-9 | utf-8 | Z Gesundh Wiss | 2,022 | 10.1007/s10389-022-01789-x | oa_other |
==== Front
China Int Strategy Rev.
China International Strategy Review
2524-5627
2524-5635
Springer Nature Singapore Singapore
125
10.1007/s42533-022-00125-y
Book Review
Political economy of developed countries
Li Zhuo [email protected]
grid.418560.e 0000 0004 0368 8015 National Institute of International Strategy, Chinese Academy of Social Sciences, No. 3 Zhang Zizhong Rd, Dongcheng District, Beijing, China
13 12 2022
14
© The Institute of International and Strategic Studies (IISS), Peking University 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
==== Body
pmcBig Data and the Welfare State: How the Information Revolution Threatens Social Solidarity, by Torben Iversen and Philipp Rehm, Cambridge University Press, 2022, 230 pages, $89.99 (Hardcover).
Indebted Societies: Credit and Welfare in Rich Democracies, edited by Andreas Wiedemann, Cambridge University Press, 2021, 350 pages, $110.99 (Hardcover).
The American Political Economy: Politics, Markets and Power, edited by Jacob S. Hacker, Alexander Hertel-Fernandez, Paul Pierson, and Kathleen Thelen, Cambridge University Press, 2021, 400 pages, $89.99 (Hardcover).
The world is facing major changes unseen in a century. China’s rise is one side of this coin. Another side is the complexity of political economy in developed countries. The waning of the welfare state is considered one major cause of social tension and political disorder. In this short review, the author intends to discuss three books that could help us understand the new dynamics of political economy in western welfare states and its profound influence on inequality, social disorder, and other important issues.
The impact of the information revolution on the welfare state
As Iversen and Rehm mention in Big Data and the Welfare State, the welfare state is “a public system where low-risk types are required to contribute to the population-wide pool and hence subsidize those higher-risk types” (24–25). The logic behind this “majoritarian coercion” is the inefficiency of private insurance markets under conditions of incomplete information. People with low risk would opt out of the plan and only systematic uncertainty (like the shock of Great Depression in 1930s or the coming of deindustrialization in 1970s) could moderate their preference to opt-out.
Time-inconsistency is another difficult problem. The welfare state demands that younger, healthier, and more employable workers transfer resources to disadvantaged groups, and those workers then expect to receive the same benefits in the future. However, “even in the case of a fully funded system with little or no intergenerational redistribution, people worry about the likelihood of receiving future payouts” (33). This problem could be moderated in many political-economic contexts through the inclusion of responsible political parties, the introduction of pension systems with features that include private investment tools, etc. Specifically, leftist parties and left-leaning governments tend to represent the interests of high-risk groups and to support a welfare state as opposed to a private solution. However, the function of those moderations, including the future of left-leaning politics, depends on the preferences of constituencies, which are fundamentally influenced by the distribution of information.
Thus, the power of the information revolution cannot be ignored. With the growing availability of data and the improving capacity on the part of insurers to analyze people’s risk levels, the preferences of the public are bifurcated. The economically advantaged group, including those people with middle-level incomes, demands the differentiation of welfare policies in developed countries. Moreover, the private insurance companies have developed more attractive plans to substitute the function of the welfare state. Simultaneously, the support for left-leaning parties with strong political agendas on public welfare systems have also decreased. Those dynamics will eventually lead to the change of social insurance systems from solidaristic welfare states to segmented private insurance markets.
The interaction between the financial market and the welfare state
When facing unemployment or other financial difficulties, why do people in some countries prefer borrowing money, rather than spending their savings or executing painful spending cuts? Andreas Wiedemann explains the variety in types of indebtedness across developed countries by combining the institutional features of welfare states and credit regimes. When welfare states can cover social risks and support social investments (education, training, family support, etc.), it is not necessary to borrow money (for example, in Denmark). Private finance institutions only play a complementary role by providing financial liquidity to individuals. By analyzing the effects of introducing home equity loans in 1992, the author also found that debt increased more for individuals who intentionally left their work to get a better education or raise their family. This is a clear example of how the complementary role of financial markets works.
In countries where the resources provided by the welfare state are less generous, the availability of a financial institution often determines whether people choose to borrow money. People with better access to financial institutions borrow more. In this scenario, the financial market is substituting the effect of the welfare state. For example, Americans borrow money mainly for covering financial losses incurred through unemployment or non-standard work arrangements. Variations in sub-national borrowing levels also support the substitutive effect of financial institutions to the welfare state. The author found that unemployed people borrow more in states with less generous welfare systems. Of course, this does not suggest that less influence is exerted by government interventions. In fact, the permissive financial regime in the US and its substitutive effect are highly dependent on subsidized interest rates and secondary market operations.
For countries with less generous welfare states and more restrictive credit regimes, households rely on a combination of welfare-state support and private savings, family support, or expenditure cuts to cover their economic difficulties (for example, in Germany). The author found that the activation of the Hartz IV labor market reform in 2005 led to the declining of welfare benefits, and Germans have since depended more on savings and spending cuts, which ultimately led to debt reductions. The restrictive German credit regime not only has shaped citizens’ preferences for borrowing less money, but also has influenced their spending choices. This was true even when controlling for life-course choices and childcare spending. As the author argued, “Germans rarely use credit markets as private alternatives to social policies” (237).
Capitalism with American characteristics
From the perspectives of Jacob S. Hacker, Alexander Hertel-Fernandez, Paul Pierson, and Kathleen Thelen, authors of The American Political Economy: Politics, Markets and Power, the COVID-19 crisis and the nation’s inadequate response “brought America’s distinctive mix of multi-venue governance, limited social protection, weak labor power, and loosely regulated markets prominently—and often tragically—into display” (1). To understand the dynamics of the distinctive US political-economic mix, the authors argued that it is necessary to create the field of American Political Economy (APE) with a focus on “the ways in which institutional configurations shape coalitional politics to produce long-term developmental processes” (7). Following this intellectual pursuit, the authors identified three APE features that are most crucial to understanding contemporary American capitalism: fragmentation of governance, competition of organized interests, and conflict caused by racial oppression and division.
First, the authors argue that the fragmentation of governance (which they define as divided power, the “outsized role” of the judicial system, and the local self-rule tradition in the US) is responsible for the limited authority of the federal government and the inefficiency of coordination among contested subnational governments. Ultimately, the fragmentation of governance results in the limited provision of public goods and the failure of redistributive polices.
Second, the competition of organized interests is based on diversified access to the decision-making process within the sphere of public policymaking. Organized groups can take advantage of this favorable institutional setting to influence the coordination of government actions, especially to avoid the restrictions imposed by regulations. Moreover, interest groups have powerful resources that can be used to mobilize voters, which further amplifies their influence on long-term government policy. After all, both political parties and nearly all politicians need the support of key organized interests to win elections.
Third, racial oppression and divisions are hard to alleviate given the fragmented nature of political power and the competition of organized interests. In turn, racial issues and tensions further strengthen the policy preferences of all parties in the political system and solidify their political strategies and coalitions among state, party, and organized interests.
Regarding the response to the COVID-19 pandemic, all three features have significant implications. The problem of poor coordination was caused by government fragmentation. Specifically, partisan disputes between “red” and “blue” areas at different levels (states, counties, and even cities and towns), combined with the troubled federal bureaucracy weakened by politicization, impeded the activation of more decisive COVID-19 response measures. Additionally, organized interests contributed to the inefficiency of relief policies. As the authors write, strong interest groups (big firms and banks) took advantage of the relief policies and “were in a position to pick winners and losers” (414). Finally, economically disadvantaged groups received disproportionately lower levels of help from COVID-19 relief programs. The racial divisions became even more systemic and compounding, making them more difficult to change.
Concluding remarks
The authors of the three books presented various dynamics which caused the complexity of political economy in western welfare states. The power of information revolution, the influence of financial markets and the American characteristics of capitalism (fragmentation of governance, powerful organized interest and racial issues) has weakened the solidarity of welfare states in different ways. In the future, the integration of technology, capital and politics will be very close. The waning of welfare states in developed countries seems unstoppable. Inequality, social disorder and other issues will also be more intense.
This political-economic trend in developed world has provided important implications for China. On the one hand, the waning of welfare states and its social–political consequences in western countries would increase the difficulty of policy coordination between developing and developed countries. On the other hand, China is also facing the trend of increasing connection among capital, technology, and politics. In the context of “Chinese path to modernization,” we may also need to reconsider the pros and cons of the former model of China’s social–economic development.
| 0 | PMC9745274 | NO-CC CODE | 2022-12-15 00:02:24 | no | China Int Strategy Rev.. 2022 Dec 13;:1-4 | utf-8 | null | null | null | oa_other |
==== Front
Front Comput Sci
Front Comput Sci
Frontiers of Computer Science
2095-2228
2095-2236
Higher Education Press Beijing
2163
10.1007/s11704-022-2163-9
Research Article
FragDPI: a novel drug-protein interaction prediction model based on fragment understanding and unified coding
Yang Zhihui
Liu Juan [email protected]
Zhu Xuekai
Yang Feng
Zhang Qiang
Shah Hayat Ali
grid.49470.3e 0000 0001 2331 6153 Institute of Artificial Intelligence, School of Computer Science, Wuhan University, Wuhan, 430072 China
13 12 2022
2023
17 5 17590323 3 2022
11 7 2022
© Higher Education Press 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Prediction of drug-protein binding is critical for virtual drug screening. Many deep learning methods have been proposed to predict the drug-protein binding based on protein sequences and drug representation sequences. However, most existing methods extract features from protein and drug sequences separately. As a result, they can not learn the features characterizing the drug-protein interactions. In addition, the existing methods encode the protein (drug) sequence usually based on the assumption that each amino acid (atom) has the same contribution to the binding, ignoring different impacts of different amino acids (atoms) on the binding. However, the event of drug-protein binding usually occurs between conserved residue fragments in the protein sequence and atom fragments of the drug molecule. Therefore, a more comprehensive encoding strategy is required to extract information from the conserved fragments.
In this paper, we propose a novel model, named FragDPI, to predict the drug-protein binding affinity. Unlike other methods, we encode the sequences based on the conserved fragments and encode the protein and drug into a unified vector. Moreover, we adopt a novel two-step training strategy to train FragDPI. The pre-training step is to learn the interactions between different fragments using unsupervised learning. The fine-tuning step is for predicting the binding affinities using supervised learning. The experiment results have illustrated the superiority of FragDPI.
Electronic Supplementary Material
Supplementary material is available for this article at 10.1007/s11704-022-2163-9 and is accessible for authorized users.
Keywords
affinity score
drug-protein interaction
BERT
Bi-Transformer
virtual drug screening
issue-copyright-statement© Higher Education Press 2023
==== Body
pmcElectronic supplementary material
FragDPI: A Novel Drug-Protein Interaction Prediction Model Based on Fragment Understanding and Unified Coding
Acknowledgements
This work was supported by the National Key R&D Program of China (2019YFA0904303).
Zhihui Yang is a PhD candidate in the School of Computer Science, Wuhan University, China. His current research interests include synthetic biology, deep learning, metabolic pathway reconstruction, and metabolic flux analysis.
Juan Liu is a professor in the School of Computer Science, Wuhan University, China. Her research interests include machine learning, data mining, bioinformatics, pattern recognition, and artificial intelligence methods for medicine.
Xuekai Zhu is a master’s student in the School of Computer Science, Wuhan University, China. His current research interests are in artificial intelligence methods for bioinformatics.
Feng Yang is a PhD candidate in the School of Computer Science, Wuhan University, China. His current research interests include machine learning, retrosynthesis prediction and metabolic pathway design.
Qiang Zhang is a PhD candidate in the School of Computer Science, Wuhan University, China. Her current research interests include retrosynthesis prediction, metabolic pathway design, bioinformatics, and machine learning.
Hayat Ali Shah received his MS degree in Computer Science from Virtual University of Pakistan, Pakistan in 2018. He is currently a PhD candidate in the School of Computer Science, Wuhan University, China. His research interests are simulated alignments, multiple sequence alignments, machine learning, prediction and reconstruction of metabolic pathways.
==== Refs
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| 0 | PMC9745276 | NO-CC CODE | 2022-12-15 00:02:24 | no | Front Comput Sci. 2023 Dec 13; 17(5):175903 | utf-8 | Front Comput Sci | 2,022 | 10.1007/s11704-022-2163-9 | oa_other |
==== Front
Child Youth Care Forum
Child Youth Care Forum
Child & Youth Care Forum
1053-1890
1573-3319
Springer US New York
9723
10.1007/s10566-022-09723-8
Original Paper
Perceptions from Newcomer Multilingual Adolescents: Predictors and Experiences of Sense of Belonging in High School
http://orcid.org/0000-0002-7109-8899
McInerney Kristen [email protected]
grid.253615.6 0000 0004 1936 9510 Curriculum and Pedagogy, The George Washington University, Washington, DC USA
13 12 2022
132
28 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Background
Recently arriving to US schools, 405 immigrant adolescents in a large, urban high school shared backgrounds and perspectives on what variables and sociocultural factors contributed to their sense of belonging in their new school. This study occurred in 2019–2020 and examined belonging during a xenophobic socio-political climate.
Objective
This study examines what predictors and experiences, if any, contributed to belonging for a large population of multilingual, newcomer youth. This research extends the body of literature to include a large, linguistically and culturally diverse, adolescent newcomer population to test hypotheses that gender, GPA, grade level, employment status, relationships, and family factors impact belonging.
Methods
In this descriptive, single-site case study of newcomers enrolled in an International Academy (IA), semi-structured online interviews (N = 14) and a survey (N = 391) were utilized. Anchored with Goodenow’s belonging definition and scale, quantitative data analysis included regression analysis to reveal three demographic belonging predictors. Qualitative data analysis leveraged emergent coding of newcomer comments to surface five belonging contributing factors.
Results
Results indicated that females had higher sense of belonging scores, while students of smaller language groups and students paying rent had statistically significantly lower scores. Additionally, five sociocultural school factors emerged that contributed to belonging: support networks, language, participation opportunities, safety, and recognition.
Conclusion
Conclusions resulted for improving secondary school structures, practices, and climate to cultivate belonging for newcomers. Directly from students, this study presents educators with opportunities to ensure newcomers feel included, accepted, and valued through peer support networks, post-secondary preparation, and linguistic, emotional, and physical safety.
Keywords
Newcomers
Immigrant
Adolescent
Belonging
High school
Equity
Case study
Knapp Fellowship
==== Body
pmcIntroduction
José, a 15-year-old ninth-grade newcomer from Honduras, described the feeling of being away from beloved family members:Estar bastante tiempo lejos de nuestras familias, que a veces no podamos hablar con aquella persona que queremos. La experiencia de viajar a este país no fue tan fácil porque hay momentos, cuando vienes, hay momentos en los que no puedes dormir, hay momentos en los que no puedes sentirte muy cómodo porque hay cosas difíciles y cosas fáciles en este mundo que son muy diferentes a lo que yo he vivido.
[To stay a long time away from our families, sometimes we can’t talk to that person we love. The experience of traveling to this country was not so easy because there are moments when you come, there are times when you cannot sleep, there are times when you cannot feel very comfortable because there are difficult things and easy things in this world that are very different from what I have experienced.]
Newcomer adolescents spend considerable time in high school settings. Schools have an incredible opportunity to provide support for the whole child, which includes social-emotional, physical, psychological, and academic support, especially for adolescents who are newly arrived immigrants (Kreuzer, 2016). The term newcomers in this case study describes immigrant multilingual learners entering high school within the past three years and scoring between one and three English proficiency level as measured by the ACCESS for ELs assessment designed by the “World Class Instructional Design and Assessment” consortium or WIDA (WIDA, 2020). Newcomers in these three levels ranged from entering, emerging, and developing their English language skills when they first entered their new school; they aim to show growth in language acquisition throughout their educational experience (WIDA, 2020). This study occurred in 2019–2020 and focused on newly arrived high-school-aged students between the ages of 14 and 22, who were born in and spent two-thirds or more of their life in their home country. The 585 students enrolled in an International Academy, the site of this research, were the newcomers in this study, and the students in the study chose their own pseudonyms.
It is known that nearly 100,000 undocumented immigrant youth graduate from U.S. high schools each year (MPI, 2017); however, immigration patterns slowed “to a trickle” due to Trump administration immigration bans (Tavernise, 2019) and the colloquially-called Muslim ban (Gomez, 2018). Also, COVID-19 travel bans and border closures left migrants and their families stranded, separated, and vulnerable to the virus (Guadagno, 2020), and, therefore, delayed enrollment to schools. Newcomers arriving during their secondary school years face the greatest and most long-lasting consequences of their high school experience (Sugarman, 2017). A closer examination of belonging and support of newcomers is critical, especially during a time of what teachers called a hostile, anti-immigrant environment (Ee & Gándara, 2020). In a time when physical (social) distancing is the new norm, distancing has been a hurdle for immigrant students for many years, both physical (geographical) and metaphorical (the invisible line drawn by anti-immigrant rhetoric).
The focus on students entering at the high school level is intentional as research has shown that late-arriving immigrants, particularly those who first enter US schools at ages 12 and above, experience greater acculturative stress compared to younger immigrants (Mena et al., 1987; Patel et al., 2016; Portes & Rumbaut, 2006). This study did not focus on MLLs who entered the US in elementary or middle school, nor did this study focus on Generation 1.5, or second-generation students, or students who were born in the US to immigrant parents. Data from the US Census Bureau’s American Community Survey suggests that between 2000 and 2014, an average of 154,100 newcomer youth aged 12–21 immigrated to the US annually (Sugarman, 2017), and these MLLs are often positioned as English deficient or are even invisible (Mitchell, 2012). Systemic inequities and language-based discrimination against recent immigrants (García, 2009), who are primarily students of color, warrant further investigation into student belonging in this sociopolitical context. All newcomers, regardless of documentation status, are entitled to a free, public education until age 21 or 22 in most states (Sugarman, 2017).
The study focused on the experiences of high school MLLs being welcomed into the US education system. According to Mitchell (2012), “A multilingual learner is a student whose daily lived reality necessitates the negotiation of two or more languages” (p. 1), one of them being English. MLLs are at all stages of language development in both English and their home languages (Mitchell, 2012). Scholars argue that MLLs are more than a combination of two monolinguals (Brisk, 2006; Canagarajah, 2011; García, 2009). Brisk noted that MLLs are “influenced by a dynamic cross-cultural experience, rather than rigid cultural stereotypes,” and understanding this “is vital for designing school policy, classroom practices, and assessment procedures” (2006, p. 3). MLLs access their linguistic repertoires to translanguage (García, 2009) and draw upon their single united language system to codemesh (Canagarajah, 2011) when navigating classroom assignments, communicating thoughts and feelings, and building relationships. This dynamic co-constructed, sociocultural school experience is the center of the research.
Youth who immigrate during their teenage years contend and cope with three areas of transition: adolescence, migration, and entrance to high school. The literature overwhelmingly affirms that belonging can have long-term, positive impacts on academics, physical and psychological health, happiness, and well-being (Allen & Kern, 2017; Correa-Valez et al., 2010; Hombrados‐Mendieta et al., 2013; Khawaja et al., 2017; Kia-Keating & Ellis, 2007; Moallem, 2013; Walton & Cohen, 2011). Cultivating belonging is neither easy nor linear, yet it is particularly critical for immigrant students (Gonzalez & Padilla, 1997; Motti-Stefanidi & Masten, 2017; Suárez-Orozco et al., 2009). However, regarding feeling a sense of belonging to his school’s newcomer program, David, a 17-year-old tenth grader from Honduras, shared,It’s like a family because they help you. They give you support; they make you feel that you’re important to them; they give you attention, respect, affection, and everything. So, yes, for me it’s like a family. We spend eight hours seeing each other, five days a week, so I do recognize that they are like my family.
David’s school is the site of this research; his school community is called the International Academy, nested within a larger traditional high school of more than 4000 students. The Academy is designed for high school students who had arrived in the US within the previous three years; students receive holistic and language development support on their journey to graduation from a US high school. This International Academy instructional model is part of a network of 30 schools called the Internationals Network for Public Schools, originating in New York City with current sites located across the United States. Historically, newcomers enrolled in these schools and academies have met graduation requirements within three to five years of entry to the US, depending on transfer credits from their home countries and other factors.
The body of literature on belonging has called for increased investigation among diverse student populations (Allen & Kern, 2017; Goodenow, 1993; Kia-Keating & Ellis, 2007; Schachner et al., 2018; Suárez-Orozco et al., 2009; Vera et al., 2018). Belonging describes an affective component of a student’s feelings of being accepted, valued, included, and encouraged by teachers and peers in the classroom and feeling like an important part of the daily activity of the class (Goodenow, 1993). A sense of belonging in students has been evaluated, researched, and captured qualitatively and quantitatively in the literature, but fostering it is not simple or straightforward (Allen & Kern, 2017). To explore belonging in this subset of a broader study, a large survey administration utilizing well-recognized Goodenow’s (1993) Psychological Sense of School Membership (PSSM) scale and semi-structured online interviews were analyzed to describe newcomers and their experiences in a large, urban high school. This study is unique as it utilized the PSSM with a newcomer population larger than had been previously studied and aimed to test and extend existing findings.
For immigrant adolescents, studies have found that the sociocultural factors that lead to a sense of belonging include feeling safe and secure to be themselves (Craggs & Kelly, 2018), feeling acceptance or rejection by their peer group (Moallem, 2013), building relationships with supportive bilingual staff and adults (Vera et al., 2018), having peers and teachers who were perceived to be interested in and respectful of newcomer development (Khawaja et al., 2017), celebrating multilingualism (Motti-Stefanidi & Masten, 2017), fostering a sense of identity (Perez et al., 2009), grouping students intentionally (Kessler et al., 2018), and providing social-emotional support (Kreuzer, 2016), among others. This study aimed to explore what newcomers identified as additional factors that contributed to belonging.
Further, the study’s population represents more linguistically and culturally diverse immigrant adolescents from a wider variety of countries—within Central and South America, Africa, and Central Asia—than previously studies have included. Few studies have researched adolescent MLLs’ sense of belonging in their new school community (e.g., Kia-Keating & Ellis, 2007; Schachner et al., 2018) during a period of heightened xenophobia (Ee & Gándara, 2020; Guadagno, 2020) and ongoing nation-wide examinations of systemic and racial injustices, such as the Black Lives Matter movement (see Terriquez & Milkman, 2021; Washington Post Staff, 2020). Additionally, building upon the construct of belonging, this study also extends and complements the research of Suárez-Orozco et al. (2008), who conducted a five-year longitudinal study of recently arrived students living in Boston and San Francisco regarding academic engagement, performance, and networks of relationships. Their study deeply analyzed academic, cognitive, relational, and behavioral engagement, and it bundled sense of belonging among many other factors within their relational engagement category. Their study and methods grounded this research and provided a foundation to build on newcomers' experiences with a sense of belonging.
This study explored what variables, if any, could predict belonging. Grounded in the broader belonging literature among youth, the hypotheses of this study were that female students would have a higher sense of belonging (Allen & Kern, 2017; Goodenow, 1993; Itzhaky & Levy, 2002; Sánchez et al., 2005; Smerdon, 2002; Wojtkiewicz & Donato, 1995), that a higher GPA would indicate a higher sense of belonging or connection to school (Close & Solberg, 2008; Roeser et al., 1996), that those who worked a job while attending school would have higher belonging scores (Suárez-Orozco et al., 2009), that belonging was related to strong peer and teacher relationships (Close & Solberg, 2008), and that belonging would increase over time in the program (see Schachner et al., 2018). To test these hypotheses, both quantitative and qualitative data collection methods were employed to provide descriptive data that one approach alone could not. This study informs implementable secondary school practices and state/district policies by adding newcomer belonging predictors and newcomer-identified school belonging components to the body of literature.
The sociocultural theories of Vygotsky (1978) underpin the study, which explores the variables, social structures, and experiences newcomers identified as being helpful to fostering belonging. Newcomers are adjusting to a new country, a new language, a new culture, and a new school (Suárez-Orozco et al., 2008), doing so with the support of others in a social environment. Consequently, a sense of belonging can affect newcomers’ personal and psychological well-being (Allen & Kern, 2017; Correa-Valez et al., 2010; Khawaja et al., 2017; Kia-Keating & Ellis, 2007; Walton & Cohen, 2011) as well as their academic achievement (Moallem, 2013). This research aims to describe quantitative survey results with qualitative interviews in a descriptive, single-site case study. The questions guiding this case study were as follows:How do newcomers experience a sense of belonging in a secondary newcomer program?
What predictors, patterns, or trends exist, if any, for newcomers’ sense of belonging in a secondary newcomer program?
Study outcomes can inform secondary schools about what newcomers declare fosters belonging in their new school in a new country and language. This study aimed both to quantify and qualify belonging for a newcomer population that is continuously “overlooked and underserved” (Ruiz-de-Velasco et al., 2000, p. 1) by exploring in-depth demographics and belonging experiences in a social context.
Method
Descriptive case studies provide insight into complex issues and experiences; they describe a natural phenomenon within the context of the data that are being questioned (Lambert & Lambert, 2012; Zainal, 2007). The design was chosen to gain a rich description of newcomers’ backgrounds and belonging experiences in their new high school (Yin, 2018). Two data collection methods were used: a 391-participant survey and 14 semi-structured online interviews. Within well-designed case studies, quantitative methods help to define the case (Yin, 2018), and qualitative methods help to present an in-depth understanding of cases in which one data collection method is typically not enough (Creswell, 2013). Robust case study can result through leveraging the strengths of each method. In this study, a holistic, single-site case study was designed, utilizing both types of methods to achieve an in-depth understanding of the case, students enrolled in the International Academy, and their experiences with a specific phenomenon, belonging. Goodenow’s (1993) definition and measurement scale of a sense of belonging for adolescents was used to anchor the analysis. Additionally, interviews were utilized to enhance the survey results and were coded using emergent and a priori coding for Allen and Kern’s (2017) belonging framework.
Survey Methods
Survey methods provided a versatile and efficient way to collect perception data, demographic characteristics, attitudes, feelings, beliefs, and opinions from a large population. The research participants were enrolled at a single site and took the survey in class in a simultaneous, large-survey administration. The goal was to reach a census, or survey participation from all 585 students enrolled in the International Academy program. Data were analyzed quantitatively to find larger trends and patterns.
Site
To access hundreds of immigrant youth arriving within the past three years, the research site or “bounded case” (Yin, 2018) was a secondary newcomer program, called the International Academy, at a large, urban high school in Virginia. The research site is a member of the Internationals Network of Public Schools, which has been found to be effective in welcoming, educating, and supporting high school newcomers (e.g., Bajaj & Suresh, 2018; Jaffe-Walter, 2018; Kessler et al., 2018; Roc et al., 2019). The 30 International Academies and School sites provide instruction designed with language and content integration in project-based instruction with heterogeneous, collaborative student groups (Internationals Network for Public Schools, 2020). Additionally, a bilingual team of Spanish- and English-speaking counselors, social workers, administrative assistants, and administrators provides acculturation support.
Participants
This study gathered data solely from immigrant youth. The participant population was 585 newly arrived immigrant students. Participant inclusion criteria were as follows: (a) they had arrived in the United States within the previous three years upon enrollment, (b) they were between 14 and 22 years old, (c) their native language was not English, (d) they scored between one and three as measured by the WIDA assessment of English proficiency upon entry to US schools, (e) they may have had limited or interrupted formal education (SLIFE), and (f) they may have been refugees, asylum seekers, or undocumented persons. Persons having these characteristics constitute a rare population (de Leeuw et al., 2008). De Leeuw et al. (2008) state that in early adolescence (ages 12–16), cognitive functioning is already well developed, and it is possible to use questionnaires similar to those designed for adults. With this number of students experiencing migration as an adolescent in the same location, a carefully planned, group administration of the survey was used to capture as many participants as possible. The entire population of students enrolled in the program was targeted because all students have a unique history and world view.
The survey respondent sample was comprised of adolescents (n = 391; age 14–21; 45.2% female, 72.6% Spanish-speaking [37.9% Salvadorean, 17.4% Honduran, 14.9% Guatemalan]; 7.4% Arabic-speaking, 4.3% Amharic-speaking, and 2.5% Dari-speaking; see Table 1). Adolescents represented grade levels 9–12 and had a mean GPA of 2.53 (of 4.0); most had experienced a change in family structure when moving to the US (64%). A description of the adolescents participating in this study is critical to situate the findings.Table 1 Summary of descriptive statistics of demographics of survey respondents
n Percent
Total 391 100
Male 213 54.6
Female 177 45.4
Grade level
9 94 24
10 121 30.9
11 112 28.6
12 63 16.1
Country of origin
El Salvador 148 37.79
Honduras 68 17.39
Guatemala 58 14.83
Afghanistan 25 6.39
Ethiopia 18 4.6
Egypt 5 1.28
Eritrea 3 .77
Home language
Spanish 285 72.89
Arabic 29 7.42
Amharic 17 4.35
Dari 10 2.56
Sampling Procedures
Total population sampling was utilized in this study. Of the target population of 585, all students consented and were invited to participate, and 391 took the survey. During the initial administration, 350 students participated, a response rate of approximately 60%, due to student absences and 13 students opting out. Absent students were invited the following day to take the survey should they choose, and an additional 41 students took the survey, bringing the response rate to 67% and a total of 391 participants, which surpassed the amount needed for a 95% confidence interval. A sample of more than 384 participants was needed for a 95% confidence interval for a population of 590 students (de Leeuw et al., 2008). The expected response rate for this survey was high due to its in-person, personalization, relevance, and advanced-notice qualities (Anseel et al., 2010). A uniform administration of a face-to-face survey helped to achieve a high response rate (de Leeuw et al., 2008).
The sample responding to the survey was representative of the total population in two of three categories (see Tables 2 and 3). The chi-square analyses revealed no significant differences for home country (χ2 [df = 3, N = 386] = 3.896, p = 0.272). There was also no significant difference from the population for grade level (χ2 [df = 3, N = 386] = 7.420, p = 0.060). Slightly more females responded to the survey than are represented within the population (χ2 [df = 1, N = 386] = 4.712, p = 0.032). However, Cohen’s w (0.109) indicates a small effect size, which is consistent with the research finding that females have a higher response rate on surveys than males (Smith, 2008). Therefore, the PSSM sense of belonging analysis controlled for gender.Table 2 PSSM belonging score descriptive statistics
n M SD
Total 380
Gender
Male 213 20.95 6.80
Female 177 22.67 5.75
Grade level
9 94 21.55 6.78
10 121 21.86 6.28
11 112 22.47 6.05
12 63 20.47 6.44
Home language
Spanish 276 21.73 6.44
Arabic 29 22.34 6.33
Dari/Persian/Pashto 24 20.67 5.29
Amharic 17 22.41 6.72
Other 48 21.50 6.15
WIDA Level
1 98 21.23 6.74
2 106 21.61 6.52
3 112 22.47 5.86
4 38 22.11 6.32
5 5 20.00 8.53
6 5 20.00 5.28
Hours working per week
0–10 46 21.09 6.92
11–20 63 20.97 5.84
20+ 83 22.52 6.26
No job currently 188 21.80 6.46
Paying for rent
No 248 22.22 6.24
Some 88 20.97 6.58
All 33 19.97 6.93
M and SD represent mean and standard deviation, respectively. Languages represented in “other” were Bengali, Dutch, Ewe, Farsi, Filipino, French, Greek, Italian, Krio, Portuguese, Tigrinya, Time, Twi, Urdu, and Wolof
Table 3 Chi-square goodness-of-fit results of sample in context
Chi-square goodness-of-fit Sample versus Pop Sample Population
Frequency % of n n Average/raw # % of N N
GPA 2.53 (0.86) 391 2.12 587
Gender χ2 = 4.712 211 Male 54.66 386 351 Male 60 585
p = .032 175 Female 45.34 234 Female 40
Grade level χ2 = 7.420 9–93 24.09 386 9–166 28.38 585
p = .060 10–119 30.83 10–168 28.71
11–111 28.76 11–142 24.27
12–63 16.32 12–109 18.63
Country of origin χ2 = 3.896 El Salvador—144 37.31 386 El Salvador—237 40.51 585
p = .272 Honduras—68 17.62 Honduras—109 18.63
Guatemala—58 15.03 Guatemala—88 15.04
Ethiopia—18 4.66 Ethiopia—25 4.27
Afghanistan—25 6.48 Afghanistan—37 6.32
Egypt—5 1.30 Egypt—6 1.02
Eritrea—3 0.78 Eritrea—3 0.51
Other—65 16.84 Other—80 13.68
Ethical Considerations
IRB approval was received, and informed consent opt-out forms and assent forms were obtained from the parents and adolescents, respectively. Survey forms were translated into Spanish, Amharic, Arabic, and Dari for participants and their families. Due to linguistic differences within this population, all directions and survey items were carefully chosen or worded in simplified English sentences, avoiding idioms, to ensure that translation into multiple languages would retain meaning and increase reliability. Back translation with interpreters familiar with the International Academy context and pilot testing with alumni were used. Back translation interpreted the survey back to English to ensure the translated text was faithful to the original source survey (de Leeuw et al., 2008).
Instrument
The survey instrument consisted of 73 questions designed to gather information from students in the following major areas: respondents’ backgrounds and demographics, opinions on their experiences in four primary structures embedded in their instructional program, and their sense of belonging.
School belonging was assessed by Goodenow’s (1993) Psychological Sense of School Membership Scale (PSSM), with 13 positively worded and 5 negatively worded items. This construct is the only scale on the survey that was summed and used as the dependent variable in all data analyses following all reliability measures. The PSSM includes items such as, “I feel like a real part of this school,” and “People here notice when I’m good at something.” Items on the PSSM contained a 5-point Likert-type format (1 = not at all true; 5 = completely true). These were then summed to produce a scale score ranging from 0 to 32.
There were 32 demographic questions and 19 open-ended or multiple-response questions to garner perceptions, opinions, and examples. Students were asked their opinions in the first half of the survey, and easier demographic questions followed to increase the likelihood that students complete the survey and avoid submitting incomplete data. Multiple demographic questions (32) enabled specific ways of aggregating students beyond home country, language, age, and gender. Research has supported the contribution of these variables as having a significant impact on student performance in school, their academic resilience, and their sense of belonging at school (Mena et al., 1987; Perez et al., 2009; Suárez-Orozco et al., 2008, 2009). Based on that research, the in-depth demographic indicators collected were the length of time in the program, age upon arrival in the US, self-report of grades, extracurricular involvement, personal valuing of school, family structure before and after emigration, family reunification, parental education and valuing of school for their children, number of siblings, hours worked per week, and rent obligations.
Surveying MLLs is a difficult task, and ensuring valid data collection despite linguistic differences was at the forefront. Suárez-Orozco et al. (2008) surveyed MLLs for a five-year longitudinal study on immigrant experiences in school. The content and wording of many items were inspired by their survey and interview protocols. Their permission is granted by their citation request here (see Suárez-Orozco et al., 2008).
Validity and Reliability
Many measures were taken to ensure the validity and reliability of this survey and its administration. First, acceptable internal consistency reliability was established (Cronbach’s alpha) for this sample using the PSSM eight-item scale and was 0.85 (greater than the generally recognized threshold of Cronbach’s alpha of 0.70). Internal consistency of this scale ranged from 0.73 to 0.95 across samples and countries (Abubakar et al., 2016; Goodenow, 1993; You et al., 2011) and was 0.80 in Goodenow’s (1993) initial study. Goodenow’s original survey (1993) was the blueprint for the response order for the present study.
There are many studies on the validity and reliability of the PSSM given in English (Goodenow, 1993; Ibañez et al., 2004; Sánchez et al., 2005), and there are a growing number of studies on the validity of the PSSM given in multiple languages. The PSSM has been widely used, mainly in English-speaking countries, and has been associated with increased competence and self-efficacy (Ibañez et al., 2004), increased school attendance (Sánchez et al., 2005), and higher grades (Booker, 2007). However, this survey was taken in the students’ preferred language; the largest groups preferred Spanish (65%), English (21%), and Arabic (5%). In alignment with this study, the PSSM scale has been administered in multiple languages (e.g., Cheung, 2004; Cheung & Hui, 2003; Gaete et al., 2016; Togari et al., 2011) and in multiple countries. To increase validity, the study of this scale is increasing internationally, such as in China (Cheung, 2004; Cheung & Hui, 2003), Japan (Togari et al., 2011), and multi-country settings (The Netherlands, Kenya, Indonesia, and Spain; Abubakar et al., 2016).
When using the Spanish PSSM scale specifically, Gaete et al. (2016) studied the use of the PSSM among Latin American adolescents and found that using only the positively worded questions in the Spanish version was valid and highly reliable. They studied the validity and reliability of this scale in a sample of 1250 early adolescents in Chile and found that the internal consistency of this new abbreviated version was 0.92. Because the survey in this study was taken in multiple languages, the majority being Spanish, Gaete et al. (2016) guidance was followed and the negatively worded items were removed. The translated negative items, cognitive development, and proficiency in reading comprehension for students may have caused difficulty in understanding the intercalated question format (Gaete et al., 2016); therefore, those questions in the scale were removed. In this study, the unidimensional PSSM scale of the positively worded items was used in English, Spanish, and multiple other languages to assess belongingness.
Survey Data Collection Procedures
Approval was received to invite all students enrolled in the International Academy to participate in the study for total population sampling. One week before the survey was administered, students took home a parental consent form, available in families’ preferred languages. The day before the study, teachers collected opt-out forms and student assent forms; provided explanations and reminders, such as to charge their Chromebook; and showed a short student-created instructional video of how students could translate the Google Form into their preferred language. The study took place in students’ first-period class on a Wednesday, as data showed higher student attendance occurred mid-week. The survey was administered with a teacher script to reduce potential bias; the survey was given in one session rather than dividing it, as multiple surveys tend to reduce response rates (Porter et al., 2004). No identifiable student information was collected. Students were provided with a personalized handout to record the correct GPA, teacher team, and WIDA score in the survey. Thirteen students who opted out or students whose parents had opted out were provided a handout with free-response questions about their experience in school and the ways they belong to reflect on the same constructs; their data was not used, but the opt-out survey recipients maintained a reflective class atmosphere.
Interviews
The second data collection method was student interviews. Student voice is a quintessential element of a sense of belonging, and, therefore, interviews were chosen to enhance what students wrote in the survey about their sense of belonging and school community experiences. Interviews can support survey data by suggesting explanations for the “hows” and “whys” of key events and provide insights reflecting participants’ perspectives (Yin, 2018, p. 118). The interview phenomenon of interest was the newcomers’ experience with dynamic connections with new people, a new school, a new language, and a new country. Because of COVID-19 restrictions, 14 participant interviews were conducted via Zoom, a video conferencing online platform familiar to students. All students chose their own pseudonym and its spelling. Nicholas et al. (2010) state that online interviews can create a non-threatening and comfortable environment that provides greater ease for participants when discussing sensitive issues. The interviews were to enhance, explain, or elaborate on the initial survey data to bring greater insight into the research question.
Stemming from Bronfenbrenner’s (1994) and Goodenow’s (1993) seminal work on sense of belonging, Allen and Kern (2017) devised a recent iteration of a sense of belonging framework, called the bio-psycho-socio-ecological model of school belonging (BPSEM), which shows that there is no single component leading to school belonging for an adolescent. Rather, belonging is a blend of biological, psychological, social, and ecological qualities and experiences. This framework was used to code the qualitative research data to analyze the complex layers of a student’s sense of belonging.
Participants
Purposive sampling (Chein, 1981; Merriam, 1998) was used to recruit interview participants. Using a criterion-based selection process, all students enrolled in the International Academy were sorted into three categories that indicated their academic engagement based on grades and attendance. Suárez-Orozco et al. noted that academic engagement is important for academic success: “Highly academically engaged students are actively involved in their education, completing tasks required to perform well in school” (2008, p. 42). Students were grouped into three categories: high- (0–2 blocks missed and grades higher than 75%), medium- (3–15 blocks missed and grades higher than 68%), and low-engaged students (16–43 missed blocks and grades lower than 50%). To be clear, these indicators of academic grades and attendance are not to be confused with a lack of desire or interest in school. The two criteria tools aligned with previous research as indicators of academic success and foreshadowed students’ dropping out of school (Rumberger, 2004; Suárez-Orozco et al., 2008). By no means is a low academically engaged participant uninterested in education; the participant may be very interested in graduating and learning a new language but may have other life circumstances thwarting that desire.
Within each category, recruitment began with a randomly generated list of students per category. Interview rounds continued to ensure representation in each group. Although equal proportions could not possibly be achieved unless every student was interviewed, loosely proportional representation can be seen with gender, grade level, home language, and age that represent the makeup of all participants within the high (5 students), medium (5 students), or low (4 students) categories (see Table 4). Interviews continued until data saturation. Overall, 42 students were contacted, and 14 agreed to participate with parental permission or with their permission and consent if they were over 18 (see Table 4).Table 4 Summary of interview participant demographics
Pseudonym Academic engagement level Age Country of birth Grade completed Home language Gender Time in US Schools Working Family Language of interview
Alexis High 18 Guatemala 12 Spanish Female 4 years Yes—Restaurant With father Spanish/English
Maryam High 18.6 Afghanistan 11 Dari Female 3 years Was—Dollar Tree With both parents English
Tatiana High 16.9 El Salvador 11 Spanish Female 5 years Yes—Dunkin Donuts With father English
Gabriella High 17 El Salvador 10 Spanish Female 5 months No With both parents Spanish
Maynor High 17.5 Honduras 9 Spanish Male 10 months No With both parents Spanish
Ben Medium 17.6 Ivory Coast/ France 11 French Male 3 years No With both parents English
Natasha Medium 18 Dominican Republic 11 Spanish Female 3 years Yes—Chipotle With mother Spanish
José Medium 15 Honduras 9 Spanish Male 10 months No With both parents Spanish
Jutt Medium 16 Pakistan 10 Urdu Male 2 years No With both parents Urdu/English
Shani Medium 16 Pakistan 10 Urdu Male 2 years No With both parents English
David Low 17.2 Honduras 10 Spanish Male 4 years Yes—Restaurant With mother Spanish
Jave Low 20 El Salvador 11 Spanish Female 4 years Yes—Chipotle Alone Spanish/English
Liya Low 18 Afghanistan 11 Dari Female 3 years Yes—Dunkin Donuts With both parents Dari/English
Luis Low 19 Guatemala 11 Spanish Male 4 years Yes—Construction With brother—parents in Guatemala Spanish/English
Protocol
The interview protocol consisted of 27 questions, and the interviews lasted approximately 90 min. The questions were devised based on the survey analysis and students’ experience of belonging (e.g. “Can you tell me about a time when you felt like you were a part of the school community?” and “Can you tell me about a time when you did not feel a part of the school community?”) Hoppe et al. (1995) recommended that student feedback sessions last no longer than one to two hours to maximize students’ attentional resources. Probing questions were prepared, and frequently used, to follow up any responses that required more nuanced answers, such as, “Tell me more about that,” or “Why did you feel that way?” The interview was conducted in the language most comfortable for students. Interviews were conducted by the bilingual researcher/author (English/Spanish), who built a sustained relationship and level of trust with participants at their school. To mitigate bias, interview protocols received outside review, all consent/assent procedures were followed, students could opt-out at any time, and critical friends reviewed each stage of the interview process, including coding. The author acknowledges that while it does not eliminate all bias, the sustained relationship, extended commitment to students, and conscious reflexivity aimed to mitigate some notions of power and privilege as an honorary insider. Carling et al. (2014) state that honorary insiders can produce findings and access that other researcher roles and perspectives cannot produce. Interviews were transcribed to conduct coding and analysis.
Data Analysis
Surveys
The first round of statistical data analysis consisted of three parts, utilizing SPSS and NVivo. First, descriptive statistics regarding a wide range of student demographics were synthesized to provide context for the study population. Second, the eight items in the Sense of Belonging section were summed into a scale score to measure the larger construct of belongingness (Goodenow, 1993). Regression analysis was conducted between student demographics and the scale score of sense of belonging on the PSSM to describe the population’s sense of belonging at a snapshot in time. Cohen’s (1988) recommendations for large association (r2) of 0.25 or higher, medium association (r2) of 0.09 or higher, or low association (r2) of 0.01 or higher were used to determine which variables explained a statistically significant proportion of the variance in a sense of belonging. Alpha was set at 0.05. Five main assumptions for regression were both checked and met: independence of observations, normal distribution, homoscedasticity, linearity of data, and non-zero variances. Third, student open-ended response text data were coded for emergent codes and then the belonging framework (Allen & Kern, 2017) for patterns. The quantitative survey data are the focus of this manuscript, with qualitative data used for recommendations from students themselves.
Interviews
The student interviews were coded and analyzed iteratively in three rounds utilizing NVivo. There was frequent code-switching between languages during the interview, and these language switches were transcribed and retained in the language the students used for each comment. English interpretations were then added by a certified transcription and interpretation service. Utterances such as “uh,” “um,” and pauses were removed.
First, inductive coding was conducted for emergent themes in all the interviews. Inductive codes are developed by the researcher by examining the data (Creswell, 2013). Creswell (2013) recommends researchers be open to emergent codes, avoiding any “prefigured” codes that may serve to limit the analysis. By coding for emergent themes within the research question first, unbridled themes could develop. Next, codes were reviewed for secondary codes, to clarify their titles, add details, combine, and reorganize. Creswell and Báez (2020) recommend looking for “overlap and redundant” codes, then reducing the number of codes and collapsing them into five to seven themes that become the major headings (p. 162). This was an iterative process, while themes and categories surfaced. A mind map was created from emerging secondary themes (parent codes) with child codes/themes. Memoing and field notes were maintained throughout the process to provide a supplemental check on analysis and reflexivity.
The next step was the third round of a priori coding for the circular, BPSEM Sense of Belonging framework from Allen and Kern (2017). The coding of each interview began again with the framework saturating the mind of the researcher, identifying which layer students were referencing when discussing their experiences. Lastly, each layer of the framework was reviewed to look for common trends, patterns, and commonalities with the emergent coding. The results of the two rounds of coding helped to qualify the quantitative findings.
Results
Results were analyzed for statistical significance and implications for the student experience. Table 5 provides regression analyses conducted using students’ PSSM belonging score as the dependent variable to determine which independent variable or factor may have been a predictor of belonging. Notably, trends emerged to push belonging research in a new direction. For the open-ended survey and interview responses, findings consisted of four larger themes that described aspects of participants’ experiences that fostered belonging.Table 5 Sense of belonging regression results
Variable N r2 B
Unstandardized Beta SE B
Standard error of unstandardized beta Β
Standardized beta T p-value
GPA 380 .007 .634 .377 .086 .094
Sex [females] 379 .018 1.719 .655 .134 .009*
Language [Spanish] 380 .003 21.738 .385 56.436 .888
[Amharic] .673 1.607 .022 .419 .675
[Arabic] .606 1.255 .025 .483 .629
[Dari] − 1.538 2.071 − .038 − .743 .458
[All other Lang] − .338 1.034 − .017 − .327 .744
WIDA [ALL] 380 .000 − .033 .277 − .006 − .120 .905
WIDA level, [WIDA 1] 380 .010 21.196 .650
[WIDA 2] .665 .883 .048 .753 .452
[WIDA 3] 1.353 .886 .097 1.527 .128
[WIDA 4, 5, 6] − .450 1.081 − .025 − .417 .677
Grade level [ALL] 380 .001 − .153 .322 − .024 − .476 .634
Grade level [Grade 12] 380 .010 20.468 .813
[Grade 9] 1.087 1.052 .073 1.033 .302
[Grade 10] 1.397 1.004 .101 1.391 .165
[Grade 11] 2.004 1.020 .141 1.965 .050*
Grade level [Grade 12] 380 .030 19.552 .870 22.462 .020*
[Grade 9] 1.226 1.044 .082 1.175 .241
[Grade 10] 1.350 .995 .098 1.356 .176
[Grade 11] 2.225 1.014 .157 2.194 .029*
[Gender–females]—control 1.831 .659 .142 2.780 .006*
Years in program, [one year or less] 377 .011 21.673 .516 42.025
[Two years] .696 .761 .052 .915 .361
[Three years] .160 .939 .010 .170 .865
[Four or more years] − 1.923 1.311 − .079 − 1.467 .143
Separated from a parent 361 .001 .466 .666 .037 .699 .485
Mother’s education, [High school grad] 344 .001 21.888 .505 43.360
[Elementary or middle school] − .154 .794 − .011 − .194 .846
[Technical school or some college] .596 1.256 .027 .474 .636
[College graduate] .065 1.100 .003 .059 .953
Father’s education, [high school grad] 326 .003 22.281 .490 45.494 .024*
[Elementary or middle school] − .767 .901 − .050 − .851 .395
[Technical school or some college] − .531 1.292 − .024 − .411 .681
[College graduate] − .495 .947 − .031 − .522 .602
Students working 380 .001 − .379 .658 − .030 − .575 .565
Paying rent 369 .022 − 2.036 .709 − .148 − 2.872 .004*
α = .05*; SOB, sense of belonging; SOB found using PSSM questionnaire responses
Important Predictors
Of particular interest, significant results arose for the variables of gender, home language, and paying rent.
Gender
First, aligned to previous belonging research (see Allen & Kern, 2017; Goodenow, 1993; Sánchez et al., 2005; Smerdon, 2002), gender (being a female) explained a statistically significant proportion of variance in sense of belonging score, t(379) = 2.623, p = 0.001, r2 = 0.018. However, in this study, gender explained only 1.8% of the variance in a sense of belonging. Using Cohen’s (1988) power tables, this would be considered a low association. Studies have shown that Latina females are more likely to finish high school than Latino males (Wojtkiewicz & Donato, 1995), and they tend to have higher grade point averages (López et al., 2002). This finding raises questions about support for belonging for male students.
Home Language
Next, in this sample, home language did not explain a statistically significant proportion of variance in sense of belonging score, F(4, 375) = 0.285, p = 0.888. However, students who do not speak Spanish, Amharic, or Arabic (the three languages spoken most in the population) had a lower sense of belonging score on average. In this sample, the order of highest sense of belonging scores to lowest by language spoken was Amharic (MAmharic = 22.41, SD = 6.72), Arabic (MArabic = 22.34, SD = 6.33), Spanish (MSpanish = 21.73, SD = 6.44), all other languages, then Dari (MDari = 20.67, SD = 5.29). This finding raises questions for future research about belonging for students without many common-language peers, such as Dari speakers in this study.
Paying Rent
Third, 24.1% of students surveyed paid some of their rent, and 9.1% paid all their rent. Students who paid some or all their rent had a statistically significantly lower sense of belonging score. Paying rent explained a statistically significant proportion of the variance in sense of belonging scores, t(369) = −2.872, p = 0.004, r2 = 0.022. For those who were responsible for providing a roof over their head, paying rent influenced their sense of belonging.
Trends
Most variables did not have a statistically significant effect on their sense of belonging but did provide some interesting insights into trends (see Table 5), such as GPA, English proficiency level, grade level, time in the program, parental factors, and employment status. These variables alone did not explain variance in their sense of belonging and failed to show that they can predict belonging.
Grade Point Average (GPA)
This variable was hypothesized to have an impact on belonging, but the data showed otherwise. Interestingly, a student’s GPA was not a statistically significant predictor of sense of belonging scores, t(378) = 1.681, p = 0.094, nor was a student’s belonging score a predictor of a student’s GPA.
English Proficiency Level
As students’ English proficiency (WIDA level) increased, their belonging scores increased (see Fig. 1). However, students’ WIDA level did not explain a statistically significant proportion of the variance in sense of belonging scores, F(3, 376), p = 0.277. Interestingly, WIDA 4, 5 and 6 students had a lower sense of belonging score than WIDA 1. As English proficiency increased up to a WIDA 3, sense of belonging increased. Studies have related being able to express and understand the language with high academic performance over time (Suárez-Orozco et al., 2010). There was also a connection within student interview comments between a student’s grasp of English and their success in classes, performance on tests, and sense of belonging. Additionally, there is a phenomenon of decreased belonging at the end of high school that merits future research.Fig. 1 Belonging trends as grade level and English Proficiency score increase
Grade Level
The evidence shows a connection between grade levels and language growth with a sense of belonging (see Fig. 1). As students are promoted to the next grade level, their belonging scores increase. For example, as students move from ninth to eleventh grade, their sense of belonging score increases slightly, but twelfth graders have the lowest sense of belonging score (M = 20.47; SD = 6.44). Importantly, when controlling for gender, grade level explained a statistically significant amount of the variance in sense of belonging, F(4, 375) = 2.946, p > 0.05, r2 = 0.030. However, despite its statistical significance, grade level did not explain much of the variance in belonging. As compared to a student’s first year in the program, a student’s sense of belonging score increases each year and then declines in their fourth year or more in the program.
Family Factors
This study explored many family variables as possible predictors of belonging in participants’ new school. Family separation and reunification were experienced by 64% of students surveyed, meaning almost two-thirds of the students experienced a change in who was responsible for them when they were growing up and whom they were living with now (see Table 6). Whether students were separated from a parent during the process of migration did not explain a statistically significant proportion of variance in sense of belonging score, t(361) = 0.699, p = 0.485. The study examined the level of parental educational attainment as a gauge of socioeconomic status (see Table 7), one factor that is particularly pertinent to the educational and academic attainment of their children (Suárez-Orozco et al., 2008). Although a mother’s level of education was not a significant predictor of sense of belonging score, F(3, 340) = 0.111, p = 0.953, students whose mothers finished elementary school or elementary and middle school had a lower sense of belonging score than those students whose mothers finished high school. Similarly, a father’s level of education was not a significant predictor of belonging, F(3,322) = 0.284, p = 0.837. Interestingly, students across all demographics whose fathers graduated from high school had the highest sense of belonging score (M = 22.28 out of 32). Regardless of levels of parental education, 86% of students said their parents think that getting good grades in school is very important. The study revealed that students place a very strong value on their education, and 98.7% of students feel that it is important to do well in school. This finding verifies the importance and value of education that students and families hold.Table 6 Survey respondents change in family structure in the transition to the US
Responsible for student growing up Student lives with now n
Both mom and dad in same house Both mom and dad in same house 98
Only my mother 20
Only my father 3
Mother/father and step-parent 5
Aunt/Uncle/Sibling/Grandparent 24
Alone 1
Only my mother Only my mother 35
Only my father 9
Both my mom and dad 2
Mother/father and step-parent 10
Aunt/Uncle/Sibling/Grandparent 12
Alone 1
Foster parents 1
Only my father Only my father 8
Both my mom and dad 1
Mother/father and step-parent 2
Aunt/Uncle/Sibling/Grandparent 4
Alone 1
Foster parents 1
Mother/father and step-parent Mother/father and step-parent 9
Only my father 1
Only my mother 1
Aunt/Uncle/Sibling/Grandparent 4
Aunt/Uncle/Sibling/Grandparent Both my mom and dad 8
Mother/father and step-parent 18
Only my mother 11
Only my father 2
Aunt/Uncle/Sibling/Grandparent 14
Lived alone Still live alone 4
Aunt/Uncle/Sibling/Grandparent 2
Table 7 Parental education levels
n Percent
Elementary school
Mother 66 16.9
Father 44 11.3
Middle school
Mother 41 10.5
Father 26 6.6
High school
Mother 74 18.9
Father 70 17.9
Technical school
Mother 10 2.6
Father 11 2.8
Some college
Mother 21 5.4
Father 17 4.3
College
Mother 42 10.7
Father 57 14.6
I don’t know
Mother 79 20.2
Father 91 23.3
Mother and father categories include stepparents
Working a Job
Lastly, students in this study were learning to balance working and going to school at the same time, and 40.9% of students were sending money back to families in their home countries due to the need to support family members and repay fees for moving to the US. Employed students did not have a statistically significantly higher or lower sense of belonging score. Importantly, 50% of the survey respondents had a job and were working and going to school at the same time (see Table 8). Perhaps most notably, 21.2% of students work 20 or more hours per week, all while attending school.Table 8 Summary of financial responsibilities of newcomers
n %
Work
Total 197 50.3
Male 123
Female 74
Grade 9 29
Grade 10 51
Grade 11 71
Grade 12 46
Work 20+ hours per week
Total 83 21.2
Female 27
Male 57
Grade 9 4
Grade 10 18
Grade 11 35
Grade 12 27
Send money home
Total 160 40.9
Female 70
Male 90
Grade 9 35
Grade 10 42
Grade 11 49
Grade 12 34
Pay for some rent 87 22.2
Pay for all rent 31 7.9
Pay for some or all rent
Female 39 9.9
Male 79 20.2
9 18
10 30
11 37
12 33
Common Themes
Five themes regarding student belonging emerged in the qualitative comments through open-ended survey responses and interviews.
Language
First, the construct of language (all home languages and English) played a dynamic, sensitive, and nuanced role in developing a sense of belonging at school. This study went beyond the five components of language (i.e., phonology, morphology, syntax, semantics, and pragmatics; Berko Gleason, 2005) and focused on language as a social semiotic system, and sociocultural, receptive, and expressive method of communication (Halliday & Hasan, 1985). Using language gives way to socioculturally distinctive ways of thinking, acting, interacting, talking, and valuing (Gee, 1990). Students mentioned language frequently, what others said and how they said it, when describing themselves and how they felt they were accepted, valued, included, comforted, and encouraged by peers and staff. Specifically, translanguaging was used in the classroom daily and contributed to belonging. Students navigated assignments in two or more languages, accessing their linguistic repertoires to coach each other, communicate, and showcase their learning (García, 2009). Language differences, language acquisition, language learning, language challenges, and language fears wove through student comments. Language was also used to exclude and oppress, decreasing belonging. For example, Natasha, an 18-year-old eleventh grader from the Dominican Republic, felt excluded due to her Spanish accent, which differed from that of her Spanish-speaking peers from El Salvador. Language as a dynamic, social component contributed to newcomers’ belonging.
Network of Support
Second, this study revealed that newcomers built an intricate web of support from peers, staff, and families that contributed to their sense of belonging so that school felt like a second family or second home. The “IA is where students get to know and learn about a lot of cultures, languages, and the most important thing: they will have friends from other countries. Also, students can learn English and other languages easily” (Ben, a 17-year-old eleventh grader from the Ivory Coast). Ben’s observation highlights the network of international peers, friends, and staff who support their academic journey. Alexis, an 18-year-old twelfth grader from Guatemala, shared that students learn about themselves through experiences at school. The school “es como una familia, porque te ayudan, te dan apoyo, te hacen sentir que sos importante para ellos, te dan atención, respeto, cariño y todo. [School is like a family, because they help you, they give you support, they make you feel that you’re important to them, they give you attention, respect, affection, and everything.]” (David, a 17-year-old tenth grader from Honduras). When discussing how students provided support in L1, students shared that they explained, clarified confusion, took the initiative of helping others, called and texted peers to get them into virtual classes, and made friends while helping each other out.
Opportunity to Participate
Third, the opportunity to participate in activities, experiences, and practices in and out of high school fostered belonging. School structures that students referenced as opportunities were grouped into four categories: future preparation, tailored and extensive course offerings, during- and after-school activities, and resources. Experiencing these opportunities and activities together helped students belong and feel included, accepted, and valued.
Emotional, Linguistic, and Physical Safety
Fourth, emotional, linguistic, and physical safety and security were embedded within almost every interviewee’s comments. Feeling safe is a basic human need (Maslow, 1943). If a student does not feel safe, belonging cannot occur. Feeling emotionally safe to share your feelings, linguistically safe to make mistakes with language, and physically safe and secure from danger were foundational components of a rich school environment where newcomers feel like they belong.
Acknowledgment and Recognition
Lastly, students appreciated recognition of hard work, a celebration of successes, and feeling valued, seen, and heard. Goodenow’s (1993) definition directly addresses how feeling valued and encouraged by others defines school belonging. Acknowledgments of hard work along with a difficult life transition reinforced student value and showed that they are seen, heard, and appreciated. This recognition ranged from Honor Roll Assemblies and awards to personal words of advice and praise, to asset-based recognition and interaction with native speakers.
Many of the statistical results contradicted hypotheses about factors within a student’s life experience that may have affected their sense of belonging at school. Others shed light on the phenomenon of a student’s journey through their instructional program. Knowledge regarding the complexities of students’ transition into adolescence, a new language, a new country, a new school community, and, for 64%, a new family structure, provides insight into how school culture and programming may impact and support feelings of belonging, rather than variables that can predict belonging. These findings led to recommendations to foster belonging directly from students.
Limitations
Whereas many steps were taken to increase the validity and reliability of the data, there were a few limitations to each data collection component of this study. First, quantitatively, limitations of the survey methodology included social desirability bias in students’ responses and response rates for absent students the week of the survey. Although the sample size of 391 was quite large, low power resulted for many variables with few statistically significant results. Most of the variables studied could not predict belonging. For the qualitative data collection measures, 42 participants were contacted and 14 agreed to participate. Although the demographics of the students interviewed reflected a strong attempt at proportional representation, the student participants were not fully representative of the full population of the bounded case, which consisted mostly of Spanish speakers. Truthfulness in interviews and the survey and researcher reflexivity are limitations. The requirements for the protection of humans perhaps adversely affected the study because consenting to any kind of form may have dissuaded any particularly skeptical families. Lastly, common home countries, home language, age, or grade may not generalize to students from different places. This is always a limitation unless an interview were possible with all 585 students in the population. Although generalizability is not needed to draw important conclusions, this study’s findings, among other studies, can aid in generalizability.
Discussion
The central contributions to the body of literature is that this study reinforces existing knowledge and provides new insights on newcomer belonging.
Contributions
Regarding the study design, the methods used further confirm the validity of the unidimensional PSSM for multilingual youth. The large scale of multilingual adolescents taking the survey in 13 languages is unique and exemplifies the possibility and importance of careful methodological research planning including interpretation, back translation, pilot testing, and building on the work of others. The study occurred in 2019 and 2020 during a period of criminalization of immigrants, fear of deportation, and DACA uncertainties (Ee & Gándara, 2020; Ybarra, 2018) due to the harsh immigration enforcement policies implemented after the 2016 United States presidential election (Ee & Gándara, 2020). Belonging for newly arrived adolescents is impacted by these types of policies, sentiments, and rhetoric. Therefore, findings are relevant to current sociopolitical realities for immigrant youth and their sense of belonging to a school community. Future research could replicate these study methods at multiple types of sites such as Internationals sister schools, traditional high schools, and other secondary newcomer programs to compare and strengthen findings and aid in generalizability.
Regarding the quantitative findings, three of the 11 variables examined are found to be statistically significant predictors of belonging. The most significant results are that females had a higher sense of belonging; students from less-dominant language groups and students paying rent had the lowest sense of belonging; and as students progressed from ninth, tenth, then into eleventh grade, their sense of belonging increased until their senior year (see Fig. 1), making only two of the hypotheses true for this population. The statistical analysis failed to show that many variables were predictors of belonging.
This type of statistical analysis has not been conducted on such a large and diverse sample of newcomers and warrants further research. The results align with previous research regarding female students and the importance of relationships; results extend belonging research to include particular attention to students in smaller language groups and students paying some or all of their rent. Furthermore, the findings extend Suárez-Orozco and colleagues’ (2008) study to add that experiences, gender, home language, and paying rent may decrease belonging, and that some hypothesized predictors cannot predict belonging, such as GPA, working a job, or family factors.
Additionally, patterns were observed for students’ grade level and English proficiency. Future research is also warranted into trends in English language development and belonging (see Fig. 1). The phenomenon of belonging decreasing during senior year and as students attain higher English proficiency levels is an additional area for future research. The evidence suggests that there is a connection between grade levels and language growth with a sense of belonging (see Fig. 1). The trend results push belonging research in a new direction. The evidence suggests that many students connect language growth and acquisition with an increased sense of belonging. The longer students were in the program, the more English they acquired, and the more they felt they belonged. As students are promoted to the next grade level, their belonging scores increase. As students’ English proficiency (WIDA level) increases, their belonging scores increase. Students enter the program between a WIDA level one and three and maintain their enrollment in the IA as they aim to increase to a level six English proficiency—six is the highest score, called “reaching” native-English proficiency (WIDA, 2020). Studies have related being able to express and understand the new language with high academic performance over time (see Suárez-Orozco et al., 2010). Students’ comments show a relationship between their grasp of English and their success in classes, on tests, and belonging.
When coupled with other studies, schools may consider adjustments in their programming to support students based on this data, specifically within the populations of male students, students of smaller home language groups, and students paying rent.
Regarding the qualitative findings, evidence from this study describes how students are experiencing belonging in school. Five themes emerged as the components of students’ school experiences that contributed to their sense of belonging. The themes of language used to orient and encourage, networks of peer and teacher support, opportunities to participate in activities during and after school, safety (linguistic, emotional, and physical), and acknowledgment and recognition of student growth were critical contributing factors to newcomers’ sense of belonging. Stemming directly from these themes and student comments, district and school leadership may reference the following student-derived recommendations.
Considerations
Based on these findings, educators, researchers, and advocates may consider what students shared as recommendations to support belonging. These recommendations either came directly from the participants or emerged through the analysis of the open-ended survey responses and interviews. For male students and students who are members of smaller language groups, schools may consider the following five recommendations to foster belonging in secondary school spaces.
Create Peer Networks of Support
Support networks for peers who have a shared immigration experience serve a specific purpose: students feel that their classmates and friends play distinct and important roles in their acculturation, comfort, and experience at a new school. Recommendations include implementing ways to enhance peer relationships in and outside of the classroom, implementing collaboration in heterogeneous groups into classroom curriculums, and creating formalized peer mentorship programs. Many students mentioned that they love when they share ideas, hear from each other, and participate in Community Circles. Sharing ideas can also occur beyond the classroom walls in shared text groups (WhatsApp), and informal spaces such as hallways, cafeterias, and buses. The strength of peer relationships or bonds cannot be understated. Within peer groups of four, students explained that they helped each other navigate assignments. For example, David shared why he prefers to collaborate in small groups with others:Por ejemplo, si no le entiendo a algo y otro alumno sí y está en mi grupo él “me echa la mano,” me ayuda a entender; ayuda bastante eso de los grupos de cuatro porque si cae uno están los otros tres que lo pueden levantar, entonces es útil. [If I don’t understand something and another student does, and he’s in my group, he “gives me a hand.” He helps me understand. It helps a lot to work in groups of four because if one falls, there are the other three who can lift him, then it’s useful.]
These planned, collaborative, classroom structures provided opportunities for students to belong. Although many students informally mentored new students as they arrived through mixed ninth- and tenth-grade classes, more formal mentorship programs can provide structured opportunities for all students to mentor and be mentored. These relationships provide social-emotional and academic learning support as a part of a newcomer transition.
Safety
In this study’s open-ended questions and interview responses, emotional, linguistic, and physical safety were critical aspects that contributed to newcomers’ belonging. First, emotional safety, which consists of confidence, trust in others, and freedom from embarrassment, is imperative for belonging. Next, linguistic safety to take risks with language and the freedom to make mistakes are critical to belonging. Lastly, physical safety (freedom from danger and violence) is one of Maslow’s (1943) basic needs and is also integral to belonging. Consistent with previous research (see de Graauw, 2014; López-Bech & Zúñiga, 2017) students recommended creating a culture of trust, respect, and patience, and providing school ID cards. Students frequently mentioned that they had a profound respect for classmates and friends, their points of view, and their learning. Students also referenced their teachers’ patience while “asking a million times” (José) as a critical quality of peers and staff when working together. Through trust, respect, and patience, students felt safe sharing feelings and ideas and, therefore, feeling emotionally and linguistically safe. For example, López-Bech and Zúñiga (2017) provided details on one method on how to create a healthy classroom climate using digital storytelling and spaces for intercultural dialogue.
School ID cards provide a form of ID for students who do not yet have a driver’s license, are ineligible for a State ID card, or do not want to carry their passport around. Regarding ID cards, Shani, a 16-year-old tenth grader from Pakistan, shared,At school they give you a school identity card, like if a police stops you then you can show the school identification; other is like a school bus on the come back from school. . . . Also in the bus, if they don’t check your identity card, they don’t know if you are from the school or not, you can go to school and get inside; no one is checking you.
Students expressed that they were accustomed to maintaining forms of ID in case they were ever stopped and asked for ID. Similarly, de Graauw (2014) found that in New Haven and San Francisco, municipal ID cards for undocumented immigrants to access basic city services fostered belonging. Belonging also increased when all members of the community have a card, allowing newly-arrived neighbors to “blend in, … stand out less, and it’ll be easier to integrate” (p. 319). Likewise, school-issued ID cards allowed students to identify themselves, access services, feel physically safe, and feel a part of the school community.
Preparing Students for the Future
For students paying some or all of their rent, three additional considerations are as follows: implementing a future orientation curriculum beginning in ninth grade, planning for a two-month welcoming window, and time and budget management support for students simultaneously working a job and attending school. First, some students shared that they did not know their graduation requirements nor did they know the opportunities available to them after high school. Beginning these conversations in the eleventh grade is too late, as their academic profiles and GPAs begin the day they enter high school. Schools should shift quickly from a comfortable, welcoming place to a launch pad to future success with options and awareness, including discussions of individualized plans with students and their families.
Next, schools should consider planning for a suite of welcoming experiences during the first two months of a student’s entry. The students in this study experienced a Newcomer Orientation with their family, personal one-on-one enrollment meetings with their counselors, peer mentors in class (tenth graders), collaborative structures in class, cohorts of students traveling class to class together, and building relationships with peers and teachers. As is typical of newcomer programs, a trickle of new enrollments continues all year, so efforts should be made to track and implement a coherent orientation schedule for each newcomer.
Lastly, students viewed the ability to work while going to school as a huge opportunity. However, most students shared that they never had to balance work and school before and would benefit from explicit support in school. Similarly, in the post-secondary setting, Diaz-Strong et al. (2011) chronicled the incredible financial stress for immigrant students, often ineligible for financial aid for college, and shouldering financial responsibilities of the family’s bills and remittances. Balancing seemingly competing interests of working a job and attending school can cause stress for students (Kreuzer, 2016), and having support in juggling would benefit many.
Implications
Importantly, this research moves the body of literature towards understanding the linkages between newcomer sociocultural experiences and their sense of belonging within secondary newcomer programs. Using a large population of more than 400 high school newcomers from five continents, representing 34 countries, and speaking 21 languages, this study is unique for using previously recognized methods on a significantly larger scale. Further, this study notes five experiential opportunities recommended by newcomers that would impact belonging. Importantly, the data and findings suggest that rather than individual student characteristics or variables predicting school belonging, the experience of being and becoming a part of the new school and developing a feeling of belonging is influenced by social dynamics, relationships, and language. Belonging grows through the actions, practices, and experiences of being a high school student, particularly during times of heightened xenophobia. Schools can apply these findings to build systems, structures, and social relationships to foster belonging for newcomers, paying attention to specific grade-level experiences and English proficiency. The purposeful inclusion of only participants who were high school newcomers allows educators, leaders, and policymakers to learn directly from student voices and ensure schools are a place where newcomers belong.
Acknowledgements
This study was supported by Maia Sheppard (University of Iowa), Marguerite Lukes (New York University), Sharon Dannels (The George Washington University), Joel Gómez (Center for Applied Linguistics), Lottie Baker (Department of State), the Honey W. Nashman Center and Knapp Fellowship, along with family, colleagues, students, friends, and cohort sisters. Gratitude is shared with the International Academy staff and brilliant young scholars that participated in this study, offering the opportunity to learn with, from, and through them.
Funding
This work was supported in part by the Honey Nashman Center’s Knapp Fellowship.
Data availability
The author maintains deidentified data and takes responsibility for the integrity of the data and the accuracy of data analysis.
Declarations
Conflict of interest
The author declares no conflict of interest.
Ethical Approval
The author received IRB approval for this study, and informed consent has been appropriately obtained. This study followed the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed Consent
Informed consent was obtained from all individual participants included in the study.
The author has research interests in multilingual learner policy, practice, and programming, specifically newcomers, equity, and communities of practice utilizing mixed methods.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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| 0 | PMC9745280 | NO-CC CODE | 2022-12-15 00:02:24 | no | Child Youth Care Forum. 2022 Dec 13;:1-32 | utf-8 | Child Youth Care Forum | 2,022 | 10.1007/s10566-022-09723-8 | oa_other |
==== Front
Infection
Infection
Infection
0300-8126
1439-0973
Springer Berlin Heidelberg Berlin/Heidelberg
1962
10.1007/s15010-022-01962-0
Research
Tumor necrosis factor-alpha blockade suppresses BK polyomavirus replication
Li Yi-Jung 12
Wang Jiun-Wen 13
Wu Hsin-Hsu 14
Wang Hsu-Han 25
Chiang Yang-Jen 25
Yang Huang-Yu 12
Hsu Hsiang-Hao 12
Yang Chih-Wei 12
Tian Ya-Chung [email protected]
12
1 grid.454211.7 0000 0004 1756 999X Kidney Research Center and Department of Nephrology, Linkou Chang Gung Memorial Hospital, No 5, Fusing St., Taoyuan, 333 Taiwan
2 grid.145695.a 0000 0004 1798 0922 Department of Medicine, Chang Gung University, Taoyuan, Taiwan
3 grid.145695.a 0000 0004 1798 0922 Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
4 grid.145695.a 0000 0004 1798 0922 Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
5 grid.454211.7 0000 0004 1756 999X Department of Urology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
13 12 2022
114
19 7 2022
5 12 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Purpose
BK Polyomavirus (BKPyV) infection manifests as renal inflammation and can cause kidney damage. Tumor necrosis factor-α (TNF-α) is increased in renal inflammation and injury. The aim of this study was to investigate the effect of TNF-α blockade on BKPyV infection.
Methods
Urine specimens from 22 patients with BKPyV-associated nephropathy (BKPyVN) and 35 non-BKPyVN kidney transplant recipients were analyzed.
Results
We demonstrated increased urinary levels of TNF-α and its receptors, TNFR1 and TNFR2, in BKPyVN patients. Treating BKPyV-infected human proximal tubular cells (HRPTECs) with TNF-α stimulated the expression of large T antigen and viral capsid protein-1 mRNA and proteins and BKPyV promoter activity. Knockdown of TNFR1 or TNFR2 expression caused a reduction in TNF-α-stimulated viral replication. NF-κB activation induced by overexpression of constitutively active IKK2 significantly increased viral replication and the activity of the BKPyV promoter containing an NF-κB binding site. The addition of a NF-κB inhibitor on BKPyV-infected cells suppressed viral replication. Blockade of TNF-α functionality by etanercept reduced BKPyV-stimulated expression of TNF-α, interleukin-1β (IL-1β), IL-6 and IL-8 and suppressed TNF-α-stimulated viral replication. In cultured HRPTECs and THP-1 cells, BKPyV infection led to increased expression of TNF-α, interleukin-1 β (IL-1β), IL-6 and TNFR1 and TNFR2 but the stimulated magnitude was far less than that induced by poly(I:C). This may suggest that BKPyV-mediated autocrine effect is not a major source of TNFα.
Conclusion
TNF-α stimulates BKPyV replication and inhibition of its signal cascade or functionality attenuates its stimulatory effect. Our study provides a therapeutic anti-BKPyV target.
Keywords
BK polyomavirus
BKPyV-associated nephropathy
Tumor necrosis factor-α
Large T antigen
Nuclear factor-κB
Chung Gang Medical Research ProjectCMRPG3K0592 CMRPG3H0601 CMRPG3H0601 Li Yi-Jung Wang Jiun-Wen Tian Ya-Chung National Science Council of TaiwanNRRPG3J6023 Tian Ya-Chung
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pmcIntroduction
BK Polyomavirus (BKPyV) reactivation and virus-induced inflammation are the main causes of kidney allograft damage in BKPyV-associated nephropathy (BKPyVN) [1]. Several risk factors including acute rejection, ischemia/reperfusion and surgical trauma precipitate renal inflammation and subsequent BKPyV reactivation [2, 3]. Once reactivated, BKPyV rapidly replicates, leading to viruria, viremia and even BKPyVN. Recently, BKPyV has even been considered as an oncogenic virus [4, 5]. Because effective anti-BKPyV therapy is not yet available, immunosuppressant reduction is the mainstay of treatment but increases the risk of rejection of the graft. Therefore, finding a specific therapeutic target against BKPyV infection is a crucial issue.
The BKPyV genome consists of a noncoding control region (NCCR) and regions of early gene encoding large T antigen (TAg) and small t antigen, and late gene encoding agnoprotein and viral capsid proteins (VP1, VP2, VP3). NCCR is important in the regulation of viral latency and reactivation and contains many transcription factor-binding sites, including sites that bind nuclear factor-κB (NF-κB) and activator protein-1. Similar to many viruses, BKPyV infection activates various kinds of antiviral responses in host cells and results in tissue inflammation accompanied by increased production of cytokines and chemokines, which not only affect viral survival but also cause tissue damage. In patients with BKPyVN, increased expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was found in their biopsy specimens [6]. Proinflammatory cytokines are responsible for the necrosis of virus-infected cells and attract inflammatory cells for virus killing; however, some viruses have evolved to make use of these cytokines to facilitate their replication. For example, TNF-α activates cytomegalovirus (CMV) and human simplex virus type 1 replication, which further exacerbates inflammation and damage to the host [7, 8].
TNF-α production can be triggered by kidney injury such as ischemia/reperfusion injury, acute rejection and infectious diseases [8–10]. For instance, TNF-α level was increased 2–3 days prior to clinical evidence of acute rejection [8]. TNF-α and its receptors, TNF-α receptor 1 (TNFR1) and receptor 2 (TNFR2), are not normally present in the kidneys but are abundantly expressed in the context of renal inflammation. After activation by TNF-α, the intracellular domain of TNFR1 is bound by the adaptor protein TNF receptor-associated death domain (TRADD), which recruits other adaptor proteins to activate the inhibitor of κB kinase (IKK) complex [11]. The IKK complex subsequently phosphorylates and degrades IκBα to free NF-κB to activate its targeted genes.
Sadeghi et al. showed an increase in urinary TNF-α levels in kidney transplant recipients with BKPyV DNAuria [6]. In contrast, Ribeiro et al. demonstrated that BKPyV infection caused a downregulation of TNF-α mRNA expression in human collecting duct epithelial cells [12]. However, the mechanism is not fully understood and whether TNF-α blockade suppresses BKPyV replication is unknown. In this study, we investigated whether TNF-α stimulated BKPyV replication and its blockade could inhibit viral replication in human renal proximal tubular cells.
Materials and methods
Cell culture and materials
Recombinant TNF-α was purchased from R&D Systems (MN, USA). Etanercept was purchased from Vetter Pharma-Fertigung GmbH & Co KG (Ravensburg, Germany). N4-[2-(4-phenoxyphenyl)ethyl]-4,6-quinazolinediamine (QNZ) was purchased from Abcam (Cambridge, UK). The constitutively active IKK2-expressing vector was purchased from Addgene (USA). TNFR1 and TNFR2 small interfering RNA (siRNA) were purchased from Qiagen (Hilden, Germany). Urinary levels of TNF-α, TNFR1 and TNFR2 were measured using Quantakine ELISA kits (R&D Systems).
The human renal proximal tubular cell line (HRPTEC) and human monocytic cell line (THP-1) were purchased from the American Type Culture Collection (ATCC). Cells were cultured in DMEM/F-12 1:1 (Gibco™, NY, USA) supplemented with 1% fetal bovine serum under 5% CO2. THP-1 cells were cultured in RPMI-1640 (Gibco, NY, USA) containing 10% FBS under 5% CO2.
For transient transfection, cells were incubated with 1 µg plasmid and 3 µL of Fugen 6 (Fugene 6TM Roche Diagnostics Ltd, Mannhein, Germany) in 1 mL of culture medium for 4 h and then washed with phosphate buffered saline (PBS) prior to further experiments according to the manufacturer’s instructions.
Quantitative polymerase chain reaction (qPCR)
qPCR was performed as described previously [13]. Primers used to assay BKPyV TAg and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) transcript levels (BKPyV TAg: 5-CTGTCCCTAAAACCCTGCAA-3 and 5-GCCTTTCCTTCCATTCAACA-3; BKPyV VP1: GAPDH: 5-TTCCAGGAGCGAGATCCCT-3 and 3-CACCCATGACGAACATGGG-5) were constructed to be compatible with a single reverse transcription-PCR thermal profile (95 °C for 10 min, 40 cycles of 95 °C for 30 s and 60 °C for 1 min). Experimental results are presented as the transcript levels of the analyzed genes relative to the GAPDH transcript level.
Quantitative measurement of BKPyV load
BKPyV load in the urine samples, culture medium or cell lysate was determined by qPCR as described previously [14]. DNA was extracted from the specimens using a QIAamp DNA Mini Kit (Qiagen, Hilden, Germany). To determine viral copies, qPCR was performed as described above. The BKPyV DNA was normalized by analyzing samples in parallel by qPCR for cellular glyceraldehyde-3-phosphate dehydrogenase DNA (a housekeeping gene). The limit of detection was 10 copies/mL of BKPyV DNA.
Construction of the BKPyV NCCR-luciferase reporter vectors and luciferase assay
The full-length BKPyV NCCR-luciferase reporter vector was constructed as previously described [15]. To clone the gene between the start codon of TAg and the origin of replication (TAg-Ori) into the luciferase reporter, the BKPyV genome was used as a template, and primers mapping to TAg-Ori (forward primer 5-GCCGGTACCACCGAAAGCCTTTACACAAATGCAAC-3 and reverse primer 5-GCCGGATCCACCGGAAGGAAAGGCTGGATTCT-3) were used. The TAg-Ori fragment in early or late orientation was amplified by PCR and cloned into a pGL4 luciferase reporter vector (Promega, Madison, WI).
A luciferase assay was conducted using the luciferase reporter assay system (Promega, Madison, WI). Luciferase activity (relative light units) was measured in duplicate samples using a luminometer (MLX microtiter plate luminometer, Dynex Ltd, Chantilly, VA). Data are presented as firefly luciferase activity normalized to Renilla luciferase activity.
Western blot analysis
Western blot analysis was conducted as previously described [16]. Anti-SV40 TAg antibody was purchased from Calbiochem (La Jolla, CA). Anti-VP1 antibody was obtained from Abnova (Taipei, Taiwan). Anti-TNFR1 and anti-TNFR2 antibodies were purchased from Abcam (Cambridge, UK). IκBα, p-IκBα and anti-tubulin antibodies were obtained from Cell Signaling Technology (MA, USA).
Enzyme-linked immunosorbent assay (ELISA)
Urine sample was centrifuged at 3000 rpm for 10 min to remove the cellular debris, and the cleaned urine samples were used for further measurement. Urinary levels of TNF-α, TNFR1 and TNFR2 were measured using Quantakine ELISA kits (R&D Systems) according to the manufacturer’s instructions.
Patients
A total of 57 kidney transplant recipients at Chang Gung Memorial Hospital from June 2000 to May 2021 were included in this study. Ethics approval (201801596B0) was obtained from the Medical Ethics Committee of Linkou Chang Gung Memorial Hospital. Among these 57 recipients, twenty-two subjects had biopsy-proven BKPyVN based on histological findings according to the criteria of the 2018 Banff Working Group classification.
Statistical analysis
All the data are presented as the means ± standard error. Student’s t test was applied to compare the means of two datasets. The correlation analysis used Spearman’s correlation coefficient. A value of p < 0.05 was considered statistically significant.
Results
Increased urinary levels of TNF-α, TNFR1 and TNFR2 in patients with BKPyVN
Among 57 kidney transplant recipients, urine samples were obtained from 35 patients without BKPyVN and 22 patients with BKPyVN. As expected, the urinary BKPyV loads in the BKPyVN group were significantly higher than those in the non-BKPyVN group (1.37 ± 0.95 × 109 vs. 1.42 ± 0.94 × 103 copies/mL, p < 0.05). When compared with the non-BKPyVN group, the urinary TNF-α level was significantly higher in the BKPyVN group (Fig. 1a). Similarly, the urinary levels of TNFR1 and TNFR2 were also higher in the BKPyVN group than in the non-BKPyVN group (Fig. 1b, c). The correlation analysis also demonstrated positive correlations between urinary TNFR1 levels and urinary BKPyV loads (Fig. 1d) and between urinary TNFR2 levels and BKPyV loads (Fig. 1e). These results suggest that there is an association between BKPyV infection and the activation of TNF-α receptors.Fig. 1 Urinary TNF-α, TNFR1 and TNFR2 levels in kidney transplant recipients with and without BKPyVN treatment. a–c Urine specimens from 57 kidney transplant recipients with BKPyVN (n = 22) and without BKPyVN (n = 35) were collected for measurements of TNF-α (a), TNFR1 (b) and TNFR2 (c) concentrations by ELISA. *p < 0.05; **p < 0.01. d Correlations between urinary TNFR1 level (log10) and BKPyV load (log10). e Correlation between urinary TNFR2 level (log10) and BKPyV load (log10)
TNF-α enhanced BKPyV replication and promoter activity
To determine the effect of TNF-α on BKPyV replication, HRPTECs were infected with BKPyV and then stimulated with TNF-α. Addition of TNF-α to BKPyV-infected cells stimulated a significant increase of TAg and VP1 transcripts in a dose-dependent manner (Fig. 2a). Because a BKPyV life cycle needs 72 h, HRPTECs were infected with BKPyV and stimulated with TNF-α for an additional 72 h. Figure 2b shows a significant increase of viral titers in culture medium. Western blot analysis also showed a proportional increase in expressions of TAg and VP1 proteins in response to the increased doses of TNF-α (Fig. 2c).Fig. 2 Stimulatory effect of TNF-α on BKPyV replication. a HRPTECs were seeded to 6-well plates (5 × 104 cells/per well) and grown to confluence. Cells were then infected with BKPyV (1 × 106 copies/mL) for 2 h and subsequently incubated in the presence or absence of TNF-α (0.5–10 ng/mL) for 24 h. TAg and VP1 mRNA expression levels were determined by qPCR (n = 3). b–d HRPTECs were seeded to 6-well plates (5 × 104 cells/per well) for 1 day, followed by infection with BKPyV (1 × 106 copies/mL) for 2 h and subsequent incubation in the presence or absence of TNF-α as indicated in the figure for 72 h. The viral load in the culture medium (b) was determined as described in the “Materials and methods” (n = 4). TAg and VP1 protein expression levels were assessed by immunoblotting analysis and one of three replicates was shown (c). d, e Cells were transfected with the full-length NCCR-luciferase reporter in early orientation (d) and late orientation (e) overnight followed by the addition of TNF-α (0.5–10 ng/mL) for an additional 24 h. The activity of the BKPyV NCCR reporter was measured by the luciferase assay (n = 4). The fold change of viral transcripts (a) and luciferase activity (d, e) was normalized to the control (no addition of TNF-α) in each experiment. *p < 0.05; **p < 0.01; ***p < 0.001
The NCCR is the main regulatory region on BKPyV genome to initiate viral replication. To determine whether TNF-α could enhance the BKPyV NCCR-reporter activity, cells were transfected with the full-length NCCR-luciferase reporter followed by stimulation with different doses of TNF-α. The luciferase assay showed that TNF-α significantly stimulated an increase in the activity of the BKPyV NCCR reporter in both early orientation (Fig. 2d) and late orientation (Fig. 2e). This result verifies the finding that TNF-α stimulates both TAg and VP1 transcription.
TNF-α stimulated BKPyV replication through TNF-α receptors and its downstream mediator, NF-kB
To determine the role of TNF receptors in BKPyV replication, expressions of TNFR1 and TNFR2 were knocked down by siRNA prior to addition of TNF-α. Upon TNF-α stimulation, productions of TAg and VP1 proteins were increased, while suppression of either TNFR1 or TNFR2 expression by siRNA significantly blocked the TNF-α-stimulated TAg expression (Fig. 3a) and VP1 expression (Fig. 3b). Knockdown of either TNFR1 or TNFR2 abrogated TNF-α-stimulated increase in TAg and VP1 mRNA expressions detected by qPCR (Fig. 3c, d). Compared to TNFR2 knockdown, TNFR1 knockdown or combination of TNFR1 and TNFR2 knockdown caused more substantial reduction in TAg and VP1 expression. These results suggested that both TNF-α receptors were indispensable for TNF-α-regulated BKPyV replication.Fig. 3 Inhibition of TNF-α-stimulated BKPyV replication by knockdown of TNFR1 and TNFR2 expression. a, b HRPTECs were seeded to 6-well plates (5 × 104 cells/per well) overnight. Cells were then transfected with TNFR1 (a) or TNFR2 (b) siRNA (10–40 nM/mL) for 24 h followed by infection with BKPyV (1 × 106 copies/mL) for 2 h and further incubated in serum-free medium containing TNF-α (10 ng/mL) for 72 h. TAg and VP1 protein expression levels were assessed by Western blot analysis and one of three replicates was shown. C&D. Cells were transfected with TNFR1 (20 nM/mL), TNFR2 (20 nM/mL) or a combination of TNFR1 (20 nM/mL) and TNFR2 (20 nM/mL) for 24 h followed by infection with BKPyV (1 × 106 copies/mL) for 2 h and stimulation with TNF-α (10 ng/mL) for an additional 24 h. TAg (c) and VP1 (d) mRNA expression levels were analyzed by qPCR (n = 3). The fold change of viral transcripts (c, d) was normalized to the control (no addition of TNF-α) in each experiment. *p < 0.05; **p < 0.01
NF-κB is a crucial downstream mediator of the TNF-α-associated cascade, and IκBα phosphorylation, which prevents NF-kB degradation, is considered an indicator of NF-κB activation [17]. BKPyV infection led to a slight increase in the expression of phospho-IκBα (IκBα) (Fig. 4a). The addition of TNF-α to BKPyV-infected cells further enhanced the expression of p-IκBα and VP1. To clarify the importance of NF-κB in BKPyV replication, cells were transfected with a constitutively active IKK2-expressing vector, which can activate p-IκBα [17], followed by infection with BKPyV for an additional 72 h. Compared to transfection with the control vector, transfection with the IKK2-expressing vector significantly increased BKPyV VP1 protein expression (Fig. 4b). A previous study revealed an NF-κB binding site located between the origin of replication and the start codon for the early coding region, which is the consensus region in different BKPyV strains (Fig. 4c). To test the effect of NF-κB overexpression on BKPyV promoter activity, the gene between the start codon of TAg and the origin of replication (TAg-Ori) in early or late orientation was cloned into a luciferase reporter. In line with the finding that used the full-length NCCR-luciferase reporter, TNF-α also stimulated TAg-Ori reporter activity in both orientations (Fig. 4c left panel). Cotransfection of the IKK2-expressing vector and the TAg-Ori reporter caused prominent increases in the reporter activity in both orientations (Fig. 4c right panel). These results further confirm the importance of TNF-α and its main downstream mediator, NF-κB, in BKPyV replication.Fig. 4 Suppression of BKPyV replication by NF-κB inhibition. a HRPTECs were seeded to 6-well plates (5 × 104 cells/per well) overnight and infected with BKPyV (1 × 106 copies/mL), followed by incubation in the presence or absence of TNF-α (2.5–20 ng/mL) for 72 h. VP1 and p-IκB expression levels were determined by Western blot analysis and one of three replicates was shown. b Confluent cells were transfected with a constitutively active IKK2-expressing vector (0.5, 1 μg/mL) or a control vector (1 μg/mL) overnight followed by infection with BKPyV (1 × 106 copies/mL) and incubated for an additional 72 h. VP1 and flag-tagged IKK2 expression levels were assessed by Western blot analysis and one of three replicates was shown (b). c The picture depicts the gene between the start codon of TAg and the origin of replication (Tag-Ori), and the NF-kb binding site is displayed in red color and italicized font. HRPTECs were seeded to 6-well plates (5 × 104 cells/per well) overnight and then cotransfected with the TAg-Ori luciferase reporter vectors (white bar: early orientation; black bar: late orientation) or the control luciferase reporter vector and the Renilla luciferase reporter vector overnight followed by stimulation with TNF-α (10 ng/mL) for additional 24 h. The reporter activity was normalized by the Renilla luciferase activity (n = 4). d, e Cells seeded on 6-well plates (5 × 104 cells/per well) overnight were pretreated with QNZ (10–50 ng/mL) for 2 h followed by infection with BKPyV (1 × 106 copies/mL) and further incubated in the presence or absence of TNF-α (10 ng/mL) for 72 h (d) or 24 h (e). The expression levels of TAg and VP1 proteins were assessed by Western blot analysis and one of three replicates was shown (d). The mRNA expression levels of TAg (white bar) and VP1 (black bar) were assessed by qPCR (n = 4) (e). The fold change of viral transcripts (e) was normalized to the control (no addition of TNF-α and QNA) in each experiment. # indicates TNF-α vs. control p < 0.05. *QNZ vs. TNF-α alone p < 0.05; **QNZ vs. TNF-α alone p < 0.01
To further verify the role of NF-κB in TNF-α-stimulated BKPyV replication, cells were treated with a potent NF-κB inhibitor, QNZ, prior to administration of TNF-α. The TNF-α-stimulated p-IκB expression was abrogated in the presence of QNZ, verifying its inhibitory effect on NF-κB activation (Fig. 4d). The addition of QNZ significantly reduced the TNF-α-promoted protein expression of TAg and VP1 (Fig. 4d), and mRNA expression (Fig. 4e). These findings confirm the importance of NF-κB activation in TNF-α-promoted BKPyV replication.
Etanercept suppressed TNF-α-stimulated BKPyV replication
To further examine whether TNF-α blockade could attenuate viral replication, etanercept, a fusion protein of TNFR2 with a constant portion of IgG1 antibody efficiently binding to functional epitopes of TNF-α, was used to inhibit TNF-α functionality. The qPCR results showed that BKPyV infection stimulated the mRNA expression of IL-1β, IL-6 and IL-8 (Fig. 5a), and upon stimulation with TNF-α, the expression of these cytokines was further augmented. In the presence of etanercept, the BKPyV-stimulated increase in TNF-α expression was significantly reduced. In addition, the TNF-α-enhanced expression of IL-1β, IL-6 and IL-8 was markedly suppressed, and the expression of IL-1β was even lower than that of the unstimulated control. Furthermore, in the presence of etanercept, the TNF-α-mediated increase in TAg and VP1 transcripts was nearly abolished when compared with the unstimulated control (Fig. 5b). The inhibitory effect of etanercept on the TNF-α-stimulated BKPyV replication was further verified by the finding that etanercept inhibited TNF-α-augmented TAg and VP1 protein expression (Fig. 5c). Similarly, administration of etanercept to BKPyV-infected cells for 24 h followed by stimulation with TNF-α for an additional 24 h also suppressed the TNF-α-enhanced increases in TAg and VP1 transcript levels and protein expression (data not shown).Fig. 5 Inhibition of TNF-α-stimulated inflammatory cytokines and viral replication by TNF-α blockade. HRPTECs were seeded to 6-well plates (5 × 104 cells/per well) and grown to confluence. Cells were infected with BKPyV (1 × 106 copies/mL) followed by incubation in the presence or absence of TNF-α (10 ng/mL) for 24 h, and then, etanercept at doses ranging from 0.01–1 μg/mL was added for an additional 24 h. The mRNA expression levels of IL-1β, IL-6 and IL-8 (a) and of TAg (white bar) and VP1 (black bar) (b) were assessed by qPCR (n = 3). TAg and VP1 protein expression levels were determined by Western blot analysis and one of three replicates was shown (c). The fold change of IL-1β, IL-6 and IL-8 mRNA expressions (a) and viral transcripts (b) was normalized to the control (no addition of TNF-α and etanercept) in each experiment. aBKPyV vs. the non-BKPyV control p < 0.05; bBKPyV vs. BKPyV + TNF-α p < 0.05; cTNF-α + etanercept vs. TNF-α alone p < 0.05, #TNF-α vs. control p < 0.05, and *TNF-α + etanercept vs. TNF-α alone p < 0.05
As BKPyV infection stimulated inflammatory cytokines, we examined whether etanercept inhibited BKPyV infection stimulated cytokines. Administration of etanercept to BKPyV-infected cells caused decreased production of IL-1β, IL-6 and IL-8 and concurrently reduced TAg and VP1 transcript levels (Fig. 6). These results suggest that neutralization of endogenous TNF-α by etanercept attenuated BKPyV replication. Together, etanercept suppresses exogenous or endogenous TNF-α-stimulatory BKPyV replication.Fig. 6 Inhibition of BKPyV-stimulated inflammatory cytokines and viral replication by TNF-α blockade. HRPTECs were seeded to 6-well plates (5 × 104 cells/per well) and grown to confluence. Cells were then infected with BKPyV (1 × 106 copies/mL) for 2 h and cultured in the presence or absence of etanercept (0.1 μg/mL) for an additional 24 h. The mRNA expression levels of IL-1β, IL-6, IL-8, TAg and VP1 were determined by qPCR (n = 3). The fold change of TNF-α, IL-1β, IL-6 and IL-8 mRNA expressions was normalized to the control (no addition of etanercept and no BKPyV infection) in each experiment. The fold change of viral transcripts was normalized to the control (BKPyV infection only). *TNF-α vs. control p < 0.05; #TNF-α + etanercept vs. TNF-α alone p < 0.05
Monocytes/macrophages and renal proximal tubular cells produced TNF-α following stimulation
Monocytic cells activated by multiple stimuli, including ischemic/reperfusion injury, rejection and viral infection, play important roles in renal inflammation and TNF-α production [18–20]. We first determined whether monocytic THP-1 cells in responding to inflammatory stimulation could release TNF-α. THP-1 cells activated by PMA were stimulated with polyinosinic acid-polycytidylic acid (poly(I:C)). Results of qPCR demonstrated that following stimulation with poly(I:C) for 24 h, expressions of TNF-α were significantly increased (Fig. 7a). To assess whether BKPyV also stimulated TNF-α expression, PMA-stimulated THP-1 cells were infected with BKPyV for 24 h. Results of qPCR demonstrated that TNF-α expression was elevated at 2 h post-infection (h.p.i.) but returned to the baseline level at 4 h.p.i. (Fig. 7b). IL-6 and IL-1β RNA expression was also elevated following BKPyV infection. These results suggest that upon stimulation with poly(I:C) or BKPyV infection, the expression of TNF-α is increased in activated THP-1 cells.Fig. 7 Proinflammatory cytokines induced by poly(I:C) or BKPyV infection in THP-1 cells and HRPTECs. a THP-1 cells were seeded to 6-well plates (2 × 105 cells/per well) and grown for 1 day. Cells were then activated by PMA (100 nM) for 24 h and stimulated with 10 μg/mL of poly(I:C) for an additional 24 h. TNF-α mRNA expression was determined by qPCR (n = 3). b Similarly, PMA-activated THP-1 cells were infected with BKPyV (1 × 106 copies/mL) in serum-free medium for 24 h. The control in A&B was PMA-stimulated TPH-1 cells without poly(I:C) stimulation or BKPyV infection in serum-free medium for 24 h (con). The mRNA expression levels of IL-1β, IL-6 and TNF-α were assessed by qPCR (n = 3). The fold change of TNF-α, IL-1β and IL-6 mRNA expressions was normalized to the control [no stimulation with poly(I:C) (a) or no BKPyV infection (b)] in each experiment. c–e HRPTECs were seeded to 6-well plates (5 × 104 cells/per well) for 1 day and were then stimulated with 10 μg/mL of poly(I:C) for 24 h (c) or infected with BKPyV (1 × 106 copies/mL) for 96 h (d, e). TAg (white bar) and VP1 (black bar) mRNA expression levels were analyzed by qPCR (n = 3) (d). The folds of mRNA expression levels of TNF-α, IL-1β, IL-6 and IL-8 were normalized to the unstimulated control at 24 h (c, e). *p < 0.05; **p < 0.01; and ***p < 0.001 or less
To determine whether HRPTECs were also responsible for TNF-α production, cells were stimulated with poly(I:C) for 24 h or infected with BKPyV. Upon addition of poly(I:C), a marked increase of TNF-α, IL-1β, IL-6 and IL-8 expression was observed (Fig. 7c). Following BKPyV infection for 96 h, TAg and VP1 transcripts increased with time, indicating active BKPyV replication (Fig. 7d). At 24 h, mRNA levels of TNF-α, IL-1β, IL-6 and IL-8 were significantly increased although the levels of these cytokines were not markedly elevated as those upon poly(I:C) stimulation (Fig. 7e). These results suggest that monocyte/macrophages and renal proximal tubular cells are one of the cells responsible for TNF-α production.
Discussion
TNF-α is one of the most abundant cytokines in inflamed kidneys, and the plasma and urine levels of TNF-α are increased in different inflammatory kidney diseases, such as acute rejection and glomerulonephritis [8, 21, 22]. In addition, increased urine TNFR levels reflect their shedding from the cell membranes of activated TNF-α-expressing renal cells and are considered a marker of renal inflammation [23, 24]. Our study demonstrated that the levels of TNF-α, TNFR1 and TNFR2 in urine were all significantly increased in BKPyVN patients. Sadeghi et al. reported that the levels of urinary proinflammatory cytokines, including IL-3, soluble IL-6 receptor (sIL-6R), IL-6 and sIL-1R antagonist, were higher in patients with BKPyV DNAuria than those without DNAuria, suggesting a role of inflammation in the pathogenesis of BKPyVN [6]. However, in their study, the difference of the urinary TNF-α levels in these two groups did not reach statistical significance. In contrast, our study demonstrated that in patients with more severe BKPyV infection, biopsy-proven BKPyVN, TNF-α, TNFR1 and TNFR2 levels were all significantly increased, verifying the importance of TNF-α stimulation in BKPyV infection. In addition, urinary levels of TNFR1 and TNFR2 were significantly correlated with urinary BKPyV loads. This study demonstrates a concurrent increase in TNF-α and its receptors, suggesting an amplified effect of TNF-α on renal inflammation in BKPyVN.
TNF-α stimulates or suppresses viral replication depending on viral species. TNF-α promotes the replication of different viruses, including JC virus (JCV), HIV, cytomegalovirus and hepatitis C virus, while TNF-α can also exert a protective effect on herpesvirus family infection [25–29]. In this study, upon TNF-α stimulation, the transcripts and proteins of BKPyV TAg and VP1 and viral load were increased, and its promoter activity was also enhanced, suggesting that TNF-α stimulates transcription and translation. We observed the differences in expressions of viral transcripts, proteins and viral load upon TNF-α stimulation. We speculate that TNF-α may have different effects on transcription, translation of viral components, the packing of viruses and the release of virions from the host cells. Nevertheless, our results indicate a stimulatory effect of TNF-α on BKPyV replication and may reflect our finding of increased urinary TNF-α level in BKPyVN patients.
The present study shows evidence that targeting TNF-α blockade would be beneficial for attenuation of BKPyVN replication. Our study showed that knockdown of either TNFR1 or TNFR2 was sufficient to abrogate TNF-α-stimulated BKPyV replication, suggesting that both TNFR1 and TNFR2 were indispensable for TNF-α-regulated BKPyV replication. NF-κB, an essential TNF-α-associated signaling mediator, is crucial for the replication of several viruses, such as influenza A virus, HIV and CMV [30–32]. Our finding showed that overexpression of the constitutively activated IKK2 stimulated viral protein production, indicating that activated NF-κB is also crucial for BKPyV replication.
The NF-κB binding site on BKPyV NCCR has been verified to be located near the early gene initial codon, and overexpression of the p65 subunit of NF-κB activates BKPyV promoter activity [33]. One study demonstrated that NF-κB and nuclear factor of activated T cell 4 (NFAT4 or NFATc3) interacted cooperatively to enhance the promoter activity and replication of JCV, another human polyomavirus [34]. Our study demonstrated that the BKPyV Tag-Ori promoter containing an NF-κB binding site was triggered by TNF-α and constitutively activated IKK2 expression, confirming an important role of NF-κB in BKPyV reactivation. This finding was further verified, as QNZ blocked the TNF-α-mediated increases in BKPyV TAg and VP1 expression and its promoter activity. Targeting NF-κB inhibition may provide a therapeutic approach against BKPyV infection.
The present study demonstrated a marked inhibitory effect of etanercept on TNF-α-stimulatory BKPyV replication and a BKPyV-induced increase in proinflammatory cytokines. Regardless pre- or post-TNF-α stimulation in BKPyV-infected cells, etanercept significantly suppressed BKPyV replication. Although anti-TNF-α monoclonal antibodies increase the infectious risk of mycobacteria or the reactivation of the herpesvirus family and hepatitis B virus (more in the use of infliximab and adalimumab; less in the use of etanercept), etanercept can be used as an antiviral adjuvant therapy against HCV and HIV [35, 36]. Recently, etanercept was even evaluated as a potential treatment for SARS-CoV-2 infection [37]. The use of anti-TNF-α therapy needs to be cautious in kidney transplant recipients as it might increase malignancy and viral infection [38]. Our study shows a nearly complete suppression of BKPyV replication and may indicate a possibly clinical application of a low-dose etanercept or other TNF-α inhibitors to inhibit BKPyV replication.
Monocytes/macrophages are an important source of TNF-α production in autoimmune and infectious diseases, and allograft rejection [39, 40]. Our study demonstrated a prominent increase of TNF-α and inflammatory cytokines following poly(I:C) stimulation in PMA-activated THP-1 cells, suggesting that monocytes/macrophages play an essential role in inflammatory cytokine production. Another important resource of TNF-α is renal proximal tubular cells. Our study also showed a significant increase of TNF-α upon poly(I:C) stimulation in HRPTECs. Similar to other viruses, our results showed that BKPyV infection stimulated HRPTECs and THP-1 cells to produce inflammatory cytokines including TNF-α [39]. However, the increased TNF-α magnitude by BKPyV infection was far less than that induced by poly(I:C) or other stimulants such as rejection and ischemia/reperfusion injury, suggesting that the BKPyV-mediated autocrine effect is not a major source of TNF-α. Acute rejection characterized by abundant inflammatory cytokine production frequently precedes the development of BKPyVN or coincides with the occurrence of BKPyVN. We speculate that kidney injury promotes TNF-α production and triggers subsequent BKPyV replication.
Conclusion
Our study showed increases in the urinary levels of TNF-α, TNFR1 and TNFR2 in BKPyVN patients. TNF-α stimulation and NF-κB activation promoted BKPyV replication, and TNF-α blockade reduced viral replication, providing a therapeutic target. Our results suggest that TNF-α neutralization by etanercept may have clinical application as an anti-BKPyV treatment. It would be worthwhile to initiate clinical trials of anti-TNF-α therapy for the treatment of BKPyV infection.
Acknowledgements
The authors would like to thank Chun-Lin Yen (Kidney Research Center, Linkou Chang Gung Memorial Hospital) for preparation of experiment materials.
Author contributions
Y-JL was involved in conceptualization, data curation, formal analysis; J-WW helped in conceptualization, methodology; H-HW contributed to software, visualization; H-HW and Y-JC were involved in resources; H-YY helped in project administration; H-HH contributed to review and editing; C-WY was involved in conceptualization; Y-CT helped in conceptualization, roles/writing—original draft.
Funding
This study was supported by Grants (NRRPG3J6023) from the National Science Council of Taiwan and Grants (CMRPG3H0601 BKPyV, CMRPG3K0592 BKPyV infection) from the Chung Gang Medical Research Project to Dr. Ya-Chung Tian and Dr. Yi-Jung Li.
Data availability statement
The data underlying this article cannot be shared publicly due to privacy reasons. The data will be shared on reasonable request to the corresponding author.
Declarations
Conflict of interest
All authors declare no conflict of interest. No financial or non-financial interests are directly or indirectly related to the work.
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| 36512270 | PMC9745287 | NO-CC CODE | 2022-12-15 00:02:24 | no | Infection. 2022 Dec 13;:1-14 | utf-8 | Infection | 2,022 | 10.1007/s15010-022-01962-0 | oa_other |
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Environ Sci Pollut Res Int
Environ Sci Pollut Res Int
Environmental Science and Pollution Research International
0944-1344
1614-7499
Springer Berlin Heidelberg Berlin/Heidelberg
24494
10.1007/s11356-022-24494-4
Research Article
Efficiency and productivity analysis of innovation, human capital, environmental, and economic sustainability nexus: case of MENA countries
http://orcid.org/0000-0002-2577-6927
Ibrahim Mustapha D. [email protected]
12
1 grid.444463.5 0000 0004 1796 4519 Industrial Engineering Technology, Higher Colleges of Technology, Sharjah, United Arab Emirates
2 grid.9983.b 0000 0001 2181 4263 CERIS - Civil Engineering Research and Innovation for Sustainability, Instituto Superior, Técnico, University of Lisbon, Lisbon, Portugal
Responsible Editor: Ilhan Ozturk
13 12 2022
112
28 6 2022
27 11 2022
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Innovation, human capital, economic, and environmental nexus is essential in sustainable development. The Middle East and North Africa (MENA) is an emerging market with the potential to transcend the dilemma of attaining economic and environmental sustainability. Data envelopment analysis through the Malmquist-Luenberger productivity index is utilized to estimate MENA country’s innovation, human capital, economic, and economic sustainability efficiency and productivity. Results indicate an upward trend in efficiency, with a 26% increase in average efficiency between 2017 and 2019 compared to 2011 and 2016. However, there is variation in efficiency between countries. The decomposition of the productivity index into technical change and technological change indicates that the efficiency growth in 2017–2019 could be attributed to technical improvement than technological increase. However, there is a shift to more technological progress than technical increase. Study shows that developing human capital and capacity is as integral to sustainable development as innovation advancement. Strategies to simultaneously augment human capital and innovation towards sustainable development are presented.
Keywords
Innovation
Human capital
Data envelopment analysis
Malmquist-Luenberger
Sustainable development
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pmcIntroduction
Human capital is integral to economic growth and sustainability. Several studies have linked increased economic activities to the growing environmental degradation. Today, innovation has been shown to enhance sustainable growth. This has led many countries and regions to become intentional about eco-innovation as a method of reducing emissions. Energy-rich countries and regions such as the Middle East and North Africa (MENA) have outlined strategies and policies to support eco-innovation. However, the literature on empirical findings on these policies is profoundly sparse, coupled with the absence of the human capital factor. Many fail to look at the nexus between human capital and innovation as environmental and economic sustainability factors. Hence, there needs to be a healthy balance between human capital and innovation processes to attain sustainable environmental and economic development. The emerging nature of the MENA region makes it a perfect case study to explore the nexus between innovation, human capital, environmental, and economic sustainability.
Sustainability is the capacity to generate resources that will compensate for factors of production, replace used resources, invest, and continue competing (Barbieri et al., 2010). Innovation is essential for realizing sustainability (Adams et al. 2016). Studies show that technological innovation is vital for sustainable development (Barbieri et al. 2010; Hallenga-Brink and Brezet 2005; Nill and Kemp 2009). Betz (2003) opined that innovation aims at bringing out new or enhanced processes, services, or products. Afuah (2020) suggested that innovation uses new methods to offer improved services. Moreover, innovation and sustainability drive environmental, economic, and social development (Michelino et al. 2019).
Fagerberg (2004) stated that in a broad sense, innovation includes the entire process from the moment new ideas are created to their execution and onward transmission into the economic and social system. This is notable in sustainability transitions, where changes in practice, i.e., implementation and diffusion, are essential (Mowery et al. 2010). Edquist (2011), on the other hand, identified innovation policy (and policy instruments) with policies that significantly influence innovation since what counts as tangible impact based on the transition to sustainability is the effect of a policy, not its label. Innovations would generate positive economic, social, and environmental results (Seclen-Luna et al. 2021a). Therefore, sensible sectoral innovation policies and sustainability transitions become relevant. There has been a growing literature drawing insights from innovation studies and to some extent other scientific fields, examining how innovation policy can make a difference through various concepts such as eco-innovation policy (Kemp 2011), transformative innovation policy (Steward 2012), or mission-oriented innovation policy (Mazzucato 2017). This growing innovation trend has affected human capital development, which has played a significant role in economic development. Given this trend, this study seeks to investigate the impact of pure innovation pursuit on environmental and economic sustainability. In this context, Fig. 1 illustrates the conceptual framework of the study. Innovation and human capital are considered inputs to economic and environmental sustainability to analyze the efficiency and productivity of MENA country’s sustainable development strategies and policies.Fig. 1 Conceptual framework for innovation-economic-environmental assessment
Several studies have analyzed the nexus between innovation and environmental policies adopted by countries and regions. National and regional analyses are essential because developmental and environmental spillover is inevitable (Costantini et al. 2013). However, these studies lack the simultaneous consideration of human capital as an input component of economic and environmental sustainability. Studies that have analyzed the efficiency of innovation, environmental sustainability, and economic sustainability have used the data envelopment analysis (DEA) method due to the complexities of the interconnection. For example, Chen et al. (2011) compared the relative efficiency of research and development (R&D) as an indicator of innovation for twenty-four countries, including sixteen European, four Asian, and four American countries. Wang and Huang (2007) estimated the efficiency of R&D activities for thirty countries. Guan and Chen (2012) evaluated the national innovation system efficiency for twenty-two countries of the Organisation for Economic Co-operation and Development (OECD). Guan and Chen (2010) analyzed thirty selected Chinese provinces’ knowledge production and commercialization processes. Lafarga and Balderrama (2015) measured the relative technical efficiency of thirty-two Mexican regions with R&D expenditure as a critical factor for innovation. Noticeably, the above-mentioned studies are void of the human capital component in either innovation efficiency attainment or economic and environmental sustainability. This research extends previous studies such as Bresciani et al. (2021) and Khan et al. (2022) by analyzing the role of human capacity in utilizing innovation towards efficient economic and environmental sustainability. Methodologically, a robust DEA model that accounts for the undesirable environmental consequences of human activities and innovation is utilized. Furthermore, the Malmquist-Luemberger productivity analysis is conducted to analyze and decompose productivity for further inference. Strategies and policies are proposed based on the findings.
The remainder of the paper is organized as follows: “Literature review” section presents the literature review. The “Analysis framework” section discusses the analysis framework and data description. The methodologies are then discussed in the “Methodology” section with results and discussions in the “Results and discussion” section. The “Conclusion and policy implications” section concludes the paper.
Literature review
Many studies highlight the importance of innovation for sustainable development (Nill and Kemp 2009). Given the conclusion from these studies, we can infer that innovation is a primary driver of industrial growth. Over the last couple of decades, there have been studies on regional innovation systems (Berman et al. 2020; Doloreux and Porto 2017; Gomez 2017), providing evidence of why it should be used as an instrument to assess performance (Janger et al. 2017; Yu 2020). Comparative measures on innovation such as Bloomberg Innovation Index, Global Innovation Index, and European Innovation Scoreboard are introduced to allow comparative assessment at the national level. However, these indexes have flaws that hinder their use. For example, a significant correlation between some index components means they cannot adequately capture all aspects of innovation linked to each region (Schibany and Streicher 2008; Hauser et al. 2018). Nonetheless, they highlight the innovation performance to a certain degree.
Investigating the effects of human capital on economic growth has gained much interest from scientists and policymakers and has been extensively analyzed by researchers over the last few decades. The earliest theory regarding this relationship dates back to the works of Mincer (1958), Schultz (1961), and Becker (1975), who theorized that human capital is like physical capital, which can be advanced through education, health, and training, and can, in turn, increase output and boost economic growth. Hence, human capital can significantly contribute to economic growth (Romer, 1992; Barro, 1999). In conjunction with other factors such as investment in technology, human capital is essential to economic development (Huang et al. 2021). Human capital contributes to increased technical progress since education makes the innovation, transmission, and adoption of new technologies faster and easier. Recent studies have emphasized the need for human capital to attain sustainable development. Given the emergence of innovation-focused strategies for economic and environmental sustainability, the role of human capital is minimized. The MENA region, as an emerging economy, aims to attain a sustainable economic and environmental ecosystem by pursuing aggressive innovation practices. However, how sustainable is this approach in the long term?
Chen et al. (2011) analyzed innovation efficiency using R&D expenditure. Their result shows intellectual property rights protection and human capital accumulation to have a significant positive effect on innovation efficiency. Their study shows that human capital is also a component of innovation. Wang and Huang (2007) estimated the efficiency of R&D activities for 30 countries. Studies such as Carayannis et al. (2016) and Bresciani et al. (2021) build on Chen et al.(2011) and Wang and Huang (2007) using R&D activities as an input for innovation.
In evaluating knowledge processes, Guan and Chen (2010) evaluated national innovation system efficiency for 22 countries of the Organisation for Economic Co-operation and Development (OECD). In their study, a relational network DEA model was utilized. Furthermore, the effect of a policy-based institutional environment is investigated. Guan and Chen (2010) analyzed the knowledge production and commercialization processes for 30 selected Chinese provinces. By decomposing the Malmquist index, they provide a piece of multi-dimensional information to benchmark R&D efficiency. Lafarga and Balderrama (2015) measured the relative technical efficiency of 32 Mexican regions with R&D expenditure as a critical factor for innovation.
Innovation and environmental sustainability are essential elements of sustainable development. Economic development contributes significantly to the overall sustainability of countries and is essential to continuous competitiveness and market globalization. Innovation alone cannot be analyzed exclusively from a technological and market-oriented perspective Bresciani et al. (2021). The human capital component must be considered as part of the sustainable development element. Given the interconnection between innovation, economic development, and environmental sustainability, human capital is perhaps the pivotal factor that cannot be ignored. For optimal organizational structure and performance, Fonseca et al. (2019) point to human capital as a crucial dimension of the innovation process. Similarly, Diebolt and Hippe (2022) analyzed the long-run impact of human capital on innovation and economic growth in the European region. To buttress the conceptual framework of this study, the inference is drawn from industry activities such as the manufacturing industry. The manufacturing industry contributes to the economic sustainability of countries in the MENA region. The environment is also a recipient of the manufacturing industry from the CO2 emission. The findings of Seclen-Luna et al. (2021b) on the manufacturing firm performance show that human capital composition has a direct effect on manufacturing firm productivity. Moreover, in developing countries, human resources, innovation, and size play a significant role in the performance of manufacturing firms. Therefore, assessing the interconnection between the four factors human capital, innovation, economic development, and environmental sustainability is imperative to the sustainable development of countries and regions.
Analysis framework
Technical efficiency has predominantly been analyzed using two approaches: DEA and stochastic frontier analysis (SFA). While the latter is a parametric method, the former is a nonparametric approach and each has particular strengths and weaknesses and potentially measures different efficiency (Theodoridis and Anwar 2011). However, they have established robustness in estimating the efficiency of systems with multiple inputs and outputs. For example, Silva et al. (2017) show that DEA and SFA provide reliable information on the efficiency of the banking system. Zeng et al. (2021) used DEA and SFA to review 165 articles from academic journals concerning innovation efficiency. It is important to note that when dealing with scenarios involving multiple inputs and outputs in the context of non-linearity, DEA has shown to be superior (Guan and Chen 2010; Chen et al. 2021; Hoff 2007).
DEA is a nonparametric linear programming approach that enables the relative efficiency assessment of homogeneous systems known as decision-making units (DMUs) (Saati et al. 2012). Each DMU’s efficiency is estimated with respect to multiple inputs utilized and multiple outputs produced (Charnes et al. 1978). DEA has been widely applied to the problem of measuring sustainability performance (Ibrahim and Alola 2020; Ibrahim et al. 2021; Sun et al. 2020). The first DEA model was developed by Charnes et al. 1978) with its origin from Farrell (1957). The Charnes et al. (1978) model is referred to as the Charnes, Cooper, and Rhodes (CCR) model. It calculates the relative efficiency of DMUs under the assumption that constant returns to scale prevail. Banker et al. (1984) proposed an alternative model under variable returns to scale, which is referred to as the Banker, Charnes, and Cooper (BCC) model. The DEA methodology has advanced extensively to models such as direction distance function (Chambers et al. 1998; Färe and Grosskopf 2000) and target setting models (Ibrahim et al. 2020). DEA offers the flexibility that allows multiple facets of innovation to be integrated with the need to establish the production function that defines the process (Bresciani et al. 2021). It is well suited to handle analysis with factors that are interconnected. DEA can describe the dynamic change of systems and offers comprehensive discriminatory power.
The integration of innovation to the system process can be quantified for making impactful policies that promote environmental and economic sustainability. Best practices can be identified, and holistic performance trends can be analyzed. To account for the integration of innovation and human capacity towards environmental and economic sustainability, indicators representing each factor presented in the conceptual framework (Fig. 1) are imperative. Furthermore, the socio-economic dynamics need to be considered. Table 1 describes the inputs and outputs indicators of the conceptual framework.Table 1 Data description
Dimension Role Indicator Data source
Innovation Input Patents (Eurostat 2021)
Human capital Input Number of employed persons (WDI 2022c)
Economic Output Gross domestic product (WDI 2011)
Environmental Output CO2 emissions (WDI 2022a)
WDI, world development indicators
As an input, innovation plays a key role in socio-economic transformation. The number of patents is a reliable indicator of innovation (Yafeng et al. 2018). Lee and Park (2005) used patents as an indicator to measure the international comparison of research and development efficiency. Similarly, Wang et al. (2021) used patents as an input variable to estimate innovation efficiency.
Human capital is a component of innovation development and deployment (Kalapouti et al. 2020). The diffusion of technical and operational knowledge requires human capital. Studies have shown that human capital has a statistically significant effect on environmental performance (Kim and Go 2020). The number of employed persons is utilized to incorporate human capital in the innovation and environmental socio-economical nexus. Numerous studies in different sectors have used the number of employed persons as an indicator of human capital. To assess the efficiency of renewable energy policies, Mohd Chachuli et al. (2021) used the number of employees as one of the input variables in the DEA analysis. Cavaignac et al. (2021) utilized the number of employees in an innovative two-stage DEA analysis of logistics efficiency. Given the macro scale of the analysis and innovation context, the number of employed persons in a country as a proxy variable measures the country’s human capital.
Economic and environmental sustainability are fundamental aspects of sustainable development and the primary output of innovation and human capital conjunction. Hence, the innovation-human capital-economic-environmental sustainability nexus. The gross domestic product GDP is selected to account for economic development. GDP is a primary indicator of a country’s economic performance (WDI 2022b). GDP is a prevalent indicator used to assess economic sustainability (Wang et al. 2022). To assess resource and environmental efficiency in China, Bian and Yang (2010) used GDP to account for economic sustainability. GDP has also been linked to human capital (Matos et al. 2021), and environmental sustainability (Ibrahim and Alola 2020). Sheikhzeinoddin et al. (2022) used GDP to explore new evidence between economic development and environmental sustainability in MENA. To assess economic sustainability pre and post-COVID-19 pandemic, Lozano-Ramírez et al. (2022) utilized GDP as an output in their DEA analysis.
A sustainable environment is paramount for attaining sustainable development goals (SDGs). Baloch et al. (2022) analyzed the role of innovation in attaining the SDGs in which environmental sustainability plays a vital role in interconnecting many of the goals. To account for environmental sustainability, CO2 emission is selected in the study. CO2 emission is a viable indicator of environmental sustainability. The less CO2 emitted, the more environmentally sustainable the country. Rahman et al. (2022) discussed the connection between innovation and CO2 emissions to abate climate crises. In the same lane, Bekun et al. (2019) highlighted the role of CO2 in attaining a sustainable environment. Sueyoshi and Goto (2013) used CO2 emissions as an output in DEA environmental assessment. Anser et al. (2020) also utilized CO2 emissions as an output variable in establishing the role of energy innovation in emission reduction.
Methodology
The efficiency of innovation, environmental, and economic sustainability nexus analyzed in this study measures the utilization of innovation and human capital towards economic sustainability while taking into consideration the environmental impact of the development. Since the introduction of data DEA by Charnes et al. (1978). DEA has grown to be a robust technique for evaluating the relative efficiency of systems known as decision-making units (DMUs) with multiple inputs and outputs. A prominent DEA model is the directional distance function (DDF) model (Chambers et al. 1996), especially in the eco-efficiency context. Conventional DEA models take the form of input minimization (input–orientation) or output maximization (output–orientation) for efficiency estimation while assuming all outputs are desirable products. This is inappropriate when desirable and undesirable outputs are jointly produced (Färe et al. 1994). Chung et al. (1997) used DDF to measure eco-efficiency by simultaneously increasing desirable outputs and decreasing undesirable outputs. This study applies a robust novel undesirable outputs DDF model of (Álvarez et al. 2020) to estimate efficiency and productivity.
The DDF model measures the efficiency of units by projecting input–outputs of DMU (xo,yo); inputs x0=x10,x20,⋯,xm0 and outputs y0=y10,y20,⋯,ys0 onto a pre-assigned direction g=-gx-,gy+≠0m+s,gx-∈Rmandgy+∈Rs, in a direction β with a production possibility set P=x,yx≥Xλ,y≤Yλ,λ≥0.
Model (1) illustrates the linear program associated with the estimation.1 Maxβ,λβSubject toXλ≤x0-βgx-Yλ≥y0+βgx+∑j=1nλj=1λ≥0
Given the undesirable environmental output resulting from economic activities (CO2 emissions), an estimation that does not adequately account for these outputs will yield erroneous results. To accommodate for desirable and undesirable outputs, reference is made to the DDF function that accounts for the asymmetry between both outputs. The production possibility set is then redefined as follows: P=x,yd,yux≥Xλ,yd≤Yλ,yu=Yλ,λ≥0 where the outputs are separated into desirable and undesirable, i.e., y=yd,yu with yd∈R++q and yu∈R++r respectively. Therefore, the directional efficiency measure of a DMU x0,y0d,y0u is projected along a pre-assigned directional outputs vector gy=yd,yu≠0m+s. The corresponding solution to the linear program model (2) illustrates the efficiency score. If the optimal solution β∗=0 with λ0=1,λj=0j≠0, then the unit is directional efficient. Otherwise β∗>0 implies the unit is inefficient.2 Maxβ,λβSubject toXλ≤x0Ydλ≥y0d+βy0dYuλ≤y0u+βy0umaxyiu≥y0u+βy0dλ≥0
Malmquist-Luenberger index productivity analysis
Chung et al. (1997) introduce the undesirable Malmquist-Luemberger (ML) productivity index to measure the productivity change of a system with undesirable outputs by referencing the relative efficiency across different time periods. The combined period efficiency x0t,y0t,d,y0t,u is calculated for periods t=1,2. Both scores are denoted by β1,1,andβ2,1, the first superscript refers to the observation of the first time period and the second corresponds to the reference technology. Prieto et al. (2020) relied on the work of Aparicio et al. (2013) to prevent inconsistencies in the original model by projecting observations along the pre-assigned direction. While β1,1 represents the solution to model (2), the intertemporal score β2,1 is the solution to model (3), which evaluates period 2 observation x02,y02,d,y02,u with respect to period 1 technology:3 Maxβ,λβSubject toX1λ≤x02Y1,dλ≥y02,d+βy02,dY1,uλ≤y02,u-βy02,umaxyit,u≥y02,u-βy02,uλ≥0
An ML > 1 signifies efficiency growth. Therefore, the system produces more desirable outputs and less undesirable out. A unison score of ML = 1 infers productivity remains unchanged, while ML < 1 signifies a decline in productivity. The ML index can be decomposed into two indices, efficiency changes (MLTEC) and technical change (MLTC). MLTEC refers to the operational components of the system, while MLTC refers to the technological change of the system (Grosskopf 1993).4 ML=MLTEC×MLTC=1+β1,1/1+β2,2×1+β2,2/1+β2,1×1+β1,2/1+β1,11/2
The ML indices are defined as:5 ML1=1+β1,1/1+β2,1andML2=1+β1,2/1+β2,2
The change in MLTEC is defined as:6 MLTEC=1+β1,1/1+β2,2
And the technical change MLTC:7 MLTC1=1+β2,2/1+β2,1andMLTC2=1+β1,2/1+β1,1
Results and discussions
The descriptive statistics of the data used for the analysis is presented in Table 2. Across the evaluated period, average innovation represented by no. of patents increased steadily with a slight dip in 2018 and 2019. Similarly, average human capital in MENA increases steadily, including the minimum values. However, the standard deviation for innovation is more significant than human capital. The MENA region shows tremendous economic growth with a 25% increase in GDP in 2019 compared to 2011. The minimum economic growth also shows a 38% improvement. Average CO2 emissions steadily increased with a slight decline in 2018 and 2019. Maximum CO2 emission is observed in 2015. 2018 and 2019 indicate an 8% and 4% decline, respectively.Table 2 Descriptive statistics
2011 2012 2013 2014 2015 2016 2017 2018 2019
Patent Mean 127.31 132.53 144.81 147.41 159.54 167.86 179.32 171.96 169.67
Std Dev 376.73 406.88 440.86 448.56 471.61 507.11 491.51 561.43 506.95
Min 0.25 0.02 0.02 0.33 0.17 0.02 0.02 0.20 0.09
Max 1369.43 1481.29 1603.49 1631.01 1713.34 1844.97 1771.33 2036.53 1841.54
No.of employed persons (million) Mean 10.06 10.26 10.57 10.69 10.86 11.12 11.26 11.41 11.64
Std Dev 11.17 11.32 11.63 11.78 11.83 12.16 12.32 12.47 12.75
Min 0.20 0.21 0.21 0.22 0.23 0.24 0.25 0.27 0.28
Max 36.36 37.13 38.09 38.96 38.52 39.46 39.49 39.88 40.63
GDP ($billion) Mean 17,330.70 19,037.78 20,223.26 20,441.00 21,168.18 23,258.59 23,057.74 22,815.71 23,216.77
Std Dev 40,965.09 46,184.28 49,558.70 49,744.47 51,893.05 58,589.81 57,647.29 56,901.33 59,036.93
Min 7.72 8.03 8.47 9.12 10.00 10.41 11.25 11.83 12.49
Max 142,700.22 162,587.53 174,990.64 175,335.40 183,616.25 208,932.11 205,268.15 202,776.27 211,789.77
CO2 emissions (kt) Mean 104.10 111.75 113.47 118.20 122.38 123.66 124.31 123.35 123.77
Std Dev 123.65 132.25 135.59 144.94 151.35 151.24 147.89 142.82 147.24
Min 0.48 0.51 0.56 0.46 0.54 0.49 0.47 0.49 0.48
Max 456.67 488.75 499.38 536.81 561.14 556.74 540.70 514.60 537.35
Based on the selected variables, model (1) is used to evaluate eleven MENA countries’ innovation, human capital, economic, and environmental efficiency from 2011 to 2019. Figure 2 illustrates the average annual efficiency scores, and Fig. 3 presents the individual efficiency scores for each country. The average annual efficiency ranges between 55 and 67% from 2011–2016. It increased to about 82% from 2017–2019. Post-2016, average innovation, no. of employed persons, and GDP show improvement compared to prior periods. More importantly, the percentage increase in CO2 emissions is lesser compared to the percentage of GDP increase. About 50% of the countries performed below average. Algeria, Iran, Israel, Kuwait, Malta, and the UAE are among the top-performing countries. At the same time, Jordan and Saudi Arabia are identified as the least-performing countries. There was a 26% increase in average efficiency between 2016–2019. The UAE had a 74% increase in efficiency, 59% for Tunisia, and 48% for Egypt. Currently, the UAE has the highest efficiency growth among the evaluated countries. The boost in efficiency comes as a result of its aggressive digitalization strategy. Furthermore, the UAE has embarked on major renewable energy transition projects to cut its CO2 emissions. The UAE’s sustainable development strategy put environmental sustainability and clean energy as the cornerstone of its strategy (UAE 2017).Fig. 2 Average efficiency scores of innovation-economic-environmental sustainability
Fig. 3 Efficiency scores for MENA innovation-economic-environmental sustainability
Table 3 shows the ML productivity index for the evaluated periods derived from model (4) through models 2 and 3. An index < 1 signifies decline and lower productivity, while > 1 indicates improvement and productivity gains. A unitary value implies that the reference frontier is unchanged. On average, 45% of countries evaluated show productivity gains post-2016 compared to 35% between 2011 to 2016. The average annual ML continued to increase across the evaluated period and leveled slightly in 2017–2018. The increase in ML could be interpreted as an improvement in the innovation, economic, and environmental efficiency of the region. The 2016–2017 period showed the highest number of countries with productivity gains. Egypt, Malta, Saudi Arabia, and Tunisia showed improvement, while Morocco remained the same. Other countries indicate productivity decline. In the 2018–2019 productivity analysis, Malta has the highest score. The Malta government launched the digital Malta program, which introduced innovation in various sectors such as business and management, food technology, and the environment (Malta 2016). The initiative expands its human capital and infrastructure while strengthening its regulation and legislation. This initiative by the Malta government could explain the productivity gains, which have a socio-economic and environmental impact.Table 3 Malmquist-Luenberger (ML) productivity index
Countries 2011–2012 2012–2013 2013–2014 2014–2015 2015–2016 2016–2017 2017–2018 2018–2019
ML ML ML ML ML ML ML ML
Algeria 0.94 0.96 1.03 0.98 0.95 0.71 1.00 1.00
Egypt 0.99 0.99 1.00 1.00 0.99 1.02 0.95 0.98
Iran 1.04 1.09 0.93 0.89 0.98 0.75 1.00 1.05
Israel 1.00 1.02 0.99 0.96 0.98 0.89 1.15 0.92
Jordan 1.01 0.63 0.93 1.01 1.01 0.99 1.00 1.00
Kuwait 1.25 0.44 0.67 2.73 0.89 0.96 1.30 0.93
Malta 0.82 1.31 1.29 1.01 0.82 1.24 0.43 1.80
Morocco 1.00 1.00 1.00 1.00 0.99 1.00 1.01 0.98
Saudi Arabia 0.97 1.01 0.99 1.01 0.99 1.03 0.85 1.08
Tunisia 0.98 0.97 1.00 0.99 1.02 1.01 0.99 0.99
UAE 0.61 0.91 1.11 0.79 0.81 0.99 0.85 0.99
By decomposing the ML productivity index into technical efficiency change in Table 4 and technology change in Table 5, the cause of productivity growth and decline can be identified for individual countries. The results show that MENA has performed outstandingly in TEC and gained ground in TC. The average TEC after 2016 is 1.2, 1.02, and 1.00, while the average TC is 0.82, 0.94, and 1.07, respectively (see Fig. 4). The majority of the countries either maintained or had a slight improvement in TEC. This observation speaks to the operational efficiency of the region in attaining sustainable development. Human capital is considered a technical improvement and an operational dimension of systems (Gangani et al. 2006). Therefore, the ability of most MENA countries to attain productivity gains so far is primarily due to the positive TEC. However, the regional TEC performance viewed from the average TEC score signifies a decline in the region’s TEC. This decline needs to be addressed to prevent a technologically dependent system that lacks operational proficiency. Systems that are heavily technologically dependent lose efficiency and productivity over time (Davis 1993). In the 2018–2019 period, Israel showed a productivity decline. In that period, the MLTEC value is unison, meaning there is no change in operational performance; however, a slight fall in MLTC results in productivity regression.Table 4 Malmquist-Luenberger technical efficiency change (MLTEC)
Countries 2011–2012 2012–2013 2013–2014 2014–2015 2015–2016 2016–2017 2017–2018 2018–2019
MLTEC MLTEC MLTEC MLTEC MLTEC MLTEC MLTEC MLTEC
Algeria 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
Egypt 1.00 1.00 1.00 1.00 1.00 1.36 0.98 1.00
Iran 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
Israel 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
Jordan 1.24 0.61 0.89 1.00 1.02 1.23 1.07 1.00
Kuwait 1.00 1.00 0.67 1.49 1.00 1.00 1.00 1.00
Malta 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
Morocco 1.00 1.00 1.00 1.01 1.00 1.31 1.04 1.00
Saudi Arabia 0.98 1.01 0.99 1.01 0.99 1.16 1.08 0.97
Tunisia 0.99 0.96 0.99 0.99 1.03 1.45 1.08 1.00
UAE 0.76 0.96 1.12 0.81 0.86 1.74 0.92 1.00
Table 5 Malmquist-Luenberger technical change (MLTC)
Countries 2011–2012 2012–2013 2013–2014 2014–2015 2015–2016 2016–2017 2017–2018 2018–2019
MLTC MLTC MLTC MLTC MLTC MLTC MLTC MLTC
Algeria 0.94 0.96 1.03 0.98 0.95 0.71 1.00 1.00
Egypt 0.99 0.99 1.00 1.00 1.00 0.75 0.97 0.98
Iran 1.04 1.09 0.93 0.89 0.98 0.75 1.00 1.05
Israel 1.00 1.02 0.99 0.96 0.98 0.89 1.15 0.92
Jordan 0.82 1.02 1.04 1.01 0.99 0.80 0.93 1.01
Kuwait 1.25 0.44 1.00 1.84 0.89 0.96 1.30 0.93
Malta 0.82 1.31 1.29 1.01 0.82 1.24 0.43 1.80
Morocco 0.99 1.00 1.00 1.00 1.00 0.77 0.97 0.98
Saudi Arabia 0.99 1.00 1.00 1.00 0.99 0.89 0.79 1.11
Tunisia 0.98 1.01 1.00 1.00 0.99 0.69 0.92 0.99
UAE 0.79 0.94 1.00 0.97 0.95 0.57 0.92 0.99
Fig. 4 Average productivity decomposition of MENA’s sustainable development. ML: Malmquist-Luenberger productivity index; MLTEC: Malmquist-Luenberger technical efficiency change; MLTC: Malmquist-Luenberger technological change
Role of innovation and human capital in economic and environmental sustainability
Decomposing the productivity index into technical change and technological change gives further insight into the analysis. The result shows that the MENA region’s technical efficiency has been the primary driver of its sustainable development. The result also indicates a decline in technical efficiency (see Fig. 4) with a shift towards technological-based development. The growth in MLTC speaks to the region’s technological advancement. However, there should be complementary technical and technological growth for sustainable socio-economic development. The result indicates that when countries maintain or increase technical or technological efficiency, productivity gains are positive. The reverse is the case; when there is a decline in either technical or technological efficiency, productivity falls.
For economic and environmental sustainability, human capital has a significant role. There is compelling evidence of innovation in the region with the socio-economic upside of digitalizing the economy. However, to attain environmental sustainability, it is essential to implement national green strategies at the industrial level. Green human resource management has been identified as an effective avenue for attaining environmental sustainability (Song et al. 2021). The economic and environmental growth will be sustained by incorporating green human resources management and innovative practices in the region.
Conclusion and policy implications
One of the most crucial strategic decisions of developing countries and regions is to ensure sustainable development. This study analyzes the role of human capital and innovation in attaining economic and environmental sustainability. The research applied DEA-Malmquist-Luenberger productivity for efficiency and productivity analysis. Unlike conventional DEA efficiency estimations, the models utilized adequately accommodate desirable and undesirable outputs of the innovation-human capital-economic-environmental nexus. The decomposition of productivity gives insight into the cause of efficiency change over time. The results of the analysis point to human capital being an integral part of the MENA region’s sustainable development. There is an improvement in average efficiency in the region. Further analysis shows a decline in technical efficiency, which is related to the human capital component of the nexus. In the long run, this might affect the economic and environmental sustainability of the region, given the interconnection of the sustainable development components. The study concludes that sustainable human capital and innovation are significant to economic and environmental sustainability—the findings of this study point to three main policy implications. First, the analysis suggests human capital augmentation parallel to the boost in innovation experienced in many parts of the region. This requires the strengthening of human capital and capacity in many aspects of the economy. This could be achieved through a human capital monitoring system—tracking the loss of human capital across the different sectors to enhance the efficiency of replacement and upskilling activities. The second implication suggests the need for human-centered environmental innovation. This requires re-engineering of the human capital to integrate emerging innovation. Re-engineering human capital under sustainable economic and environmental conditions will enhance sustainability (Kruzhkova et al. 2021). This could be achieved through increased R&D spending on eco-innovation projects for different sectors, thereby simultaneously increasing human capital and innovation activities. Lastly, continuous monitoring of the human capital-innovation dynamic is required to prevent the irreversible decline of economic and environmental sustainability gains. This study’s contextual result can influence human capital-innovation agendas in emerging economies to boost environmental and economic sustainability.
The study suffers from a set of conventional limitations. First, the time period and the number of countries limit the study to 2019. Secondly, exogenous factors that may drive efficiency are not considered. Recommendation for future research includes expanding the study to a two-stage analysis to include drivers of innovation and human capital growth. The student shows that innovation and human capital are essential for economic and environmental sustainability. Examining factors that support human capital and innovation would address the challenges from the source. Furthermore, an inter-regional comparison could yield an interesting economic and environmentally sustainable development conclusion.
Author contribution
Mustapha D. Ibrahim: conceptualization, data curation, formal analysis, methodology, supervision, validation, visualization, writing—original draft, writing—review, and editing.
Data availability
The data that support the findings of this study are openly available in (Mendeley data) at https://doi.org/10.17632/yvt8zvbt8c.14
Declarations
Ethical approval
Not applicable.
Consent to participate
Not applicable.
Consent for publication
The journal has the author consent to publish.
Competing interests
The author declares no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Immunol Res
Immunol Res
Immunologic Research
0257-277X
1559-0755
Springer US New York
9350
10.1007/s12026-022-09350-4
Original Article
Immunostimulatory activity of fluoxetine in macrophages via regulation of the PI3K and P38 signaling pathways
http://orcid.org/0000-0002-7466-2942
Önal Harika Topal [email protected]
1
Yetkin Derya 2
Ayaz Furkan 34
1 grid.449620.d 0000 0004 0472 0021 Medical Laboratory Techniques, Vocational School of Health Services, Toros University, 33140 Mersin, Turkey
2 grid.411691.a 0000 0001 0694 8546 Mersin University Advanced Technology Education Research and Application Center, Mersin University, 33110 Mersin, Turkey
3 grid.411691.a 0000 0001 0694 8546 Department of Biotechnology, Faculty of Arts and Science, Mersin University, Mersin, Turkey 33110
4 grid.411691.a 0000 0001 0694 8546 Mersin University Biotechnology Research and Application Center, Mersin University, 33110, Mersin, Turkey
13 12 2022
19
2 9 2022
1 12 2022
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Fluoxetine is an antidepressant drug that is heavily preferred in the cure of depression, which is from the selective serotonin reuptake inhibitor (SSRI) group. There are many reports on the effect of fluoxetine on the immune system, and its effect on the macrophage cells has never been looked at before. We aimed to demonstrate the cytokine production potential of fluoxetine antidepressant, which is widely used in the clinic, in the J774.2 cell line and its effect on PI3K and P38 pathways. The use of fluoxetine alone in J774.2 macrophage cells showed immunostimulatory properties by inducing the production of tumor necrosis factor-α (TNF-α), interleukin (IL) IL-6, IL-12p40, and granulocyte–macrophage colony-stimulating factor (GM-CSF) cytokines. It showed anti-inflammatory properties by completely stopping the production of cytokines (IL-6, IL12p40, TNF-α, and GM-CSF) at all concentrations where LPS and fluoxetine were used together. While PI3K and P38 pathways were not effective in the immunostimulatory effect in the presence of the drug agent, we found that the PI3K and P38 pathways were influenced during their anti-inflammatory activity.
Keywords
Fluoxetine
Macrophage
Inflammation
Cytokines
Depression
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pmcIntroduction
Fluoxetine is in the selective serotonin reuptake inhibitor (SSRI) antidepressant drug group, which is frequently preferred in the treatment of depressive syndromes. SSRIs provide treatment by increasing the level of serotonin in the brain. Serotonin is a biogenic amine that is effective in regulating vital processes such as mood, food, sexual desire, sleep, and body temperature. Serotonin neurotransmitters are especially found in the immune-inflammatory axis and can regulate immune cell activity autocrine [1].
In the findings of recent studies, it has been emphasized that 5-hydroxytryptamine (5-HT) has an important regulatory role in the immune and nervous systems [2–4]. The main cells that produce enterochromaffin 5-HT, which is one of the gastrointestinal cells, release 5-HT through platelets. This event activates platelet-activating factors and immunoglobulin E (IgE), resulting in an inflammatory stimulus effect [2]. Lymphocytes and monocytes also synthesize 5-HT. Nerve fibers in contact with lymphoid tissues are also suggested to take up and release 5-HT to stimulate nerves [5, 6]. In studies on this subject, it has been reported that 5-HT has an immunomodulatory effect by increasing mitogen-activated lymphocyte proliferation, activating natural killer (NK) cells, and increasing macrophage and dendritic cell stimulation [7, 8].
Studies of fluoxetine’s effect on the immune system have been adhered to and are being done. In recent studies, it has been shown that fluoxetine reduces proinflammatory cytokine levels by affecting the inflammatory system in experimental animals. More recently, animal studies show that fluoxetine reduces proinflammatory cytokine levels by acting on the inflammatory process [9–11]. In a study conducted with patients treated with SSRI group antidepressants, they observed that the expression level of the gene encoding the NLRP3 gene, which has an inflammatory effect, decreased in mononuclear cells taken from patients. They also reported that IL-1β and IL-18 cytokine concentrations decreased in plasma [12]. In a meta-analysis including 22 studies, it was shown that IL-1β, 1IL-6, and TNF-α cytokine levels were decreased in the serum of patients using SSRIs [13]. In another study, it was reported that fluoxetine increased the expression of the serotonin transporter in the T lymphocyte surface region to improve serotonin reuptake, resulting in a decrease in the number of lymphocytes [14]. Studies are showing that fluoxetine is an immunomodulator. It was observed that T lymphocyte levels in the peripheral blood of mice treated with fluoxetine decreased, while the CD4 + /CD8 + ratio remained stable [15]. It has been reported that patients treated with intravenous fluoxetine have a decrease in the level of T lymphocyte activity [14]. In another study conducted with 16 patients, a decrease in proinflammatory cytokine levels was observed, while an increase in Treg cell count was observed [16].
The P38 signaling pathway is a class of mitogen-activated protein kinases (MAPKs) that affects the production of cytokines by monocytes and macrophages [17]. The P38 pathway is activated as a result of ultraviolet, heat shock, stress, and activation of cytokines in the cell. While treating inflammatory diseases with intense cytokine production, drug production is made by targeting the P38 pathway [18]. In vitro-in vivo studies have stated that the P38 pathway is activated in the output of IL-6 and TNF-α with macrophages stimulated by lipopolysaccharide (LPS) [19, 20]. In a study, it was reported that paroxetine from the SSCI group induced apoptosis in breast malignant tumor cells concerning the Ca2 + and P38 pathways [21].
The PI3K signaling pathway is an oncogene-derived intracellular pathway that plays a crucial role in the setting of the cell events such as mitosis and apoptosis. PI3Ks expressing secondary messengers provide important mechanisms in intracellular signaling [22, 23]. It also has an significant role in inflammatory responses [24].
The inconsistency of the reports of studies investigating the effect of fluoxetine on immunity did not clarify these effects. In the current study, the amount of cytokine (IL-6, IL12p40, TNF-α, and GM-CSF) production of fluoxetine antidepressant alone and in combination with LPS on the mammalian macrophage cell line J774.2 was investigated. In addition, using salicylic acid combined with LPS, which has anti-inflammatory properties, its effects on the level of cytokines were compared with the group given fluoxetine. In addition, Al2O3, which is used as an adjuvant in vaccine formulations, has been used in combination with LPS to support proinflammatory activity [25]. There have not been comprehensive studies on the immune system cells specifically and their instruction with fluoxetine and how it affects intracellular pathways and their anti-inflammatory or pro-inflammatory behaviors. This study to our knowledge is the first one to focus on this aspect of fluoxetine’s effect on the immune system’s cells specifically on the macrophage.
Materials and methods
Fluoxetine was obtained from Sigma Aldrich (CAS number: 56296–78-7).
J774.2 macrophage cell culture
J774.2 mouse macrophage cell line had ATTC origin. Cells were seeded in Roswell Park Memorial Institute (RPMI) medium including 10% fetal bovine serum (FBS), 1% antibiotic (100 µg/mL for each penicillin–streptomycin), and sodium pyruvate for growth. Cells were left to incubate in the incubator (5% CO2, 37 °C). The cell culture medium was changed every 4 days and made ready for the experiments [26, 27].
Stimulating cells with lipopolysaccharide
J774.2 cells (106 cells/mL) were placed in 24-well plates and their effects were tested in combination with fluoxetine (1, 5, 10, and 20 µg/mL) and LPS. To increase the anti-inflammatory effect, LPS (1 µL, Enzo Life Sciences, Salmonella) was added to separate wells along with AL2O3 and salicylic acid, and the effects were compared with other results. One microliter of dimethyl sulfoxide (DMSO) was added to the control wells. The cells were incubated for 24 h (5% CO2, 37 °C) and then centrifuged (2000 RPM). Then they were put in Eppendorf tubes. Cells were placed at − 80 °C. For cytokine determination, cells emerging from − 80 were separated from the wells by gently pipetting. Statistical analyses were performed with 3 replications of each study. One hundred and twenty minutes before cytokine determination in macrophage cells, 5 mM ATP (Fisher Scientific) was added to each well [28].
ELISA test for cytokines
Enzyme-linked immunosorbent (ELISA) assay was performed to determine the number of cytokines IL-6 (cat number: 555183), IL12p40 (cat number: 555220), TNF-α (cat number: 555212), and GM-CSF (cat number: 555126). They were all used in 1:1000 dilution rate. The ELISA kit for the cytokine types to be administered was prepared according to the application procedure of the manufacturer of BD Biosciences, CA, USA. Ninety-six-well plates were coated (hamster anti-mouse cytokine pH = 9.5) and incubated overnight. Then the solutions were drained from the plates, washed three times with PBS (0.05% Tween), and allowed to rest at room temperature for 3 h. After the wells were cleaned, blocking buffer was added (200 µL—1% BSA PBS) followed by 3 washes and incubated at 4 °C overnight. Plates were washed 3 times with further biotin (100 µL) and human anti-mouse cytokine (0.5 µg/mL in 10). PBS was placed in each of the wells and left at room temperature for 120 min, and the solutions were removed and washed. After these procedures, TMB (100 µL—BD OptEIA) was added to each of the wells, and sulfuric acid (50 µL 1 M) was added to stop the reaction. Their absorbance was measured at 450 nm [29, 30]. Calculations were made for each sample (TNF-α, IL-6, IL12p40, and GM-CSF) using cytokine concentrations with known standards.
Flow cytometry analysis for P38 and PI3K intracellular pathways
Cells were fixed and permeabilized according to the BD (BD Fix Buffer I -557,870) procedure. It was then stained with Anti PI3K (Invitrogen PE Mouse, p85/p55, cat no: MA5-36,954) and P38 MAPK (BD PE Mouse, pT180/pY182, cat no: 562065). Flow cytometry analysis of cells was performed by repeating each experiment data 3 times (BD FACS ARIA III) [31].
Statistical analysis
Statistical data were analyzed in GraphPad Prism Software version 5. The unpaired two-tailed t-test was used to determine statistical significance. Three replicates of all experimental conditions were made, p < 0.0001, N = 3.
Results
J774.2 macrophage cells incubated with fluoxetine for 24 h were observed to induce the production of IL-6 cytokines in direct proportion to the concentration used. It was observed that IL-6 production was completely stopped when compared with the positive control groups activated only by LPS and the concentrations using only fluoxetine (1, 5, 10, 20 µg/mL) from 1 μg/mL concentration to the highest concentration when LPS and fluoxetine were used together (Fig. 1). The use of anti-inflammatory salicylic acid with LPS blocked the production of IL-6 as expected. The combined use of AL2O3 and LPS stimulated the immune system, promoting cytokine production (Fig. 1).Fig. 1 Fluoxetine (F), the application of fluoxetine to macrophage cells stimulated IL-6 cytokine release and showed immunostimulatory properties. It showed an anti-inflammatory effect in the environment where it was LPS-positive. For IL-6 ELISAs (1 × 10.6 cells/mL cell concentration), J774.2 cells were stimulated with F (1, 5, 10, 20 µg/mL) for 24 h. In the environment with LPS, it showed an anti-inflammatory effect. DMSO was the negative control; F dissolved in DMSO (concentrations of 1, 5, 10, 20 µg/mL were used) and F added with 1 µg/mL LPS (1, 5, 10, 20 µg/mL) were positive controls. Each set of experiments was repeated 3 times and statistically calculated with Student’s t-test. ***p < 0.0001, N = 3
J774.2 macrophage cells incubated with fluoxetine for 24 h exerted a pro-inflammatory effect by stimulating the production of IL-12p40 cytokines at each concentration (1, 5, 10, 20 µg/mL) used. In terms of IL-12p40 production, the drug molecule had immunostimulatory activity. When the immunomodulatory activity was measured, it was observed that IL12p40 cytokine production was completely knocked out in the presence of fluoxetine compared to the DMSive control groups activated only by LPS (Fig. 2). The use of anti-inflammatory salicylic acid with LPS reduced the IL-12p40 cytokine production by half compared to the LPS control well. The combined use of AL2O3 and LPS showed an immunostimulatory effect as expected and slightly increased IL-12p40 production compared to the single effect of LPS (Fig. 2).Fig. 2 Fluoxetine (F), the application of fluoxetine to macrophage cells stimulated IL-12p40 cytokine release and showed immunostimulatory properties. It showed an anti-inflammatory effect in the environment where it was LPS-positive. For IL-12p1240 ELISAs (1 × 10.6 cells/mL cell concentration), J774.2 cells were stimulated with F (concentrations of 1, 5, 10, 20 µg/mL were used) for 24 h. In the environment with LPS, it showed an anti-inflammatory effect. DMSO was the negative control; F dissolved in DMSO (1, 5, 10, 20 µg/mL) and F added with 1 µg/mL LPS (1, 5, 10, 20 µg/mL) were positive controls. Each set of experiments was repeated 3 times and statistically calculated with Student’s t-test. ***p < 0.0001, N = 3
Fluoxetine stimulated TNF-α cytokine production by showing immunostimulatory properties after incubation with J774.2 cells for 1 day. We found that when salicylic acid was applied in combination with LPS, it decreased the TNF-a grade compared to the LPS control well. The combined use of AL2O3 and LPS showed an immunostimulatory effect, as expected, and slightly increased IL-12p40 production equates to the effect of LPS alone. When fluoxetine was co-administered with LPS, it showed an anti-inflammatory effect and caused a decrease in TNF-α level (Fig. 3).Fig. 3 Fluoxetine (F), the application of fluoxetine to macrophage cells stimulated TNF-α cytokine release and showed immunostimulatory properties. In the environment with LPS, it showed an anti-inflammatory effect. For TNF-α ELISAs (1 × 10.6 cells/mL cell concentration), J774.2 cells were stimulated with F (1, 5, 10, 20 µg/mL) for 24 h. In the environment with LPS, it showed an anti-inflammatory effect. DMSO was the negative control; F dissolved in DMSO (concentrations of 1, 5, 10, 20 µg/mL were used) and F added with 1 µg/mL LPS (1, 5, 10, 20 µg/mL) were positive controls. Each set of experiments was repeated 3 times and statistically calculated with Student’s t-test. ***p < 0.0001, N = 3
J774.2 macrophage cells incubated with fluoxetine for 24 h exerted a pro-inflammatory effect by inducing the production of GM-CSF cytokines at each concentration used (especially 5, 10, 20 µg/mL). Therefore, fluoxetine has immunostimulatory activity by itself in the absence of LPS stimulation of the macrophages. While examining the immunomodulatory activities, it was observed that GM-CSF cytokine production was completely stopped when compared with the positive control groups activated only by LPS and the concentrations using only fluoxetine (1, 5, 10, 20 µg/mL) from the concentration of 1 μg/mL where LPS and fluoxetine were used together to the highest concentration (Fig. 4). The use of anti-inflammatory salicylic acid with LPS halted the IL-6 production as expected. The combined use of AL2O3 and LPS showed an immunostimulatory effect and slightly increased GMCSF production compared to the production levels achieved by the LPS alone (Fig. 4).Fig. 4 Fluoxetine (F), the application of fluoxetine to macrophage cells stimulated GM-CSF cytokine release and showed immunostimulatory properties. It showed an anti-inflammatory effect in the environment where it was LPS-positive. For GM-CSF ELISAs (1 × 10.6 cells/mL cell concentration), J774.2 cells were stimulated with F (1, 5, 10, 20 µg/mL) for 24 h. In the environment with LPS, it showed an anti-inflammatory effect. DMSO was the negative control; F dissolved in DMSO (1, 5, 10, 20 µg/mL) and F added with 1 µg/mL LPS (concentrations of 1, 5, 10, 20 µg/mL were used) were positive controls. Each set of experiments was repeated 3 times and statistically calculated with Student’s t-test. ***p < 0.0001, N = 3
Flow cytometry analysis was performed to define the effects of fluoxetine on PI3K and P38 intracellular changes. In this analysis, 20 µg/mL, which is the highest concentration of fluoxetine activity, which we determined as a result of our study, was used. J774.2 macrophage cells (106 cells/mL cell concentration) were stimulated for 24 h with LPS and LPS alone, salicylic acid (SA), 20 µg/mL fluoxetine alone, and LPS alone. Phosphorylated P38 cells were used in addition to DMSO for control groups, and LPS (1 µg/mL) was used for positive controls. When the effect of fluoxetine on the PI3K pathway was tested, the concentration of 20 µg/mL alone did not change the rate of PI3K positive cells relative to control data. Therefore, its immunostimulatory activity was not via activation of the PI3K pathway. Compared to the control group data, LPS + 20 µg/mL cells decreased the % PI3K positive cell rate. While fluoxetine was not effective in this pathway due to its immunostimulating properties, we found that its anti-inflammatory effect was effective through this pathway (Fig. 5). Compared with the control group, 20 µg/mL fluoxetine did not increase the ratio of P38 cells. Compared with the control group, LPS + 20 µg/mL cells increased their percentage of P38% cells. While fluoxetine was not effective on the p38 pathway in terms of its immunostimulatory properties, its anti-inflammatory effect was found to be effective through this pathway (Fig. 6). The PI3K and P38 pathways are inactive in the immunostimulatory effect in the presence of the drug agent. Meanwhile, fluoxetine acted through PI3K and P38 pathways for its anti-inflammatory properties.Fig. 5 Rate of % PI3K (positive cells); macrophage cells (10.6 cells/mL) were stimulated for 1 day in combination with LPS and LPS alone, salicylic acid (SA), 20 μg/mL fluoxetine alone, and LPS in combination. Phosphorylated PI3K cells were used in addition to DMSO for control groups, and LPS (1 µg/mL) was used for positive controls. The reference point was accepted as 1 while making floor induction calculations. Three replicates were made for each data set; Student t-test was preferred for statistical analysis. ***p < 0.0001, N = 3
Fig. 6 Rate of % P38 (positive cells); macrophage cells (10.6 cells/mL) were stimulated for 1 day in combination with LPS and LPS alone, salicylic acid (SA), 20 μg/mL fluoxetine alone, and LPS in combination. Phosphorylated P38 cells were used in addition to DMSO for control groups, and LPS (1 µg/mL) was used for positive controls. The reference point was accepted as 1 while making floor induction calculations. Three replicates were made for each data set; Student t-test was preferred for statistical analysis.***p < 0.0001, N = 3
Discussion
SSRI group antidepressants, which are frequently preferred in the cure of depression, regulate the level of serotonin. SSRIs cause an increase or decrease in the number of cytokines in circulation. There have been studies investigating the effect of fluoxetine, one of the SSRI group antidepressants, on the immune system, but there is no study on its effect on macrophage cells. In this study, IL-6, IL12p40, TNF-α, and GM-CSF cytokine production levels of J774.2 macrophage cells incubated with fluoxetine for 24 h were evaluated. In addition to fluoxetine, these effects were also examined in the presence of immunostimulating LPS. The use of fluoxetine alone in J774.2 macrophage cells showed immunostimulatory properties by inducing the production of IL-6, IL12p40, TNF-α, and GM-CSF cytokines. At all concentrations where LPS and fluoxetine were used together, it showed anti-inflammatory properties by completely stopping cytokine production (Figs. 1, 2, 3, and 4).
It is mentioned that proinflammatory cytokine production is increased in the pathophysiology of depressive disorders. Studies have found that depression is associated with changes in IL-6 and TNF-α cytokine levels [32, 33]. Kubera et al. showed that antidepressant drugs suppress the release of TNF-α and IL-6 induced by LPS [34].
A meta-analysis of 292 patients with major depressive disorder treated with fluoxetine revealed decreased levels of TNF-α or IL-6 cytokines. In the results of in vitro and in vivo studies with fluoxetine, it was stated that reducing IL-1 beta and IL-5 levels improved the symptoms of depression by regulating the neuroinflammatory system. It was found that fluoxetine regulates the neuroinflammatory system by suppressing proinflammatory cytokines, thus regulating the symptoms of depression [35, 36]. It is expected that most of the patients with depression will increase the level of proinflammatory cytokines, and the symptoms will be improved by the immunomodulatory effect of antidepressants on cytokines in the treatment. In some studies, severe decreases in C-reactive protein concentrations have been observed in patients with major depression treated with SSRIs. This decrease indicates that antidepressants initiate the anti-inflammatory response [37].
Liu et al. showed that fluoxetine inhibits IL-6 and TNF-α in the presence of LPS in LPS-stimulated microglial cells. The result of this study supports our study. In the use of fluoxetine, when there is a danger signal such as LPS in the environment, cytokine uremia is suppressed from macrophages and the inflammatory effect begins. Thus, the body remains our defense against external pathogens. They also showed that fluoxetine inhibited P38 MAPK phosphorylation [38]. When the anti-inflammatory effects of fluoxetine in mice with asthma were examined in peripheral studies with experimental animals, it was reported that it suppressed TNF and monocyte secretion [39, 40].
Ghosh et al. tested the anti-inflammatory property of fluoxetine in tumor-associated macrophages. They observed changes in some cytokines (IL-4, IL-6, IL-10, and IL-12) levels of macrophages retained in liquid tumor cells. They reported that after fluoxetine supplementation, CD3 + T cells indicated a significant diminish in these cytokine levels like the control group, and this event triggered apoptosis. Fluoxetine may reduce the immunostimulatory properties of tumor cells by reprogramming macrophages in inflammatory conditions [41].
Currently, TNF-α and IL are used in the treatment of autoimmune diseases and other immune-related diseases. For this reason, it is necessary to determine the cytokines that are effective in the pathogenesis of major depressive disorder (MDD) and explain how antidepressants used in the treatment of this disease change the number of cytokines. An abnormal immunological profile observed in the pathogenesis of the major depressive disorder, studies of pro-inflammatory (IL-1β, TNF, IFN-y, IL-12, IL-17, IL-18) the increase in the cytokines IL-12 and TGF-β anti-inflammatory cytokines have been shown to have low levels. [42, 43].
In autoimmune disorders such as rheumatoid arthritis and multiple sclerosis, differences in the number of cytokines have been observed with depressive symptoms [44, 45]. In studies, TNF-a and IL6 levels in the plasma and cerebrospinal fluid of patients with MDD were found to be significantly higher when compared to healthy individuals [46, 47]. In addition, TNF-α, IL-1β, IL-6, and IL-10 levels were found to be high in suicidal MDD patients [48]. MDD supports the importance of TNF-α in the pathogenesis of depression in developed rodent models. TNF-α levels have been shown to decrease when SSRI antidepressants are administered to rodent models of depression [49].
In in vitro and in vivo studies conducted with patients with major depressive disorder, it is known that IL-6 level is increased and its amount is high in the circulation. IL-6 contributes to the development of depression through the intestinal microbiota. Intravenously, IL-6 receptor antibody has been stated to perform antidepressant effects in the murine model of MDD [50].
Immunoinflammation and autoimmune went well with IL-12 but did not grow any further than that. In those with MDD, it is believed that pressor therapy reduces IL-12 and increases TGF-β1 [51]. Despite this study, in another study, proinflammatory levels (TNF-α IL-2, IL-12, and monocyte chemoattractant protein-1 (MCP-1)) were found to be very high [52]. In another study conducted on depressed patients, TNF-α, GM-CSF, IL-2, IL-5, IL-12, and IL-13 levels were found to be higher than in non-depressed groups. Compared to the non-obese and non-depressed groups, these cytokine levels were found to be higher [53, 54].
Immunoinflammatory disorders are common in the development of depression. There are existing preclinical and clinical studies in the literature suggesting that the proinflammatory cytokine macrophage migration inhibitory factor (MIF) and a member of the MIF family play a role in the pathogenesis [43]. In our study, fluoxetine stopped IL-6, IL12p40, TNF-a, and GM-CSF cytokine production in LPS-induced macrophage cells. However, future comprehensive studies are needed to evaluate the effects of other proinflammatory cytokines that play a role in major depressive disorder, such as fluoxetine MIF.
There are positive and negative results in studies on fluoxetine administration in autoimmune disease models. In a placebo-control group study investigating the effects of fluoxetine in patients with relapsing multiple sclerosis (MS), fluoxetine was shown to reduce the formation of lesions that strengthened in MS [55]. As a result of a study that tested the immunomodulatory effects of fluoxetine in a mouse multiple sclerosis model, it was reported that fluoxetine delayed the onset of autoimmune encephalomyelitis and reduced clinical paralysis. As a result, it has been stated that fluoxetine has immunomodulatory effects by suppressing the formation of T cells, antigen-presenting cells, and inflammatory cytokines [56]. In a recent study, it was stated that fluoxetine did not show any neuroprotective effect in the treatment of patients with progressive multiple sclerosis compared to the placebo group [57]. Fluoxetine and cytolamin from the SSCI group showed potent anti-inflammatory effects when applied to human and murine models of rheumatoid arthritis, greatly reducing disease progression [58]. Antidepressant drugs are preferred to reduce pain specific to rheumatoid arthritis. Fluoxetine antidepressant was administered to rats with rheumatoid arthritis for 26 days, and it was shown that there was no analgesic effect on rats with rheumatoid arthritis [59].
The P38 signaling pathway was discovered to regulate the proinflammatory cytokine production by macrophages [60]. It can activate the P38 pathway, which is one of the extracellular signals, in the activation of cytokines formed as a result of stress in the cell. The P38 pathway is targeted when treating inflammatory diseases with high cytokine production [18]. Studies have been conducted indicating that LPS-induced macrophages are included in the P38 signaling pathway and produce TNF-α and IL-6 [19, 20].
To see the effect of fluoxetine on macrophage intracellular pathways, cells were stained with PI3K and P38 in the presence of a drug agent alone or after incubation with LPS. Since fluoxetine observed its highest activity at a concentration of 20 µg/mL, this concentration was used to observe changes in PI3K and P38 intracellular levels in flow cytometry analysis. Compared with the control group, 20 µg/mL fluoxetine concentration did not increase the percentage of P38 and PI3K positive cells. LPS + 20 µg/mL cells reduced the proportions of P38 and PI3K positive cells compared to LPS-containing control cells. While PI3K and P38 pathways were not effective in the immunostimulatory effect of the fluoxetine, we found that the PI3K and P38 pathways were part of the mechanism of its action during its anti-inflammatory activity.
Zhao et al. found that in rats treated with 10 mg/kg fluoxetine for 2 weeks, fluoxetine ameliorated depression-like behaviors by targeting P38 MAPK signaling, suppressing neuroinflammation and apoptosis [61]. Fluoxetine has been shown to inhibit P38 phosphorylation in LPS-stimulated microglial cells [38]. In another study, it was reported that fluoxetine and salicylic acid caused the inhibition of anti-inflammatory properties, NF-KB, and P38 MAPK pathways in BV2 microglia cells. In addition, it was stated that fluoxetine increased the anti-inflammatory effect in BV-2 cells induced by salicylic acid and LPS [60]. Consistent with this study, in our study, fluoxetine increased the anti-inflammatory effect through the P38 pathway.
It has been reported that the expression of TNF‑α and IL-6 is decreased in the lungs of rats treated with fluoxetine, and it also provides protection against lung infection caused by methamphetamine by stopping oxidative stress via P38 [62]. The PI3K signaling pathway is an oncogene-derived intracellular pathway that has a critical role in the regulation of cell metabolisms such as proliferation and apoptosis. Secondary messengers expressed by PI3Ks provide important mechanisms for cell fate in intracellular signaling [22, 23]. Since the effects of fluoxetine on the PI3K signaling pathway have not been studied in macrophage cells before, there is no study in the literature on this subject. In a study with diabetic rats, fluoxetine was reported to regulate lipid metabolism via the PI3K/AKT signaling pathway [63]. Lei et al. reported that fluoxetine increased the proliferation of breast cancer cells by inducing low concentrations of PI3K/AKT signals in SKBR3 and MCF-7 breast cancer cells [64]. In our study, we also found that PI3K was another target of fluoxetine during its anti-inflammatory activity (Fig. 6). In addition to immunoinflammatory diseases, the PI3K/Akt/mTOR pathway includes infectious diseases such as HIV and SARS-CoV-2 and it also includes mTOR cancers as a multifunctional therapeutic target in HIV infection [65–67].
This study is the first to research the effect of fluoxetine, one of the SSRI group antidepressants, on the macrophage cells specifically. Fluoxetine exhibited immunostimulatory properties by promoting the production of IL-6, IL12p40, TNF-a, and GM-CSF cytokines in the J774.2 macrophage cell line. At all concentrations where LPS and fluoxetine were used together, IL-6, IL12p40, TNF-α, and GM-CSF production went down to undetectable levels (Figs. 1, 2, 3, and 4). In addition, using salicylic acid combined with LPS, which has anti-inflammatory properties, its effects on the level of cytokines were compared with the group given fluoxetine. In addition, Al2O3, which is used as an adjuvant in vaccine formulations, has been used in combination with LPS to support proinflammatory activity. Although fluoxetine had immunostimulatory activity by itself, in the presence of an inflammatory reaction it was suppressing the inflammation. It should be used with caution in the clinical setting by considering these activities. Besides, PI3K and P38 protein percentage values were measured for the intracellular mechanism of action of fluoxetine. According to these results, we found that the PI3K and P38 pathways were not effective in the immunostimulatory effect, while these pathways were downregulated during fluoxetine’s anti-inflammatory action which overlaps with the previous studies’ findings.
Conclusion
More studies should be conducted with different cell types by focusing on different signaling pathways to fully decipher the effects of the antidepressant drug molecules on the immune system of the patients. This information will be imperative for their effective and safe usage.
Author contribution
The manuscript was written through the contributions of all authors. All authors have approved for the final version of the manuscript. All authors contributed equally.
Data availability
Not applicable.
Declarations
Ethics approval and consent to participate.
Not applicable.
Conflict of interest
The authors declare no competing interests.
Publisher's note
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| 36512200 | PMC9745289 | NO-CC CODE | 2022-12-15 00:02:24 | no | Immunol Res. 2022 Dec 13;:1-9 | utf-8 | Immunol Res | 2,022 | 10.1007/s12026-022-09350-4 | oa_other |
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Ital Econ J
Italian Economic Journal
2199-322X
2199-3238
Springer International Publishing Cham
212
10.1007/s40797-022-00212-4
Research paper - Europe and Italy
Having Trouble Making Ends Meet? Financial Literacy Makes the Difference
http://orcid.org/0000-0001-7132-2769
Sconti Alessia [email protected]
grid.253615.6 0000 0004 1936 9510 The George Washington University School of Business, Global Financial Literacy Excellence Center, Duques Hall, 2201 G St, NW, DC 20052 USA
13 12 2022
132
6 4 2021
29 9 2022
© The Author(s) under exclusive licence to Società Italiana di Economia (Italian Economic Association) 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Financial stability is an important contributor to economic and psychological well-being. However, even before the economic upheaval of the Covid-19 pandemic, many households around the world had trouble making ends meet. The aim of this paper is twofold. First of all, we investigate financial literacy’s effect on householders’ ability to easily make ends meet. Then we focus on any financial literacy differential effects on female householders. We use subsamples from the Bank of Italy Survey on Household Income and Wealth (SHIW) and find that the data support the positive impact of higher financial literacy. Householders who correctly answer the Big Three questions-the standard assessment of financial literacy-are 8 percentage points more likely to make ends meet easily. When we apply a more comprehensive financial literacy indicator (21-score) based on the Organisation for Economic Co-operation and Development (OECD) methodology, the effect is even stronger (13.5 percentage points). Household financial stability is lower in southern regions of Italy and among women householders, but no findings support differential effects on women. Our estimates are robust to different models such as OLS, Probit and Ordered Probit and financial literacy specifications. Overall, our results underscore the economic importance of financial literacy in ensuring social and economic well-being.
Keywords
Financial literacy
Personal finance
Household finance
Wealth management
Financial stability
JEL Classification
G53
G51
D14
==== Body
pmcIntroduction
Even before the outbreak of the Covid-19 crisis, financial mismanagement practices and the lingering effects of past exogenous financial shocks threatened the financial stability of households throughout the world (Hasler et al. 2020b; Clark et al. 2021; Klapper and Lusardi 2019). Monthly income serves as a limit on a household’s pursuit of its needs and its aspirations. Therefore, to achieve higher economic well-being, households must engage in robust wealth management. There is an urgent need to understand financial literacy’s impact on the ability to make ends meet and enjoy economic well-being. To the best of our knowledge, this is the first paper to investigate the relationship between financial literacy and financial stability-as measured by the ease in making ends meet-in Italy.
Three main considerations factor into a householders’ ability to make ends meet. First, while monthly income serves as a limit in satisfying the needs and aspirations among the 8 million households in Italy, a lack of basic financial knowledge (D’Alessio et al. 2020) and the failure among a large segment of those households to address unexpected expenses (Lusardi 2019) are also contributors. Second, the ongoing technological evolution of payment instruments and the trend toward a cashless society both accelerate the risk of households losing control of their money and depleting their budget resources prematurely (Hasler et al. 2020a). Finally, empirical evidence shows that the best financial practices are learned in the family and translate into better economic behavior in adulthood (Bucciol et al. 2022; Fornero et al. 2019). This means household wealth management offers the first financial socialization opportunity for children. Householders who have not been exposed to this modeling as children carry a disadvantage.
These considerations carry implications for policy focused on household stability. They also are factors in economic disparity, including in developed countries, since greater financial constraints lead to lower participation in economic and social life. The lowest participation is found among vulnerable groups, notably the young, women, and senior citizens. Only 47% of women and 55% of men around the world have access to an account at a formal financial institution and they have lower access to formal credit (Worldbank 2013).
Mainstream literature finds that better financial practices are more likely among financially literate people. While there is strong debate in the literature on how to measure financial literacy (Kaiser and Menkhoff 2017; D’Alessio et al. 2020; Lusardi and Mitchell 2014) the results converge: The higher the knowledge, the better the financial performance. To investigate the relationship between financial literacy and household financial stability in Italy, we use the Bank of Italy Survey on Household Income and Wealth (SHIW). Of particular interest are the 2006, 2008, 2010, and 2016 surveys in which financial literacy questions are included.1 Due to the structure of the SHIW data, this paper adopts two different measures of financial literacy. First of all, considering only the 2016 survey, we conduct the analysis using the Big Three questions, which assess the basic knowledge needed to be considered financially literate, following the approach of Lusardi and Mitchell (2011). The questions cover three simple, but essential, topics: inflation, compound interest and risk diversification (Lusardi and Mitchell 2011)2. While the Big Three questions assess whether individuals are financially literate or not, they provide limited evidence on the depth of that knowledge. Furthermore, the use of the Big Three questions limits our analysis to only one year’s survey, exposing our cross-section inference to the omitted variable bias. For this reason, we apply a second measure of financial literacy that looks at a more detailed knowledge indicator, standardized across different waves, following D’Alessio et al. (2020). In fact, D’Alessio et al. (2020), using the Bank of Italy Survey “Indagine sull’Alfabetizzazione e le Competenze Finanziarie degli Italiani” (IACOFI) data from 2017 and 2020, suggests that more extensive way to measure financial literacy. An analysis of behavior and attitudes other than knowledge results in a 21-score indicator following OECD (2016, 2017, 2020) methodology.3
Hasler et al. (2022) analyzing data from the Teachers Insurance and Annuity Association of America (TIAA)—GFLEC 2021 Personal Finance (P-Fin Index),4 find 31% of Americans struggling to manage their finances and feeling constrained by their debt both before and during the pandemic. In looking at long-term effects, the TIAA 2021 P-Fin Index finds that debt-constrained people plan and save less for retirement. However, financial literacy makes the difference, as reflected in lower levels of debt constraint and higher probability to plan and save for retirement. The ability to make ends meet not only carries an economic impact, but it also affects mental health. De Bruijn and Antonides (2020) find that income and making ends meet are the main determinants of financial worry and rumination (FWR). Their study suggests that improving people’s ability to make ends meet may contribute to lower FWR-scores.
Even before the pandemic, previous crises underscored the critical importance of financial literacy as a contributor to the soundness and stability of the system as a whole, both at the micro and macro levels.5 Lo Prete (2018, 2013) shows how financial knowledge reduces inequality across countries and over time. Lusardi et al. (2017) show that 30–40% of US wealth-inequality can potentially be attributed to differences in financial knowledge which, in turn, amplify disparities in wealth accumulation. In Italy, data at the regional level highlight another discriminant in northern/southern households’ economic development. From a policy perspective, these results suggest that financial education programs need to target Italian inhabitants in regions with lower household financial stability. Among the most vulnerable subgroups, which are more likely to experience financial-related anxiety and fragility, tailored financial knowledge holds promise for improving household financial stability.
The remainder of the paper is organized as follows. Section 2 reviews the related literature. Sections 3 and 4 describe our subsample of SHIW data and the method used to address our hypotheses, respectively. Section 5 summarizes the main findings, and Sect. 6 provides our conclusions.
Literature Overview
Although the best way to measure financial literacy levels is strongly debated in the literature (Kaiser and Menkhoff 2017; D’Alessio et al. 2020; Lusardi and Mitchell 2014), mainstream literature finds huge predictive power in the Big Three questions of Lusardi and Mitchell (2014). This basic knowledge addressed by the questions is the turning point between good financial practices and bad ones. A higher level of financial knowledge is associated with better wealth management, lower fee payments, higher stock market participation, higher level of saving, lower debt and more retirement planning (van Rooij et al. 2011, 2012; Lusardi and Mitchell 2014; Bucciol et al. 2022; Kaiser et al. 2021; Fornero et al. 2019; Almenberg et al. 2020). Individuals who do not understand the basic, but essential, economic concepts of inflation, compound interest and investment diversification fail to deal appropriately with personal wealth management. This failing illustrates financial literacy’s role as a crucial skill in the 21st century (Lusardi 2015; OECD 2014). In Italy, the low level of financial literacy is well documented (D’Alessio et al. 2020; Klapper and Lusardi 2019). Using the OECD methodology, D’Alessio et al. (2020) cluster the Italian population aged between 18 and 79 into four financial types: the excluded (24%), the incompetent (30%), the competent (26%) and the expert (17%). In line with previous evidence, they find that 26.3 million Italian people-mostly residents of southern regions-lack basic financial knowledge. They spend more than they receive and have low income and low educational levels. Among them, the young, women and older people face even greater challenges, such as longevity risks and related wealth loss. A lower ability to make ends meet involves a higher probability of being or becoming financially fragile in the future.
These findings carry especially troubling implications for women. For example, 7.8 million Italians declare that they can manage the daily household budget. This alarming overconfidence may negatively affect households’ financial stability. Moreover, with female financial literacy levels lower than those of male householders, women may have less access to banking or lower participation in the stock market (Bucher-Koenen et al. 2021; Di Salvatore et al. 2018; van Rooij et al. 2012). Past literature turned a light on men’s disproportionate role as financial decision-makers within households (Hsu 2016; Fonseca et al. 2012), which may deepen the gender gap. Recent literature found gender differences also existed among singles and teenagers (Lusardi and Mitchell 2014; Bucher-Koenen et al. 2021; Driva et al. 2016). Italy is the only OECD country in which the financial literacy gap appears to be strongly statistically significant still at an early stage of life (OECD 2006, 2014).
Furthermore, women demonstrate poorer debt and pension literacy than men, as well as a lower level of financial inclusion and a higher degree of financial fragility (Bucher-Koenen et al. 2021; Gathergood 2012).
Financial overconfidence in tandem with an inadequate level of knowledge may fuel excessive risk-taking, with negative financial outcomes (Bruhn et al. 2016; Brugiavini et al. 2018). However, some recent research suggests that one-third of the financial gender gap is explained by women’s lack of confidence (Bucher-Koenen et al. 2021). Other studies reveal that cultural male stereotypes could potentially contribute to lower financial literacy among females (Bottazzi and Lusardi 2021; Giuliano 2017) and confirm women’s already-lower self-assessments of their own financial literacy (Di Salvatore et al. 2018; Sconti 2022; D’Alessio et al. 2020). Despite the overall cross-cutting impact of the Covid-19 pandemic, the worst consequences have fallen on already vulnerable groups (young, women and older people) (Lusardi and Mitchell 2014). Yet even before the pandemic, females were the most financially fragile group of respondents in research on financial literacy, lacking confidence in their ability to meet an unexpected expense of 2000 dollars (Bolognesi et al. 2020). Moreover, the new easy payment instruments in the era of a cashless economy increase the probability of overdrawn accounts (Hasler et al. 2020a).
The link between personal finances and anxiety shows that household financial fragility can have a cascading effect on mental health. A recent report from the Teachers Insurance and Annuity Association of America (TIAA Institute) based on the TIAA-GFLEC Personal Finance Index (P-Fin Index) shows that the majority (68%) of the Millennials in the United States (68%) admit to feeling anxious when thinking about their personal finances (Bolognesi et al. 2020). Noteworthy, 37% are financially fragile, meaning that they are not confident about their ability to overcome relatively small unexpected expenses within 30 days. Financial fragility and household financial instability are two sides of the same coin, both boosting negative psychological distress.
Empirical evidence also shows that informal financial education at home, received during childhood, translates into better economic behavior in adulthood (Bucciol et al. 2022; Fornero et al. 2019). The effectiveness of the first socialization opportunity is reduced in households where financial literacy is low.
Finally, the most recent work from Bucci et al. (2022) identifies two distinct ways through which finance can benefit economic growth: a “financial return channel” and a “human capital channel.” This new work extends Uzawa (1965) and Lucas (1988)’s pathbreaking two-sector human capital-based endogenous growth model through the addition of a financial sector that transfers savings intertemporally. In looking at the inclusion of investment in financial literacy, they found that financial literacy has a positive impact on long-term economic growth if the financial sector return positively relates to the investment, or with its aggregate level. Bucci et al. (2022) conclude that investment in financial literacy is the main driver of economic growth because it increases the return generated by financial sector.
Interest in targeting and addressing both formal and informal financial education programs is growing, especially in light of evidence that the programs’ effects on economic behavior will be measurable and economically important in the future (Kaiser et al. 2021; Kaiser and Menkhoff 2017, 2020; Brugiavini et al. 2018; Frisancho 2020; Bruhn et al. 2016; Sconti 2022; Bucciol et al. 2021; Lusardi et al. 2020).
Data and Summary Statistics
We use data from the Bank of Italy’s Survey on Household Income and Wealth (SHIW).6
Unfortunately, financial literacy questions in the survey differ from year to year and, to date, only the SHIW 2016 survey measures financial literacy in accordance with the mainstream literature, through the Big Three questions (see Footnote 2). To obtain the most rigorous index of financial literacy, we first restrict our study to the subsample of householders interviewed in the 2016 wave. We then extend the analysis to several other surveys with a standardized indicator.Fig. 1 Average Householders’ financial literacy across Italian regions
Based on the Big Three questions, Fig. 1 shows the householders’ average financial literacy across Italian regions. The lower the householders’ financial literacy, the lighter the blue color. Looking at the map, it is clear that financial illiteracy is more widespread among lower economically developed regions, such as in the South of Italy. An analog picture of the ability of Italians to make ends meet is reported in the Appendix. Comparing the map in Fig. 1, with that one in Fig. 3, may lead to the conclusion that financially literate people reach higher financial well-being, making ends meet easily. Northern regions with a higher percentage of people who have a basic level of financial literacy are also able to make ends meet easily. In addition to the financial strength of a household, stronger monthly budgeting skills may also help reduce anxiety connected to wealth management. Based on the above evidence, this paper aims to shed light on the pressing need to both avert families’ financial distress and increase their households’ financial stability. In a time of crisis, the prevention of family financial stress could serve as a safeguard within the whole economic cycle, a scenario that should be of interest to policymakers. Growth in financial literacy would be a logical linchpin of this win-win strategy. To support this idea, we show the strong correlation, both graphically and empirically, when future interventions target those that need it the most.
Figure 2 shows how financially literacy reshapes the distribution of the ability to make ends meet. On the left side, a bar graph shows the share of each option chosen by financially illiterate people under the “making-ends-meet ability” question. Comparing the left graph with the right one, which represents the distribution among people who are financially literate, in Fig. 2, it is evident that a higher percentage of people who declare that they make ends meet easily come from among the financially literate. The last two bars in each graph, identifying a greater ability to make ends meet, show a steeper increase among the financially literate sample as compared to the financially illiterate one (from 23.5 to 35.9% and from 7.4 to 17.5%). Among the financially literate, there is also a marked decrease in the first three bars in each graph, which represent those who face major difficulties in making ends meet (from 17.9 to 8.2%, 18.1 to 10%, 33.4 to 28.4%).Fig. 2 Making ends meet ability by financial literacy (categorical variable)
In our sample, financially literate householders account for only 34%. Their ability to make ends meet (more or less) easily is equal to 49%. Figure 2 reveals that among financially literate householders, no gender gap emerges. This carries important implications for future research and policy. Whoever is more financially literate-regardless of gender-may contribute in a positive way to the management of a household’s budget.
Figure 5 confirms this result. Using a 21-score indicator, 54.9% of the householders with the lowest financially literacy are female. However, with a basic level of financial literacy both female and male householders are balanced. Among the highest financially literate householders, a slight gender gap emerges but with females leading. This contrasts with previous literature.
Figure 6 confirms past findings that show a positive relationship between higher education and financial literacy. In fact, 48.9% of householders with higher education are considered financially literate; 30.3% of them are financially illiterate. Using the standardized indicator, Fig. 7 shows that those who have at least a high school diploma are less likely to show a low level of financial literacy than those who do not have a diploma (17.4% compared to 82.6%).
Financial literacy differs among age groups due to different financial exposure during the life cycle. The most financially educated group is adults aged 35–65 (see Fig. 8). This remains true when also looking at the different levels of financial literacy in Fig. 9. The young and senior citizens are the least financially knowledgeable. In fact, 39.2% of senior citizens show a low level of financial literacy; only 19.3% of those included in this age group show high financial literacy.
Our sample finds financial literacy equally distributed across householders with higher or lower income as reported in Figs. 10 and 11. However, sensitive data, such as income, could be misleading. People in surveys tend to report a lower income than they actually have, so caution is necessary when dealing with statistics on income collected through surveys.
In the breakdown of other demographics, financial literacy is higher among married householders. In more detail, Fig. 12 shows that 48.1% of married householders are not financially literate, compared to 51.9% of unmarried householders. Among householders with low financial literacy, Fig. 13 suggests that 46.9% are married while 53.1% are unmarried. Likewise, these results are the opposite-with married householders leading the larger segment-when considering middle or high levels of financial literacy.
Having in mind the relationship between our variables of interest, now we can go deeper into the description of our subsample. Table 1 reports summary statistics on the variables used in the first analysis. We decided to restrict the sample to the head of household. Our aim was not to focus on the person who earns more but, rather, the person who makes the financial decisions for the family. We ended up with a total sample that carried an average householder age of 64 years and was gender-balanced (46% female). It is important to focus on this vulnerable target of the population, close to retirement age, since the effect of financial knowledge among adults shows its highest impact in preventing financial distress. Senior citizens are facing the most technological challenge in this field and they need ongoing learning to cope with lower pensions and higher expenses potentially due to increasing medical issues or family needs. Moreover, they play a strategic role in Italy’s financial stability. About 42% of the householders in this subsample had at least a diploma or a degree and an average savings of EUR 8777.Table 1 Summary Statistics—2016 Wave
Variables (Wave 2016) (1) (2) (3) (4) (5)
Obs Mean Std. Dev. Min Max
Make_Ends_Meet 1035 3.397 1.101 1 5
Make_Ends_Meet_dummy 1035 0.494 0.500 0 1
FINLIT_2016 1035 0.345 0.475 0 1
Female 1035 0.457 0.498 0 1
Savings_ln 1035 8.777 1.195 0.693 12.899
Adult (35–49) 1035 0.134 0.341 0 1
Over50 1035 0.853 0.354 0 1
Married 1035 0.643 0.479 0 1
Diploma/Degree 1035 0.428 0.495 0 1
Table 1 reports summary statistics of the two dependent variables and of all the controls. ∗∗p<0.001,∗∗p<0.01,∗p<0.05
For the average household in our sample, financial stability-meaning the ability to make ends meet-is not so easily reached. The average value chosen is 3, which corresponds to the ability to respond to at least some difficulties in making ends meet. Using a dichotomous classification, just about 49% of householders in the sample declare that they make ends meet easily/very easily.Table 2 Summary Statistics—2006, 2008, 2010 and 2016 Waves
Variables (Waves 2006, 2008, 2010, 2016) (1) (2) (3) (4) (5)
Obs Mean Std. Dev. Min Max
Make_Ends_Meet 3.350 3.397 1.106 1 5
Make_Ends_Meet_dummy 3,350 0.497 0.500 0 1
FINLIT_sd 3.350 0.551 0.290 0 1
Female 3.350 0.373 0.483 0 1
Savings_ln 3.350 8.780 1.195 0.693 12.899
Adult (35–49) 3.350 0.208 0.406 0 1
Over 50 3.350 0.765 0.423 0 1
Married 3.350 0.705 0.455 0 1
Diploma/Degree 3.350 0.428 0.495 0 1
Table 1 reports summary statistics of the two dependent variables and of all the controls. ∗∗∗p<0.001,∗∗p<0.01,∗p<0.05
Hypotheses
Evidence on financial literacy’s influence on good financial practices and behavior is well documented in the literature. In our sample, some vulnerable groups lacked financial literacy more than others. The worst performance included residents of Italy’s southern regions, females, the young and senior citizens (Lusardi 2019; Di Salvatore et al. 2018; D’Alessio et al. 2020). This leads to our first hypothesis:
Hypothesis 1
Financial literacy increases householders’ probability of making ends meet.
Financial inclusion and financial fragility are the main critical issues in gender equality (Lusardi and Mitchell 2014). Recent evidence show evidence of women’s higher financial fragility (Hasler and Lusardi 2019; Lusardi and Mitchell 2011; Kaiser et al. 2021; Klapper and Lusardi 2019). However, there is no literature investigating the gender gap among female and male householders. This leads to our second hypothesis:
Hypothesis 2
Financial literacy improves female householders’ probability of making ends meet.
Empirical Strategy
To investigate our hypotheses, we analyze data from the SHIW’s 2016 wave, the only one that includes the Big Three question, thus offering comparison with worldwide surveys. To make more extensive conclusions, we also analyze a wider sample composed of the 2006, 2008, 2010 and 2016 waves.
To test our first hypothesis, we consider two different specifications of the same dependent variable: a dummy Make_ends_meet_dummy equal to 1 if the respondent declares being able to make ends meet quite easily, easily, or very easily, 0 otherwise. We then consider the full categorical variable Make_ends_meet, which takes the following values: 1 to 3 if respondents admit having great/some/difficulties in making ends meet, and values from 4 to 6 if respondents find it quite easy, easy, or very easy making ends meet. Since very few observations fall in the 6th option, we aggregate it with the 5th one.4.1 yir=α+β1FINLITir+β2Femaleir+β3Xir+δr+ϵir
where yir indicates a household’s financial stability in the sense of the ability to make ends meet for individual i, in the region r. Depending on the model specification (Ordered Probit) it takes values from 1 (great difficulties in making ends meet) to 5 (making ends meet easily/very easily) or (Probit) 1 if it is easy/very easy reaching financial stability, 0 otherwise; for each head of household i, in the region r.
FINLIT indicates the level of financial literacy. In our analysis, following mainstream literature, it takes value 1 if respondents correctly answer all three questions, 0 otherwise (FINLIT_2016). β1 indicates the effect of basic knowledge in economics and finance in budgeting ability. However, we then run the same analysis including a more extensive indicator following (D’Alessio et al. 2020)’s approach. This second approach involves a standardized financial indicator (FINLIT_sd), which allows us to discriminate among different levels of financial knowledge and to compare householders’ ability to make ends meet across different SHIW waves.
Female is a dummy variable which takes the value 1 if the householder is female, and 0 otherwise.
X is the vector of individual controls (age, savings, degree, marital status). ϵ is the error term. A robustness check includes Ordered Probit estimations to find out the financial literacy switching point in affecting budgeting behavior.
The differential effect of financial literacy on women’s financial capabilities is even more important in Italy, where a gender gap emerges at an early stage of life. Testing our second hypothesis allows us to determine how much financial ability to make ends meet is explained by financial literacy in the case of female householders. To test our second hypothesis, in an extension of the model, we add an interaction term between gender and financial knowledge to exploit gender differential effects in making ends meet.4.2 yir=α+β1FINLITir+β2Femaleir+β3FINLIT∗Femaleir+β5Xir+δr+ϵir
β3 is the coefficient of interest since the interaction dummy between each financial literacy indicator and female gender reveals any differential effect to be financially literate and female on pursuing households’ financial stability.
Results
This section reports our main findings in testing hypotheses 1 and 2. Table 3 reports robust evidence of the positive effect of having basic financial knowledge in making ends meet easily (Hypothesis 1). Columns 1 and 3 report results from OLS estimations using the mainstream financial literacy indicator based on the Big Three questions (FINLIT_2016 in columns 1 and 3). Columns 2 and 4 report marginal effects from Probit estimations based on the same standardized indicator (FINLIT_sd in column 2 and 4).
The marginal effect of being financially literate on average increases the probability to make ends meet easily by 8 percentage points (p.p.). However, taking into account the gender wage gap, a vulnerable group-female respondents-are also less likely (by 10 p.p.) to easily make ends meet. Higher levels of education and being married increase the likelihood that households will achieve financial stability, by 20 p.p. and 13 p.p., respectively.
Repeating the analysis on a wider sample and with a different measure of financial literacy (columns 3 and 4), our results supporting Hypothesis 1 are robust. Among all of the four SHIW data waves in which financial literacy is included, the probability to make ends meet by having some knowledge on financial topics increases by 13 p.p. A gender gap emerges in households’ financial stability. In fact, female householders’ probability to make ends meet is 7 p.p. lower. Higher level of savings positively affects the probability of householders making ends meet (by 5 p.p.), as does being married (11 p.p.). However, the highest impact on financial stability of households comes from education. Having a high school diploma or a degree increases the probability to make ends meet by 21 p.p.Table 3 OLS, Probit—Householders Ability in making ends meet
Variables
(1) (2) (3) (4)
OLS Probit M.E. OLS Probit M.E.
FINLIT 0.224*** 0.079*** 0.314*** 0.135***
(0.067) (0.030) (0.067) (0.030)
Female -0.174*** -0.096*** -0.170*** -0.073***
(0.064) (0.029) (0.060) (0.028)
Savings_ln 0.160*** 0.055*** 0.150*** 0.050***
(0.027) (0.012) (0.028) (0.012)
Adult (35–49) -0.162 -0.083 0.026 -0.063
(0.239) (0.126) (0.155) (0.068)
Over 50 0.112 0.030 0.254 0.041
(0.231) (0.123) (0.160) (0.069)
Married 0.296*** 0.132*** 0.208*** 0.106***
(0.066) (0.029) (0.064) (0.030)
Diploma/Degree 0.478*** 0.203*** 0.486*** 0.212***
(0.066) (0.028) (0.064) (0.027)
Constant 1.426*** 1.391***
(0.375) (0.341)
Region FE Yes Yes Yes Yes
Year FE No No Yes Yes
Observations 1035 1035 3350 3350
R2-Pseudo_R2 0.260 0.167 0.242 0.153
Table 3 reports the results from OLS estimations (columns 1 and 3) and the average marginal effects after Probit estimations (columns 2 and 4) on the ability to make ends meet (Hypothesis 1). We consider two different specifications of the same dependent variable. In the OLS estimations, the dependent variable is a categorical variable Make_ends_meet which takes the following values: 1–3 if respondents admit having great/some/difficulties in making ends meet, values from 4 to 6 if respondents find quite easy, easy or very easy making ends meet. Since very few observations fall in the 6th option, we aggregate it with the 5th one. In the Probit estimations, the dependent variable is a dummy Make_ends_meet_dummy equal to 1 if the respondent declares to be able to make ends meet quite easily/ easily/ very easily 0 otherwise Robust standard errors at the individual level are reported in parentheses. All regressions include Regional Fixed Effects. FINLIT_sd’s regressions include year fixed effects. ∗∗∗p<0.001, ∗∗p<0.01, ∗p<0.05
To investigate Hypothesis 2, we further exploit the analysis, adding an interaction term to evaluate the differential effect of financial literacy for female householders (see Table 4).Table 4 OLS, Probit—Householders’ ability to make ends meet (Female interaction term)
Variables
OLS Probit M.E. OLS Probit M.E.
FINLIT 0.219** 0.057 0.346*** 0.116***
(0.085) (0.040) (0.092) (0.040)
Female -0.179** -0.113*** -0.129 -0.099**
(0.079) (0.035) (0.095) (0.044)
FINLIT_Female 0.013 0.053 -0.075 0.047
(0.127) (0.059) (0.131) (0.061)
Savings_ln 0.160*** 0.056*** 0.150*** 0.050***
(0.027) (0.012) (0.028) (0.012)
Adult (35–49) -0.161 -0.081 0.024 -0.062
(0.239) (0.127) (0.155) (0.068)
Over50 0.113 0.033 0.251 0.043
(0.231) (0.124) (0.160) (0.069)
Married 0.296*** 0.132*** 0.211*** 0.105***
(0.066) (0.029) (0.065) (0.030)
Diploma/Degree 0.478*** 0.203*** 0.486*** 0.212***
(0.066) (0.028) (0.064) (0.027)
Constant 1.428*** 1.372***
(0.376) (0.343)
Region FE Yes Yes Yes Yes
Year FE No No Yes Yes
Observations 1035 1035 3350 3350
R2-Pseudo_R2 0.260 0.167 0.242 0.153
Table 4 reports the results from OLS estimations (columns 1 and 3) and the average marginal effects after Probit estimations (columns 2 and 4) on the ability to make ends meet. We consider two different specifications of the same dependent variable. In the OLS estimations, the dependent variable is a categorical variable Make_ends_meet which takes the following values: 1 to 3 if respondents admit having great/some/difficulties in making ends meet, values from 4 to 6 if respondents find quite easy, easy or very easy making ends meet. Since very few observations fall in the 6th option, we aggregate it with the 5th one. In the Probit estimations, the dependent variable is a dummy Make_ends_meet_dummy equal to 1 if the respondent declares to be able to make ends meet quite easily/ easily/ very easily, 0 otherwise. Both models include an interaction term between gender and financial literacy variables to investigate any differential effect for financially literate female householders (Hypothesis 2). Robust standard errors at the individual level are reported in parentheses. All regressions include regional fixed effects. FINLIT_sd’s regressions include year fixed effects. ∗∗∗p<0.001,∗∗p<0.01,∗p<0.05
Previous results persist. The main coefficient of interest in Table 4 is that one originated from the interaction between gender and the financial literacy indicator. Even though higher financial literacy increases the probability to make ends meet, higher financial literacy is not the main explanation of the gap between female and male householders.
As a robustness check, we run an Ordered Probit estimation, which is useful to highlight financial literacy’s switching point effects on budgeting. Table 5 shows that financial literacy coherently increases the likelihood to easily make ends meet and negatively affects the probability that householders will face great difficulties in making ends meet.
In particular, if financial knowledge increases by one unit percent, householders are 3 p.p. less likely to face great difficulty in making ends meet, and 5 p.p. more likely to make ends meet easily or very easily. In line with mainstream literature on financial literacy and the gender gap, we find female householders face more trouble in making ends meet. Female householders still show higher probability of financial instability (2 p.p.) Financial knowledge is strictly and positively correlated with education. Indeed householders with a diploma or a degree are 6 p.p. less likely to have trouble making ends meet. Overall, higher education registers the highest positive impact on household financial stability (11 p.p.). Although savings are essential for economic well-being, savings show the lowest impact on householders’ ability to make ends meet (reducing by 2 p.p. the great difficulty in monthly budgeting and increasing by 4 p.p. the likelihood of making ends meet very easily). Finally, being married increases the probability of better managing the monthly budget by 7 p.p. while reducing the probability of being in the worst category by 4 p.p. All these results are confirmed by repeating the analysis with a standardized indicator (FINLIT_sd). The magnitude of the financial literacy and education effects increases following D’Alessio et al. (2020) as reported in column 4. The impact is also seen when applying the standardized indicator on a wider sample: If financial knowledge increases by one unit percent, householders are 4 p.p. less likely to face great difficulty in making ends meet and 7 p.p. more likely to make ends meet easily or very easily. The gender gap in households’ financial stability is confirmed. Female householders are 4 p.p. less likely to make ends meet easily.Table 5 Ordered Probit—Householders’ ability to make ends meet
Variables
(1) (2) (3) (4)
O.Probit M.E.(1) O.Probit M.E.(5) O.Probit M.E.(1) O.Probit M.E.(5)
Hardly Easily Hardly Easily
FINLIT −0.029*** 0.053*** -0.041*** 0.073***
(0.009) (0.015) (0.009) (0.016)
Female 0.022*** -0.040*** 0.022*** -0.044***
(0.008) (0.015) (0.008) (0.014)
Savings_ln −0.020*** 0.037*** 0.019*** 0.035***
(0.003) (0.006) (0.008) (0.006)
Adult (35-49) 0.019 −0.024 −0.001 0.002
(0.034) (0.047) (0.025) (0.029)
Over50 −0.020 0.033 −0.034 0.053
(0.032) (0.046) (0.025) (0.031)
Married −0.037*** 0.068*** −0.027*** 0.048***
(0.009) (0.015) (0.008) (0.015)
Diploma/Degree −0.064*** 0.115*** −0.064*** 0.115***
(0.009) (0.015) (0.009) (0.016)
Region FE Yes Yes Yes Yes
Year FE No No Yes Yes
Observations 1035 1035 3350 3350
Pseudo_R2 0.102 0.102 0.093 0.093
Notes: Table 5 reports average marginal effects for outcomes 1 (columns 1 and 3) and 5 (columns 2 and 4) from Order Probit estimations testing Hypothesis 1. The dependent variable is a categorical variable Make_ends_meet which takes the following values: 1 to 3 if respondents admit having great/some/difficulties in making ends meet, values from 4 to 6 if respondents find quite easy, easy or very easy making ends meet. Since very few observations fall in the 6th option, we aggregate it with the 5th one. Robust standard errors at the individual level are reported in parentheses. All regression include regional fixed effects. ∗∗∗p<0.001,∗∗p<0.01,∗p<0.05
Table 6 Ordered Probit - Householders’ ability to make ends meet— Female interaction term
Variables
(1) (2) (3) (4)
O.Probit M.E.(1) O.Probit M.E.(5) O.Probit M.E.(1) O.Probit M.E.(5)
Hardly Easily Hardly Easily
FINLIT -0.029** 0.053*** -0.045*** 0.081***
(0.011) (0.015) (0.012) (0.021)
Female 0.022** -0.041** 0.017 -0.030
(0.010) (0.017) (0.012) (0.021)
FINLIT_Female -0.001 0.001 0.010 -0.018
(0.016) (0.030) (0.017) (0.030)
Savings_ln −0.020*** 0.037*** −0.019*** 0.035***
(0.003) (0.006) (0.004) (0.006)
Adult (35–49) 0.020 -0.024 -0.001 0.001
(0.034) (0.047) (0.025) (0.029)
Over50 -0.020 0.033 -0.034 0.053*
(0.032) (0.047) (0.025) (0.031)
Married -0.037*** 0.068*** -0.027*** 0.048***
(0.009) (0.015) (0.008) (0.015)
Diploma/degree -0.062*** 0.113*** −0.064*** 0.115***
(0.009) (0.016) (0.009) (0.016)
Region FE Yes Yes Yes Yes
Year FE No No Yes Yes
Observations 1035 1035 3350 3350
Pseudo_R2 0.102 0.102 0.093 0.093
Table 6 reports average marginal effects for outcome 1 and outcome 5 from Order Probit estimations. The dependent variable is a categorical variable Make_ends_meet which takes the following values: 1–3 if respondents admit having great/some/difficulties in making ends meet, values from 4 to 6 if respondents find quite easy, easy or very easy making ends meet. Since very few observations fall in the 6th option, we aggregate it with the 5th one. Both models include an interaction term between gender and financial literacy variables to investigate any differential effect for financially literate female householders (Hypothesis 2). Robust standard errors at the individual level are reported in parentheses. All regression include regional fixed effects. FINLIT_sd’s regressions include year fixed effects. ∗∗∗p<0.001, ∗∗p<0.01, * p<0.05
Moreover, we add an interaction term between gender and the financial literacy indicator. Table 6 shows strong financial literacy effects on the ability to make ends meet are robust to different estimation methods. Our results also shed light on a robust lack of evidence of any differential effect for female householders’ ability to make ends meet due to financial literacy. There are several possible explanations for the lack of evidence to support our Hypothesis 2. One partial explanation could be differing access to the labor market by male and female householders.
Finally, we extended the analysis exploring Hypotheses 1 and 2 across three different areas of Italy: the North, the Center and the South of Italy. The main results show that financial literacy is equally effective in the ability to make ends meet in the North among female and male householders (9 p.p. and 16 p.p., respectively).Table 7 OLS, Probit—Householders’ ability to make ends meet - North of Italy
Variables
OLS Probit M.E. OLS Probit M.E.
FINLIT 0.177** 0.081* 0.265*** 0.148***
(0.087) (0.043) (0.098) (0.046)
Female -0.119 -0.071* -0.151* -0.065
(0.086) (0.041) (0.083) (0.040)
Savings_ln 0.211*** 0.078*** 0.198*** 0.070***
(0.034) (0.017) (0.033) (0.017)
Adult (35–49) -0.340 -0.019 -0.149 -0.033
(0.209) (0.142) (0.157) (0.085)
Over50 -0.025 0.104 0.165 0.096
(0.191) (0.137) (0.163) (0.088)
Married 0.333*** 0.158*** 0.196** 0.103**
(0.089) (0.041) (0.085) (0.042)
Diploma/degree 0.519*** 0.193*** 0.536*** 0.210***
(0.086) (0.040) (0.086) (0.039)
Constant 1.303*** 1.309***
(0.341) (0.341)
Region FE No No No No
Year FE No No Yes Yes
Observations 534 534 1737 1.737
R2-Pseudo_R2 0.211 0.127 0.190 0.111
Table 7 reports the results from OLS estimations (columns 1 and 3) and the average marginal effects after Probit estimations (columns 2 and 4) on the ability to make ends meet in the North of Italy. We consider two different specifications of the same dependent variable. In the OLS estimations, the dependent variable is a categorical variable Make_ends_meet which takes the following values: 1–3 if respondents admit having great/some/difficulties in making ends meet, values from 4 to 6 if respondents find quite easy, easy or very easy making ends meet. Since very few observations fall in the 6th option, we aggregate it with the 5th one. In the Probit estimations, the dependent variable is a dummy Make_ends_meet_dummy equal to 1 if the respondent declares to be able to make ends meet quite easily / easily/ very easily, 0 otherwise. Robust standard errors at the individual level are reported in parentheses. FINLIT_sd’s regressions include year fixed effects. ∗∗∗p<0.001, ∗∗p<0.01, ∗p<0.05
Tables 7, 8 and 9 show that the impact of financial literacy on the ability to make ends meet is higher in the Center of Italy.Table 8 OLS, Probit—Householders’ ability to make ends meet - Center of Italy
Variables
(1) (2) (3) (4)
OLS Probit M.E. OLS Probit M.E.
FINLIT 0.410*** 0.177*** 0.498*** 0.204***
(0.120) (0.055) (0.130) (0.059)
Female -0.109 -0.063 -0.082 -0.043
(0.118) (0.055) (0.114) (0.054)
Savings_ln 0.176*** 0.055** 0.148*** 0.044*
(0.046) (0.023) (0.052) (0.024)
Adult (35–49) 0.004 -0.027 -0.488** -0.279*
(0.259) (0.199) (0.239) (0.167)
Over50 0.403* 0.217 -0.157 -0.084
(0.232) (0.193) (0.233) (0.164)
Married 0.262** 0.114** 0.226* 0.107*
(0.118) (0.055) (0.120) (0.056)
Diploma/Degree 0.417*** 0.218*** 0.421*** 0.228***
(0.127) (0.054) (0.115) (0.052)
Constant 1.163** 1.905***
(0.495) (0.531)
Region FE No No No No
Year FE No No Yes Yes
Observations 284 284 873 873
R2-Pseudo_R2 0.200 0.140 0.153 0.152
Table 8 reports the results from OLS estimations (columns 1 and 3) and the average marginal effects after Probit estimations (columns 2 and 4) on the ability to make ends meet in the Center of Italy. We consider two different specifications of the same dependent variable. In the OLS estimations, the dependent variable is a categorical variable Make_ends_meet which takes the following values: 1 to 3 if respondents admit having great/some/difficulties in making ends meet, values from 4 to 6 if respondents find it quite easy, easy or very easy making ends meet. Since very few observations fall in the 6th option, we aggregate it with the 5th one. In the Probit estimations, the dependent variable is a dummy Make_ends_meet_dummy equal to 1 if the respondent declares to be able to make ends meet quite easily/ easily/ very easily, 0 otherwise. Robust standard errors at the individual level are reported in parentheses. FINLIT_sd’s regressions include year fixed effects. ∗∗∗p<0.001, ∗∗p<0.01, ∗p<0.05
In the South of Italy, only the standardized indicator “FINLIT_sd” shows a positive effect on the ability to make ends meet.Table 9 OLS, Probit—Householders’ ability to make ends meet—South of Italy
Variables
(1) (2) (3) (4)
OLS Probit M.E. OLS Probit M.E.
FINLIT 0.171 0.021 0.309** 0.092*
(0.158) (0.059) (0.144) (0.055)
Female -0.157 -0.105* -0.170 -0.097*
(0.140) (0.055) (0.127) (0.054)
Savings_ln 0.136** 0.056** 0.151** 0.063***
(0.061) (0.023) (0.061) (0.023)
Adult (35–49) 0.235 -0.273 0.586** 0.020
(1.121) (0.342) (0.280) (0.084)
Over50 0.541 -0.189 0.829*** 0.112
(1.113) (0.340) (0.292) (0.091)
Married 0.175 0.102 0.026 0.065
(0.149) (0.062) (0.144) (0.063)
Diploma/Degree 0.553*** 0.196*** 0.546*** 0.193***
(0.142) (0.049) (0.141) (0.049)
Constant 0.945 0.519
(1.199) (0.588)
Region FE No No No No
Year FE No No Yes Yes
Observations 276 276 905 905
R2-Pseudo_R2 0.125 0.107 0.135 0.108
Table 9 reports the results from OLS estimations (columns 1 and 3) and the average marginal effects after Probit estimations (columns 2 and 4) on the ability to make ends meet in the South of Italy. We consider two different specifications of the same dependent variable. In the OLS estimations, the dependent variable is a categorical variable Make_ends_meet which takes the following values: 1 to 3 if respondents admit having great/some/difficulties in making ends meet, values from 4 to 6 if respondents find quite easy, easy or very easy making ends meet. Since very few observations fall in the 6th option, we aggregate it with the 5th one. In the Probit estimations, the dependent variable is a dummy Make_ends_meet_dummy equal to 1 if the respondent declares to be able to make ends meet quite easily/ easily/ very easily, 0 otherwise. Robust standard errors at the individual level are reported in parentheses. FINLIT_sd’s regressions include year fixed effects. ∗∗∗p<0.001, ∗∗p<0.01, ∗p<0.05
We extended the analysis to the interaction term between financial literacy and gender. The previous patterns in Table 4 and in Table 6 are confirmed (results are available upon request). No differential effect of financial literacy emerged on the ability to make ends meet for female householders. We can conclude that we have a robust lack of evidence in supporting Hypothesis 2.
Finally, we investigate the ability of male and female householders to make ends meet, in the North, in the Center and in the South of Italy, respectively, in Tables 10, 11 and in Table 12.
Table 10 reveals a different pattern for female householders when compared to men. In fact, among adults, women aged 35–49 show a lower probability of making ends meet. This is true after controlling for other observable characteristics, such as savings, education and financial literacy levels. However, the marginal effect of being financially literate is the same for both female and male householders’ ability to make ends meet in the North of Italy.Table 10 OLS, Probit—Male and Female Householders’ ability to make ends meet - North of Italy
Variables
(1) (2) (3) (4) (5) (6) (7) (8)
OLS Probit M.E. OLS Probit M.E. OLS Probit M.E. OLS Probit M.E.
FINLIT 0.238*** 0.097** 0.266*** 0.157*** 0.184** 0.088** 0.327*** 0.157***
(0.082) (0.042) (0.096) (0.045) (0.086) (0.042) (0.100) (0.046)
Savings_ln 0.200*** 0.073*** 0.211*** 0.075*** 0.204*** 0.067*** 0.185*** 0.062***
(0.036) (0.018) (0.032) (0.016) (0.036) (0.017) (0.034) (0.016)
Adult (35–49) -0.454*** -0.214*** -0.398*** -0.213*** 0.047 0.009 -0.030 0.022
(0.156) (0.077) (0.110) (0.054) (0.162) (0.079) (0.109) (0.057)
Over50 -0.127 -0.071 -0.009 -0.017 0.238* 0.067 0.187* 0.080
(0.145) (0.069) (0.110) (0.053) (0.137) (0.070) (0.106) (0.056)
Married 0.412*** 0.202*** 0.317*** 0.176*** 0.073 0.014 -0.043 -0.060
(0.095) (0.041) (0.085) (0.038) (0.108) (0.053) (0.093) (0.047)
Diploma/degree 0.535*** 0.222*** 0.586*** 0.239*** 0.483*** 0.208*** 0.512*** 0.223***
(0.086) (0.040) (0.078) (0.035) (0.087) (0.041) (0.080) (0.036)
Constant 1.376*** 1.196*** 1.324*** 1.560***
(0.353) (0.322) (0.334) (0.319)
Region FE No No No No No No No No
Year FE No No Yes Yes No No Yes Yes
Observations 528 528 1671 1671 512 512 1710 1710
R2-Pseudo_R2 0.207 0.131 0.193 0.124 0.163 0.086 0.154 0.089
Table 10 reports the results from OLS estimations (columns 1, 3, 5 and 7) and the average marginal effects after Probit estimations (columns 2, 4, 6 and 8 ) on the ability to make ends meet in the South of Italy for both male and female householders in the North of Italy. We consider two different specifications of the same dependent variable. In the OLS estimations, the dependent variable is a categorical variable Make_ends_meet which takes the following values: 1 to 3 if respondents admit having great/some/difficulties in making ends meet, values from 4 to 6 if respondents find quite easy, easy or very easy making ends meet. Since very few observations fall in the 6th option, we aggregate it with the 5th one. In the Probit estimations, the dependent variable is a dummy Make_ends_meet_dummy equal to 1 if the respondent declares to be able to make ends meet quite easily/ easily/ very easily, 0 otherwise. Robust standard errors at the individual level are reported in parentheses. FINLIT_sd’s regressions include year fixed effects. ∗∗∗p<0.001, ∗∗p<0.01, ∗p<0.05
Table 11 shows that education and financial literacy play key roles in improving the probability to make ends meet in the Center of Italy. Being married, however, only increases the ability to make ends meet for women.Table 11 OLS, Probit—Male and Female Householders’ ability to make ends meet—Center of Italy
Variables
(1) (2) (3) (4) (5) (6) (7) (8)
OLS Probit M.E. OLS Probit M.E. OLS Probit M.E. OLS Probit M.E.
FINLIT 0.376*** 0.160*** 0.494*** 0.191*** 0.524*** 0.214*** 0.564*** 0.216***
(0.113) (0.053) (0.122) (0.060) (0.114) (0.052) (0.134) (0.059)
Savings_ln 0.166*** 0.061*** 0.147*** 0.058*** 0.179*** 0.047* 0.128*** 0.032
(0.044) (0.022) (0.043) (0.021) (0.050) (0.024) (0.048) (0.022)
Adult (35–549) -0.119 -0.044 -0.141 -0.157** 0.184 0.039 -0.187 -0.090
(0.214) (0.101) (0.154) (0.076) (0.220) (0.103) (0.157) (0.079)
Over50 0.290* 0.187** 0.178 0.034 0.478*** 0.219*** 0.164 0.109
(0.173) (0.088) (0.156) (0.075) (0.181) (0.083) (0.157) (0.075)
Married 0.329*** 0.143** 0.221** 0.120** 0.039 -0.003 0.123 0.031
(0.117) (0.056) (0.105) (0.054) (0.143) (0.068) (0.130) (0.061)
Diploma/Degree 0.360*** 0.185*** 0.393*** 0.197*** 0.363*** 0.205*** 0.460*** 0.242***
(0.125) (0.056) (0.114) (0.050) (0.113) (0.054) (0.096) (0.046)
Constant 1.308*** 1.452*** 1.201** 1.835***
(0.413) (0.428) (0.492) (0.488)
Region FE No No No No No No No No
Year FE No No Yes Yes No No Yes Yes
Observations 310 310 916 916 286 286 920 920
R2-Pseudo_R2 0.173 0.114 0.126 0.085 0.178 0.109 0.126 0.084
Table 11 reports the results from OLS estimations (columns 1, 3, 5 and 7) and the average marginal effects after Probit estimations (columns 2, 4, 6 and 8 ) on the ability to make ends meet in the South of Italy for both male and female householders in the Center of Italy. We consider two different specifications of the same dependent variable. In the OLS estimations, the dependent variable is a categorical variable Make_ends_meet which takes the following values: 1 to 3 if respondents admit having great/some/difficulties in making ends meet, values from 4 to 6 if respondents find quite easy, easy or very easy making ends meet. Since very few observations fall in the 6th option, we aggregate it with the 5th one. In the Probit estimations, the dependent variable is a dummy Make_ends_meet_dummy equal to 1 if the respondent declares to be able to make ends meet quite easily/ easily/ very easily, 0 otherwise. Robust standard errors at the individual level are reported in parentheses. FINLIT_sd’s regressions include year fixed effects. ∗∗∗p<0.001, ∗∗p<0.01, ∗p<0.05
Table 12 shows that in the South of Italy, not only savings but education plays a key role in financial stability. Only a higher level of financial knowledge makes a more pronounced positive difference on the ability to make ends meet, and only among male householders (11 p.p.).
The main findings show that financial literacy equally impacts the ability to make ends meet in the North of Italy among female and male householders (9 p.p. and 16 p.p.). In the Center, both male and female householders who show a basic or higher knowledge of financial concepts are more likely to make ends meet (16 p.p. and 19 p.p., respectively, for the women, and 21 p.p. and 22 p.p. for the men). This area of Italy shows financial literacy’s greatest potential impact on a household’s ability to make ends meet. In the South of Italy, only deep financial knowledge makes a difference (11 p.p.). in whether male householders are able to make ends meet.Table 12 OLS, Probit—Male and Female Householders ability in making ends meet—South of Italy
Variables
(1) (2) (3) (4) (5) (6) (7) (8)
OLS Probit M.E. OLS Probit M.E. OLS Probit M.E. OLS Probit M.E.
FINLIT 0.152 0.012 0.273** 0.074 0.301** 0.060 0.440*** 0.109**
(0.141) (0.054) (0.127) (0.053) (0.146) (0.054) (0.136) (0.053)
Savings_ln 0.183*** 0.066*** 0.175*** 0.067*** 0.181*** 0.063*** 0.156*** 0.055***
(0.061) (0.022) (0.054) (0.020) (0.054) (0.021) (0.050) (0.020)
Adult (35–49) -0.077 -0.102 -0.018 -0.068 0.240 0.082 0.211 0.002
(0.208) (0.084) (0.158) (0.062) (0.249) (0.087) (0.174) (0.065)
Over50 0.322 0.046 0.365** 0.085 0.496** 0.141* 0.494*** 0.102
(0.209) (0.088) (0.160) (0.065) (0.228) (0.079) (0.168) (0.067)
Married 0.196 0.126** 0.064 0.094* 0.085 0.053 -0.098 0.050
(0.144) (0.061) (0.137) (0.055) (0.182) (0.071) (0.152) (0.065)
Diploma/Degree 0.647*** 0.228*** 0.643*** 0.220*** 0.413*** 0.188*** 0.452*** 0.184***
(0.128) (0.048) (0.119) (0.044) (0.130) (0.049) (0.118) (0.046)
Constant 0.672 0.648 0.650 0.872**
(0.518) (0.490) (0.487) (0.438)
Region FE No No No No No No No No
Year FE No No Yes Yes No No Yes Yes
Observations 316 316 1006 1006 311 311 1,018 1018
R2-Pseudo_R2 0.148 0.107 0.134 0.096 0.132 0.091 0.120 0.081
Table 12 reports the results from OLS estimations (columns 1, 3, 5 and 7) and the average marginal effects after Probit estimations (columns 2, 4, 6 and 8 ) on the ability to make ends meet in the South of Italy for both male and female householders in the South of Italy. We consider two different specifications of the same dependent variable. In the OLS estimations, the dependent variable is a categorical variable Make_ends_meet which takes the following values: 1 to 3 if respondents admit having great/some/difficulties in making ends meet, values from 4 to 6 if respondents find quite easy, easy or very easy making ends meet. Since very few observations fall in the 6th option, we aggregate it with the 5th one. In the Probit estimations, the dependent variable is a dummy Make_ends_meet_dummy equal to 1 if the respondent declares to be able to make ends meet quite easily/ easily/ very easily, 0 otherwise. Robust standard errors at the individual level are reported in parentheses. All regressions include year fixed effects. ∗∗∗p<0.001, ∗∗p<0.01, ∗p<0.05
To sum up, we find that financial stability matters in overcoming financial mismanagement practices. We find that making ends meet easily positively correlates with higher financial literacy, higher education, being married and higher levels of savings. Going back to our research hypotheses, we find robust evidence to support Hypothesis 1 but no evidence to support Hypothesis 2. Because of the size of the effect of better financial literacy on higher households’ financial stability, financial education is as economically important as education in other domains. Being financially literate means being more able to make ends meet, which elevates not only a householder’s ability to effectively manage the monthly budget but also offers an indirect benefit to psychological well-being. The greater the ability to manage monthly budgeting, the lower the stress and anxiety anchored around personal finance.
Conclusion
This paper affirms financial literacy’s critical role in savvy wealth management. It does so using SHIW subsample data and the Bank of Italy Survey on financial literacy, applying OECD methodology. Financial literacy enables sound wealth management, saving more for financial contingencies, better retirement planning, access to credit at lower costs and the ability to borrow at lower interest rates.
We contribute to the literature by testing two main hypotheses. First, we investigate any potential effect of financial literacy on making ends meet easily. Then, we focus on any differential effect of financial literacy on female householders’ ability to easily make ends meet. Our findings only support our first hypothesis. In more detail, data show that higher levels of financial literacy significantly and positively affect householders’ financial stability. This is true considering different financial literacy indicators. Our results find that householders able to correctly answer Big Three questions to assess financial literacy are 8 p.p. more likely to reach financial well-being, as measured by their ability to easily make ends meet. Using a more comprehensive financial literacy measure, we find financially literate householders 13.5 p.p. more likely to make ends meet easily.
This is a crucial finding in terms of the economic well-being of householders in Italy. It also is an important finding when it comes to psychological well-being. A strictly indirect positive effect of higher financial stability is a reduction in anxiety about wealth management and financial fragility.
Meanwhile, although female householders are 9.6 p.p. less likely to reach financial stability, our findings do not support our Hypothesis 2. Our results are robust to different financial literacy indicators.
In exploiting data at the regional level, we document huge geographic disparities among householders’ financial stability. In particular, householders in the South of Italy, including the islands, typically show a lower level of financial literacy and great difficulties in making ends meet, relative to the rest of Italy. The strongest ability to make ends meet-and highest levels of financial literacy-correspond with the North of Italy, for both female and male householders. In the Center, both male and female householders with basic or higher knowledge of financial concepts are more likely to make ends meet. In this area of Italy, financial literacy education offers the highest potential impact for increasing households’ ability to make ends meet. The South of Italy would require much deeper financial knowledge to make a difference in the ability to make ends meet even just among male householders.
In our opinion, these results highlight the importance of financial literacy as a safeguard against financial stress and distress, especially in times of crisis. Although our analysis finds that increasing financial literacy will enable people to make ends meet more easily, we cannot exclude the possibility that other drivers, too, can advance this goal. We believe there is a need to improve family budgeting and we are mindful that financial literacy is also connected to greater psychological well-being because it lessens the anxiety that accompanies financial fragility.
Our findings offer opportunities for future research. We also envisage public policy implications. In particular, there could be interest in establishing financial education programs in specific regions of Italy to increase household financial stability, improve psychological well-being and narrow the regional wealth gap.
A. Appendix: Additional results
See Figs. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14.Fig. 3 Average ability to Make ends meet across Italian regions. Figure 3 shows the Italian Householders’ average ability to make ends meet easily across Italian regions. Households’ financial stability is lower among the South of Italy regions. Several surveys reveal that the same regions are also those in which financial literacy levels are the lowest in Italy
Fig. 4 Financial Literacy across gender (FINLIT_2016)
Fig. 5 Financial Literacy across gender (FINLIT_sd)
Fig. 6 Financial Literacy across education (FINLIT_2016)
Fig. 7 Financial Literacy across education (FINLIT_sd)
Fig. 8 Financial Literacy across age groups (FINLIT_2016)
Fig. 9 Financial Literacy across age groups (FINLIT_sd)
Fig. 10 Financial Literacy across income (FINLIT_2016)
Fig. 11 Financial Literacy across income (FINLIT_sd)
Fig. 12 Financial Literacy across civic status (FINLIT_2016)
Fig. 13 Financial Literacy across civic status (FINLIT_sd)
Fig. 14 Education across age groups (FINLIT_sd)
Declarations
Conflict of interest
None.
1 Even though the Bank of Italy’s historical data collection began in the 1960s, financial knowledge questions were included only in these four years. In particular, six questions in 2006, nine in 2008, three in 2010, and three in 2016. Moreover, SHIW data directly ask these questions only of those who are responsible for the household wealth management. Considering the heterogeneous questions over time, through standardized indicators we can observe the ideal targets who daily manage their family’s budget.
2 The full text of the Big Three questions are available here: "(1) Suppose you had 100 dollars in a savings account, and the interest rate was 2% per year. After 5 years, how much do you think you would have in the account if you left the money to grow? Answers: (a) More than 102 dollars; (b) Exactly 102 dollars; (c) Less than 102 dollars; (d) Do not know; (e) Refuse to answer. (2)Imagine that the interest rate on your savings account was 1% per year and inflation was 2% per year. After 1 year, how much would you be able to buy with the money in this account? Answers: (a) More than today; (b) Exactly the same; (c) Less than today; (d) Do not know; (e) Refuse to answer. (3) Please tell me whether this statement is true or false. “Buying a single company’s stock usually provides a safer return than a stock mutual fund.” Answers: (a) True; (b) False; (c) Do not know; (d) Refuse to answer.
3 This indicator is composed of (i) knowledge, including the understanding of inflation, the difference between simple and compounded interest rates, and risk diversification, on a scale from 0 to 7 where 5 is sufficient; (ii) behavior, which measure the ability in wealth management such as savings, planning, setting financial objectives, planning and payments, on a scale from 0 to 9; (iii) attitude, investigating future and present orientation in precautionary saving, on a scale from 1 to 5.
4 The P-Fin Index measures financial literacy across eight common financial activities: earning, consuming, saving, investing, borrowing, insuring, understanding risk and gathering information.
5 Bernanke (2011) A statement by U.S. Federal Reserve Chair Ben Bernanke on financial literacy, provided for the record of an April 12, 2011, hearing by the U.S. Senate Subcommittee on Oversight of Government Management, the Federal Workforce, and the District of Columbia, Committee on Homeland Security and Governmental Affairs, https://www.federalreserve.gov/newsevents/testimony/bernanke20110420a.htm last visited on February 27, 2022
6 Data are available at https://www.bancaditalia.it/statistiche/tematiche/indagini-famiglie-imprese/bilanci-famiglie/distribuzione-microdati/index.html.
I thank the Italian Society of Economists (SIE) for inviting me to submit this paper as a part of my dissertation for the SIE PhD Dissertation in Economics Award. This paper is a revised version of Chapter 3 of my PhD thesis written under the supervision of Prof. Francesco Drago at the University of Messina. I thank him for helpful discussions and encouragement. I am particularly grateful to Alessandro Bucciol, Simone Quercia, the editor Marco Cucculelli and the two anonymous referees for their excellent comments and suggestions. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Research Article
Global energy markets connectedness: evidence from time–frequency domain
Rehman Mobeen Ur [email protected]
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Naeem Muhammad Abubakr [email protected]
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Ahmad Nasir [email protected]
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Vo Xuan Vinh [email protected]
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1 grid.444827.9 0000 0000 9009 5680 Institute of Business Research, University of Economics Ho Chi Minh City, Ho Chi Minh City, Vietnam
2 grid.440724.1 0000 0000 9958 5862 South Ural State University, 76, Lenin Prospekt, Chelyabinsk, Russian Federation
3 grid.43519.3a 0000 0001 2193 6666 Accounting and Finance Department, United Arab Emirates University, P.O. Box 15551, Al-Ain, United Arab Emirates
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5 grid.444827.9 0000 0000 9009 5680 Institute of Business Research and CFVG, University of Economics Ho Chi Minh City, Ho Chi Minh City, Vietnam
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We examine the presence of dependence across 51 energy markets classified into different regions from Jan 2007 to June 2021. In order to examine the presence of dependence across different energy markets, we apply standard and threshold dependence measures proposed by Diebold and Yilmaz, Int J Forecast 28:57-66, (2012) and Baruník and Křehlík, J Financ Econ 16(2):271-296, (2018). We highlight the presence of strong dependence between the energy markets at both regional level and across other regions. European and American energy markets are highly connected within the region over the long-run whereas Asia–Pacific and the African energy markets offer optimal diversification opportunities. Both short- and long-run dependence exists between Chinese and the Hong Kong energy markets and between the US and Canadian energy markets. We also witness substantial increase dependence across all the energy markets during different crisis periods.
Keywords
Energy markets
Dependence
Spillover
Connectedness
Time–frequency
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pmcIntroduction
Since the last couple of decades, investment in energy markets highlight an important avenue in the modern investment pattern. This has become more appealing especially during the recent awareness of energy shortage all across the globe and the resultant escalating energy prices. According to the International Energy Agency (2021), investments in global energy are increasing consistently and reached up to $1.8 trillion till 2019 which are mostly contributed by the fuel production (32%), energy infrastructure (30%), and power generation (28%). Despite significant growth in 2019, the first quarter of 2020 resulted in an annual decline of 20% in the global energy investment due to COVID-19 pandemic. However, according to the International Energy Agency, annual energy investments were later set to scale up significantly, rebounding approximately up to 10% in 2021, thus bringing the total volume of energy investment up to $1.9 trillion. Such rise in energy investments in 2020 also set up a forecasting level of an increasing 4.6% in 2021. These estimations are already reflected in the form of increasing global oil prices, with oil prices increasing to $83 compared to $36 per barrel, gas prices reaching to $5 from $3, and gasoline prices plunging to $80 from $45 in October 2020.1 As a result, a considerable number of investors are now keen to allocate energy assets in their investment portfolios which resulted in high volume of investments in the global energy market (Tang & Xiong 2012; Lin & Li 2015). However, the presence of integration among different energy markets displays pattern of returns co-movement, which makes portfolio allocation choices more challenging for individual as well as institutional investors (Naeem et al. 2022a, b, c). For instance, Bencivenga et al. (2010) report long-run integration among the European energy markets whereas in the short-run, relationship between these markets2 are unstable. Similarly, Mensi et al. (2021a) and Zhang and Broadstock (2020) observe the presence of dynamic connectedness among different energy commodities which increased significantly during the different crisis periods (Alawi et al. 2022; Karim and Naeem 2022). Such increase in connectedness among energy markets limiting diversification opportunities make portfolio choices more challenging for investors.
A significant strand of literature documents relationship between different energy commodities (Mensi et al. 2021b; Gupta et al., 2018; Ji et al. 2018; Wang & Guo, 2018). Singh et al. (2019) examine spillover connectedness among MSCI Europe, North and Latin America, Asia–Pacific, and the African energy market indexes and highlight significant connectedness in returns of European and the North American energy markets.3 Rehman (2020) examine pairwise returns co-movement among developed and emerging energy markets and report diversification benefits between the developed and emerging energy markets. However, after each crisis period,4 energy markets exhibit high levels of integration. Similar results are also reported by Rehman and Vo (2020) that portfolio comprising of World Developed and European alternative energy markets together with emerging or BRIC energy markets provide optimal returns under investment horizons ranging from intra-week to monthly period.
There are studies which focus on returns integration between energy commodities during the global financial crisis period in 2008–09 (Albulescu et al., 2020) and the COVID-19 pandemic period (Abadie 2021; Bouri et al. 2021; Zhang et al. 2021). According to Singh et al. (2019), energy markets in the Asia–Pacific region exhibit high connectedness with the Russia market which act as a major transmitter of spillover. Naeem et al. (2020) analyze relationship between energy, electricity, carbon, and clean energy markets and report time-varying connectedness which further intensifies during the global financial crisis period (2008–09). Increase in returns connectedness among different energy markets during the global financial crisis is also documented by Mandacı et al. (2020) who report that the volatility connectedness among global energy markets is time varying and increases significantly during the 2008–09 global financial crisis period. Lin and Su (2021) report significant increase in the total connectedness among energy markets following the outbreak of COVID-19 pandemic; however, this increase only lasted for two month’s period after which the connectedness declined to its pre-crisis level (Karim et al. 2022a, b; Billah et al. 2022; Alawi et al. 2022).
According to Akyildirim et al. (2022), connectedness among the global energy markets is high during uncertain times, COVID-19, and low economic sentiments. Benlagha and Omari (2022) examine the impact of COVID-19 outbreak on the dynamic connectedness between oil, gold, and five leading stock markets and report an increasing connectedness. They also show that gold act as a receiver whereas oil appear as a transmitter of shocks towards these stock markets. Likewise, more recently, Luo et al. (2022) investigate connectedness between gray energy and natural gas. They find that most of the gray energy indexes possess an ability to predict natural gas returns. The authors also show that connectedness from the WTI crude oil performs better for out-of-sample forecasting.
Our main contribution in this paper is to examine the presence of dependence among energy markets of Africa, America, Asia–Pacific, and Europe. Existing literature5 mainly focuses on the relationship between different energy commodities; however, we find limited studies examining the presence of dependence among energy indexes based in different countries. Therefore, our work fills this gap by examining the presence of returns dependence among a wide array of energy markets based in African, American, Asia–Pacific, and the European region. Our second contribution is to investigate dependence between energy markets during the normal and crisis periods which mainly comprise of the global financial crisis (2008–09) and the COVID-19 periods, thereby highlighting an important avenue of investigation under the short- and long-run investment periods.
In order to examine the presence of returns dependence among energy markets, we apply network dependency measure proposed by Junior et al. (2015). This technique has several advantages over other competing methods for measuring return connectedness. First, it is quite useful in estimating the dynamic structure among a large set of variables without involving the specification of complex econometric models. Second, this approach is effective in analyzing interdependence within a system without restricting the number of variables. In this way, this technique not only helps in measuring returns integration within a dynamic structure but also in examining co-movements within a system comprising of large number of variables. Another advantage of this technique over other connectedness measures is its ability to estimate the dependency network based on partial correlation which provides simple interpretation for investment purposes.
Results of our work highlight energy market dependence within as well as across different regions. Among other markets, European and American energy markets are more connected within the region in the long run. Asia–Pacific (except Russia) and African (except South Africa) energy markets are more suitable for investments attributable to their low connectedness with other energy markets within and across other regions. Chinese and Hong Kong from the Asia–Pacific region whereas United States and Canada from the American energy markets are highly connected both in the short- and long-run period during tranquil market conditions. Our results also highlight substantial increase in return dependence across all energy markets during the global financial crisis (2008–09) and the COVID-19 periods. Such increase in return dependence between different energy markets under crisis periods limits investment benefits for investors. Implications generated from our work are based on the heterogeneous behavior of energy markets across different regions which calls for careful selection of these securities in a single portfolio. Moreover, dependence among these energy markets increase during turbulent times which reduces diversification benefits during bearish market conditions. “Data and methodology” expounds data sources and estimation techniques under “Methodology.” “Analysis and discussion” provides data analysis and interpretation of results. “Conclusion” presents conclusions based on our results with implications for investment in the energy markets during normal and financially distressed periods.
Data and methodology
Data source
Data of our paper comprises 51 energy markets from different regions. These regions are classified as Europe, America, Asia–Pacific, and Africa. For the representation of European emerging markets, we sample Austria, Belgium, Croatia, Cyprus, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, the Netherlands, Norway, Poland, Portugal, Romania, Slovenia, Spain, Sweden, and Turkey. For the American region, country list include Argentina, Brazil, Canada, Chile, Columbia, Peru, and the USA. For Asia–Pacific, we sample Australia, China, Hong Kong, India, Israel, Jordan, Japan, Korea, Kuwait, Malaysia, New Zealand, Oman, Pakistan, Philippines, Russia, Singapore, Sri Lanka, Taiwan, and Thailand. Finally, for the African region, we select Egypt, Morocco, and South Africa. Daily data for all energy markets ranges from 2007 to 2020. Daily returns for all energy markets are calculated by taking natural log of the difference between two adjacent pricing levels. We extract data for all energy markets from Thomson Reuters DataStream.
Methodology
Our methodological framework comprises time-varying spillover measures proposed by Diebold and Yilmaz (2012) and Barunik and Krehlík (2018). The spillover approach by Diebold and Yilmaz (2012) is effective in measuring time-varying connectedness which is superior to the conventional static models. This method does not use Cholesky factor identification associated with the VAR model due to which results are independent to the order of the variables. The application of Diebold and Yilmaz (2012) also enables us to measure pairwise as well as system-wide connectedness in a coherent and consistent way. Following Diebold and Yilmaz (2012), we also apply the spillover index of Barunik and Krehlík (2018) because of its advantage in keeping track of time as well as frequency domain. In this way, we can measure spillover across short- and long-run periods across different financial markets.(i) Time-domain spillover framework of Diebold and Yilmaz (2012)
The time-varying spillover approach of Diebold and Yilmaz (2012) is based on the generalized vector autoregressive (VAR) model used to compute the forecast error variance decomposition. To begin, we consider the time, t=1,⋯,T, whereas the structural VAR (p) illustrates the n-variate process xt,1,⋯.,xt,n as follows:1 φLxt=εt
where φL=∑hφhLh represents an n×n coefficient matrix t with lag polynomial running into infinity. Accordingly, the forecast error variance decomposition, in line with DY (2012), is given as2 (θH)j,k=σkk-1∑h=0HΨhΣΨhΣΨhΣj,k2∑h=0HΨhΣΨh′j,j
where σkk=(Σ)k,k, and Ψh represents an n×n coefficient matrix having lag h.(θH)j,k explains the shock contributed by k-th variable to the forecast error variance of another variable j. Computationally, the summation of individual row (θH)j,k is not equal to unity. Hence, the summed-up result of the row matrix is normalizing it which can be expressed as3 (θ¯H)j,k=(θH)j,k∑k=1H(θH)j,k
where ∑k=1H(θ¯H)j,k=1 and ∑j,k=1n(θ¯H)j,k=N.
The spillover in the proportion of the cumulated elements in the off-diagonal represents an overall summed up matrix as4 CH=∑j≠k(θ¯H)j,k∑(θ¯H)j,k×100=1-Tr{θ¯H}Σ(θ¯H)j,k100
where CH denotes the overall spillover of the network and Tr{.} is the trace operator.
Thus, the directional spillover transmitted (received) by a variable j, to (from) variable k, in the network, estimated as5 (CH)j→=1001n∑j≠k,k(θ¯H)j,k
6 (CH)j←=1001n∑j≠k,k(θ¯H)j,k
where (CH)j→ represents “to spillover” and (CH)j← denotes “from spillover,” respectively. Next, the net spillover is computed by the difference between spillover transmitted and received, as below.7 (CH)j,net=(CH)j→-(CH)j←
The positive value of net spillover (CH)j,net indicate that the variable j is a net transmitter of shock whereas the negative value imply that the variable j is net recipient of shock.
(ii) Frequency domain spillover framework of Baruník and Krehlík (2018)
In order to examine the variability of return connectedness between energy markets across different frequencies, we follow Baruník and Krehlík (2018). Based on the expression in Eq. (2) where the impulse function Ψh is assumed to be time-varying, we made another assumption on the impulse function term to reflect the frequency domain. The frequency response function derived from Ψ becomes Ψe-iw=∑he-iwΨh, which captures the coefficients of the Fourier transform, with i=-1. The generalized causation spectrum is expressed as8 (fω)j,k≡σkk-1Ψ(e-iw)Σ)j,k2(Ψe-iwΣΨ′e-iw)j,j
where,(fω)j,k reflects proportion of the spectrum of the j-th variable at frequency ω, made by shocks in the k-th variable. Ψ(e-iw) represents Fourier transform of the impulse response Ψ. We compute the generalized forecast error variance decomposition on a specific frequency band d by following Baruník and Krehlík (2018) as9 (θd)j,k=12πd∫Γj(ω)(fω)j,kdω
where Γj(ω) represents the weighting function. We define frequency-based connectedness on the frequency band by considering the spectral representation of the generalized forecast error variance decomposition as10 CdF=100Σj≠k(θ¯d)j,kΣ(θ¯∞)j,k-Tr{θ¯d}Σ(θ¯∞)j,k
Therefore, the computation of the total spillover is estimated as11 CdF=100Tr{θ¯d}Σ(θ¯d)j,k
We can compute directional spillover at various frequencies like the time domain spillover framework. The “from”, “To,” and “net” spillovers can be calculated as12 CdFj→=100×∑j≠k,k(θ¯d)j,k∑(θ¯d)j,kΣ(θ¯∞)j,k
13 CdFj←=100×∑j≠k,k(θ¯d)j,k∑(θ¯d)j,kΣ(θ¯∞)j,k
14 CdFj,net=CdFj→-CdFj←
A positive value of CdFj,net indicate that a specific energy market j is a net transmitter of shocks to other variables in the network whereas a negative value shows that the variable under consideration is net recipient of shocks from other variables.
Analysis and discussion
Table 1 presents descriptive statistics of all the energy markets which we sampled for our analysis and are clustered into four different regions. We also provide codes for each energy market for the ease of understanding. Among the all-equity markets, we see a mix of positive as well as negative daily average return values. The highest daily return value among the European energy markets is 3.9 percent for Denmark followed by Sweden (3.2 percent) and Turkey (2.6 percent). On the contrary, the highest mean loss of 3.6 percent is incurred by Ireland followed by a loss of 3.5 percent by the German energy market. Maximum standard deviation of 5.07 is exhibited by Ireland whereas Belgian energy market has the minimum deviation of 1.28 among other European energy markets. Among the American energy markets, Argentine provides maximum average returns of 0.05 percent while Peru exhibits maximum deviation of 3.32 percent. The energy market of Peru, Canada, and the USA exhibit negative average returns across the sampling period. For the Asia–Pacific region, we witness a mix of positive and negative daily returns where highest average daily return is for Kuwait (4.4 percent) followed by Sri Lanka (4.2 percent). However, in the African region, only the energy market in Morocco provides positive average returns. Jarque–Bera statistics suggest that the hypothesis of normal distribution is rejected for all the energy markets which is supported by the high kurtosis and negatively skewed values in most cases. Overall, based on our descriptive statistics, a mix of positive and negative average return values and the leptokurtic distribution with fat tails and negatively skewed values calls for a careful placement of energy securities in a portfolio.Table 1 Descriptive statistics
Region Market Symbol Mean Maximum Minimum Std. Dev Skewness Kurtosis J-B Obs
Europe Austria AUT 0.002 18.154 − 20.867 2.142 − 0.471 14.178 19,707.81a 3759
Belgium BEL 0.005 9.333 − 15.142 1.297 − 0.195 12.372 13,779.69a 3759
Croatia CRO 0.009 45.431 − 12.218 1.755 4.432 127.926 2,456,666.00a 3759
Cyprus CYP 0.000 16.737 − 10.534 2.108 0.315 8.941 5591.05a 3759
Denmark DEN 0.039 21.278 − 27.814 3.115 − 0.426 12.818 15,210.37a 3759
Finland FIN 0.051 21.270 − 12.747 2.213 0.195 9.377 6393.75a 3759
France FRA − 0.012 13.519 − 18.094 1.710 − 0.282 15.538 24,669.86a 3759
Germany GER − 0.035 17.244 − 18.772 2.313 − 0.403 8.931 5611.14a 3759
Greece GRE − 0.012 14.101 − 18.540 2.112 − 0.141 8.979 5611.13a 3759
Hungary HUN − 0.004 14.027 − 16.223 2.055 0.087 10.655 9182.48a 3759
Ireland IRE − 0.036 49.247 − 47.084 5.069 0.114 18.522 37,742.93a 3759
Italy ITA − 0.022 15.698 − 19.610 1.750 − 0.519 18.047 35,629.79 a 3759
Netherlands NET − 0.017 18.751 − 20.917 2.251 − 0.464 13.060 15,984.69a 3759
Norway NOR − 0.007 12.175 − 21.235 1.882 − 0.570 11.374 11,187.87a 3759
Poland POL 0.013 10.984 − 9.093 1.682 − 0.062 5.457 947.67a 3759
Portugal POR 0.010 22.069 − 18.054 2.108 0.342 13.372 16,922.66a 3759
Romania ROM − 0.010 12.769 − 16.204 1.799 − 0.577 14.909 22,421.13a 3759
Slovenia SLO − 0.007 12.480 − 9.484 1.536 0.123 10.475 8760.94a 3759
Spain SPN − 0.013 12.387 − 13.807 1.728 − 0.437 10.006 7807.69a 3759
Sweden SWE 0.032 28.090 − 26.421 2.602 − 0.020 15.395 24,061.75a 3759
Turkey TUR 0.026 10.655 − 10.901 1.772 − 0.428 6.410 1935.80a 3759
America Argentina ARG 0.050 16.326 − 27.788 2.698 − 1.132 15.727 26,171.18a 3759
Brazil BRA 0.000 18.969 − 30.669 2.774 − 0.585 12.249 13,612.10a 3759
Canada CAN − 0.013 14.156 − 22.034 1.746 − 1.181 24.011 70,020.39a 3759
Chile CHI 0.001 11.471 − 13.145 1.632 0.037 7.604 3321.15a 3759
Columbia COL 0.014 10.975 − 20.704 1.804 − 0.555 13.512 17,501.10a 3759
Peru PER − 0.055 71.639 − 65.717 3.321 0.763 104.354 1,609,315.00a 3759
USA USA − 0.005 17.327 − 23.605 1.866 − 0.921 21.081 51,737.96a 3759
Asia–Pacific Australia AUS − 0.004 9.550 − 18.432 1.604 − 0.825 13.078 16,333.77a 3759
China CHN − 0.002 17.239 − 17.153 2.093 0.260 10.846 9684.58a 3759
Hong Kong HKG 0.013 19.145 − 15.476 2.239 − 0.079 10.106 7911.66a 3759
India IND 0.029 16.464 − 16.462 1.658 − 0.564 15.515 24,730.38a 3759
Indonesia INS 0.025 15.968 − 31.535 2.289 − 0.488 16.879 30,320.46a 3759
Israel ISR − 0.005 17.961 − 16.659 1.837 0.138 16.074 26,782.79a 3759
Jordan JOR 0.020 9.665 − 7.715 1.758 0.173 5.723 1180.55a 3759
Japan JPN − 0.018 12.327 − 14.022 1.854 − 0.255 7.441 3129.56a 3759
Korea KOR 0.019 16.935 − 14.585 2.140 0.182 9.133 5911.27a 3759
Kuwait KUW 0.044 42.119 − 38.948 2.433 0.184 48.783 328,323.00a 3759
Malaysia MAL 0.016 9.266 − 10.110 1.137 − 0.358 12.664 14,708.50a 3759
New Zealand NZL − 0.036 14.248 − 15.333 1.436 − 0.589 17.677 33,956.62a 3759
Oman OMN − 0.012 9.859 − 12.622 1.332 − 0.496 16.474 28,590.75a 3759
Pakistan PAK 0.006 9.380 − 10.777 1.500 − 0.108 6.911 2403.29a 3759
Philippines PHI − 0.030 17.191 − 21.574 1.910 0.122 18.930 39,752.79a 3759
Russia RUS 0.014 27.458 − 22.150 1.915 0.174 33.474 145,473.00a 3759
Singapore SIN − 0.015 13.882 − 12.789 1.715 − 0.051 10.857 9671.58a 3759
Sri Lanka SRI 0.042 12.452 − 15.362 1.483 0.141 14.816 21,879.24a 3759
Taiwan TAI 0.008 9.443 − 11.246 1.650 − 0.061 6.752 2206.65a 3759
Thailand THL 0.012 13.268 − 30.036 1.901 − 1.037 24.835 75,345.36a 3759
Africa Egypt EGY − 0.015 16.833 − 15.004 1.920 − 0.211 14.011 19,017.88a 3759
Morocco MRC 0.007 6.533 − 9.511 1.494 − 0.349 6.857 2406.37a 3759
South Africa SAF − 0.009 21.974 − 43.094 2.310 − 1.625 42.224 242,623.20a 3759
J–B represents Jarque–Bera test of normality. aRejection of null hypothesis of normality at 1%
Figure 1 plots results of unconditional correlation among our sample energy markets. We cluster our sample period into (a) full sample period, (b) 2008–09 global financial crisis, and (c) COVID-19 crisis period. During our analysis of the complete sample period, we show that the energy markets are weakly correlated both within a region as well as across different regions. American and the Asia–Pacific energy markets are weakly correlated within themselves as well as across each other over the complete sampling period as opposed to the European energy markets where we witness relatively high regional correlation among few pairs. The correlation among all European energy markets except Belgium, Croatia, and Cyprus further intensifies during the global financial crisis period. Similarly, the magnitude of correlation among American energy market returns also increases during the global financial crisis. On the contrary, we witness weak return correlation among the Asia–Pacific energy markets during the GFC period except the Australian, Chinese, and Hong Kong energy markets (Naeem et al. 2022d; Karim et al. 2022c, d). It is also worth mentioning that correlation among European and American energy market returns also increases during the GFC period. During COVID-19 period, the correlation heat-map clearly highlights the presence of an increased returns correlation among the energy markets. This increased correlation is more pronounced among the European and American pairs which results in more interconnectedness among the energy markets across these regions. Similarly, Asia–Pacific energy markets highlight increasing pattern of returns integration with the European and American energy markets. Nevertheless, among all the sampled energy markets in our study, the markets of the Asia–Pacific region are less correlated within the region as well as across other markets suggesting the potential from diversification of assets during the crises periods (Naz et al. 2022; Pham et al. 2022; Naeem & Karim 2021). Overall, these results highlight that portfolio comprising of cross-regional energy securities provide optimal diversification opportunities both during normal and crises periods.Fig. 1 Correlation heat-map. (a) Full sample. (b) Global financial crisis (GFC). (c) COVID-19 crisis
We start our analysis by examining the pairwise directional dependency across our sample energy markets following Diebold and Yilmaz (2012). We classify energy markets under different regions and highlight in different colors. Red color represents European, blue indicate American, green is Asia–Pacific, and purple highlights African energy markets. The graphical depiction in of Fig. 2a highlights asymmetric relationship between pairs of energy markets indicating that the effect of energy market i on j is different from the effect of energy market j on i. The arrow pointing from one market to another highlights the direction of spillover. Our results highlight a high level of connectedness within European energy markets; however, results are not homogeneous for all markets. This adds to the findings by Veka et al. (2012) who also report significant relationship between European energy markets. For instance, AUT, SWE, SPN, POR, POL, NOR, NET, ITA, and ERA energy markets exhibit maximum returns coherence within region whereas SLO, ROM, IRE, HUNG, GRE, FIN, DEN, CYP, CRO, and BEL highlight least evidence of dependence within the region. Similar to European energy markets, our results highlight significant dependence among American energy markets. USA, CAN, COL, and BRA exhibit maximum regional coherence whereas PER, ARG, and CHI show low level of integration within the region. Among the Asia–Pacific energy markets, only RUS and SIN act as a recipient of spillover within the region, while on the other hand, we find no traces of regional integration among the African region. Therefore, compared with the European and American regions, Asia–Pacific and the African regions offer more diversification benefits for investments in the energy markets attributable to their low level of returns dependence with each other. Besides return connectedness between energy markets within different regions, significant integration exists between energy markets from different regions. For instance, AUT, SWE, SPN, POR, NOR, NET, ITA, and IRE among the European energy markets act as a major recipient of spillover from energy markets based in other regions whereas USA, CAN, and BRA receive major spillover of returns from European and the Asia–Pacific energy markets. Energy markets in Asia–Pacific act a major transmitter of spillover to energy markets in other regions except Russia which receives spillover from the European energy markets. One possible reason for such dependence between Russian and European energy markets might be because Russia is a major exporter of energy to the Europe (Rapaić and Novaković 2013). However, in the case of the African region, SAF energy market acts as a recipient of change from European energy markets where transmit changes towards the Asia–Pacific energy markets. Both EGY and MRC are neither connected within the region nor integration across the region. Therefore, diversification benefits lie for investments in the energy markets of Africa and Asia–Pacific though later is connected with the energy markets in other regions. Investments within the European and American energy markets need careful examination while developing a portfolio. Though we witness cases of strong dependence cross the regions, i.e., the American, Asia–Pacific, and the European regions, there still exist opportunities for investment within the region. For example, energy markets in Asia–Pacific and Africa provide optimal return opportunities for investors.Fig. 2 The network of return connectedness using Diebold and Yilmaz (2012). (a) Without thresholding. (b) With thresholding. Note: this shows the connectedness among 51 sampled energy markets, classified by regions. In (b), we only keep the values larger than the average of the 100 largest individual pairwise connectedness
In order to get a clear view of returns dependence between different energy markets, we simplify the network structure with a restricted number of edges by capturing the values which are larger than the average of the top 100 individual risk spillover. This simplified arrangement of dependency network only captures the most important pairwise relationship. Results in Fig. 2b confirm our findings that majority of the European energy markets are dependent within the region and FRA act as a net recipient of information from other European markets within the regions and from USA and CAN energy markets across other regions. FRA, ITA, SPN, and NOR also receive changes from other European energy markets whereas NET act as a transmitter of spillover towards other European energy markets. Among the American energy markets, we witness the transmission of information is greater in magnitude between USA and CAN compared with other American energy markets. Both USA and CAN remain net recipient of information from the Asia–Pacific energy markets where USA receives spillover from AUS and JPN energy markets whereas CAN act as a net recipient of spillover from the AUS energy market. In terms of dependence within the Asia–Pacific energy market, only CHN and HKG energy markets are integrated with each other. No other market neither transmit nor receives any change within the Asia–Pacific region. Notably, African energy markets are fairly segmented within and from all other regions. Overall, within region dependence among European and the American energy markets is high highlighting few investment opportunities which are similar to the findings by Lin and Li (2015) who show that increasing number of investors allocate energy assets in their portfolios which results in high integration among this asset class. On the contrary, Asia–Pacific and the African energy markets provide optimal diversification opportunities due to their low level of dependence.
Figure 3a plots network of return connectedness between energy markets classified by regions for short-run period. We follow network connectedness approach proposed by Baruník and Křehlík (2018) to examine short-run dependency among the European, American, Asia–Pacific, and African energy markets. Our results highlight that energy markets of AUT, SWE, SPN, POR, NOR, NET, ITA, and FRA appear as net recipients of transmission from other energy markets both within and across other regions, particularly from the America and the Asia–Pacific.Fig. 3 The network of return connectedness using Barunik and Krehlik (2018)—short run. (a) Without thresholding. (b) With thresholding. Note: this shows the connectedness among 51 sampled energy markets, classified by regions. In (b), we only keep the values larger than the average of the 100 largest individual pairwise connectedness
These results are in line with the previous results of Singh et al. (2019) who also report significant connectedness of returns among European and North American energy markets. USA, BRA, and CAN among the American energy markets appear as net recipient of spillover from both the regional and cross-regional energy markets with strong spillover in magnitude between the USA and the CAN energy markets. It is worth mentioning that the US energy market acts as a net recipient of spillover more than it transmitting change to other energy markets, thereby highlighting the sensitivity of US energy markets during the short-run period. The RUS energy market from Asia–Pacific act a net recipient of information from the energy markets of other regions whereas CHN and HKG are appear as active participants within region. On the other hand, only SAF energy market among the African energy markets receives as well as transmits spillover towards the energy markets of other regions; however, these African energy markets are not integrated within the region. Overall, we show that energy markets of Europe and America exhibit high level of dependence within the region and with the energy markets of other regions, thereby suggesting a careful placement of energy securities under a short-term investment horizon. Our results support a recent work by Rehman (2020) that the presence of returns co-movement has increased between the global energy markets which requires careful placement of these assets in a portfolio.
To get a clear view of the short-run network dependency among our sample energy markets, we simplify network with a restricted number of edges and only capture values which are larger than the average of top 100 individual pairwise connectedness. Our results in of Fig. 3b support earlier findings that the European and the American energy markets are more integrated within region compared to the cross-regional dependence. The FRA, ITA, NOR, and SPN act as a net recipient of spillover from other European energy markets whereas FRA energy market remains a net recipient of spillover from both European as well as the American energy markets. For American energy markets, highest dependency is witnessed between USA and CAN whereas BRA energy market transmits change both towards the USA and the CAN. On other hand, ARG, CHI, and PER energy markets neither receives nor transmits information in the short-run. Among the Asia–Pacific region, CHN and HKG exhibit high level of dependence with each other over the short-run investment horizon. It worth mentioning that only FRA from the Europe and USA among rest of the American energy markets act as a net recipient of change from other regions. These results suggest that significant diversification opportunities exit for investment under short-run period in the global energy markets. These results support the findings by Rehman and Vo (2020) that portfolio comprising of developed and the emerging energy securities provide maximum diversification benefits for investors.
Figure 4 presents network connectedness for all the energy markets using Baruník and Křehlík (2018) over the long-run period. Overall, we witness quite similar results as presented in Fig. 2. However, we note traces of information transmission towards BRA and RUA energy markets as shown in Fig. 4a. Regarding the integration level between energy markets within the European region, our results highlight that the SPN, NOR, ITA, and FRA energy markets exhibit maximum returns dependence whereas all other energy markets highlight low level of spillover. Beside regional dependence, significant integration exists among the cross-region energy markets. For instance, energy markets of AUT, SWE, SPN, POR, NOR, ITA, and FRA appear as net recipients of spillover from the American and Asia–Pacific energy markets. Among the American energy markets, USA acts as a major recipient of information followed by the BRA energy market. Notably, the CAN energy market acts as net transmitter toward the US and the CHI energy markets. On the other hand, the PER energy market shows no traces of dependence, neither within a region nor across other regions. For the Asia–Pacific region, the RUS energy market is the net recipient of spillover within the region as well as from its European counterparts whereas THI, AUS, and JPN appear as major transmitters of spillover towards the US and the European energy markets. Our findings are consistent with the results of Lin and Li (2013) who report significant correlation between the energy markets in Europe and Japan. However, energy markets within Asia–pacific highlight low dependence except only one case of high level of dependence between the CHI and the HKG energy markets. However, the SAF energy market exercise high returns dependence with the energy markets in other regions.Fig. 4 The network of return connectedness using Barunik and Krehlik (2018)—long run. (a) Without thresholding. (b) With thresholding. Note: this shows the connectedness among 51 sampled energy markets, classified by regions. In (b), we only keep the values larger than the average of the 100 largest individual pairwise connectedness
Figure 4b highlights a simplified view of long-run dependency network by restricting the number of edges and only keeping values larger than the average of the top 100 individual pairwise connectedness. We find traces of dependence within regions as well as across other regions. For example, the NOR and the FRA from the European energy markets appear as major recipients of spillover within region as well across other regions; however, POR and AUT act as net transmitters of spillover within Europe as well as towards the US energy market. Likewise, the US market appears as a net recipient of information from the energy markets in other regions whereas the CAN energy market act as a major recipient of spillover from the SAF, AUS, and JPN energy markets. Among the Asia–Pacific region, THL, AUS, and JPN appear as major transmitters of spillover towards the NOR, FRA, US, and CAN energy markets. However, energy markets of CHN and HKG are highly integrated with each other in the long run. The SAF energy market is a major transmitter of spillover towards NOR, FRA, US, and CAN energy markets. Notably, all the energy markets in Asia–Pacific and Africa appear as net transmitters of spillover with not a single market acting as a recipient of spillover during the long-run investment horizon. These results support the findings by Shen et al. (2018) that Asian energy markets highlight more integration in terms of risk transmission compared to the US and the European markets.
Figure 5 presents total time-varying connectedness among all energy markets following Diebold and Yilmaz (2012). The purpose of such analysis is based on the fact that the sampling period does not follow a smooth timeline rather consists of financially turbulent periods including the Global financial crisis (2008–09), the ESDC period (2012–14), and the recent COVID-19 pandemic. Therefore, the interdependency among our sampled energy markets tends to vary considerably following a dynamic correlation patterns. Our findings highlight significant increase in connectedness among energy markets during all the crises periods. For instance, the escalated value during 2008–09 is attributed to the global financial crisis (GFC) period which marks high level of dependency among the energy markets. Later, this increase is followed by a decline during the post crisis period until the beginning of 2012–14 ESDC. The total dependency again increased in the beginning of the ESDC in 2012; however, the magnitude of increase in relatively low compared to the 2008–09 GFC. Later, we witness that the total dependency decreases substantially between 2013 and 2015 indicating diversification opportunities for investors. This decrease in dependency is followed again by increasing level of connectedness when the global economy was faced by one the largest decline in oil prices in modern history, thereby limiting benefits from diversification. We again witness high dependency among the energy markets at the end of the sample period mainly attributed to the global COVID-19 pandemic. Overall, the dependency network suggests turbulent patterns across the entire sample period with escalated dependence levels during economic and financial distressed periods. These results are consistent with the findings by Albulescu et al. (2020) that co-movement among different energy markets increases during extreme market conditions. Such volatility in the total dependence correspond with the pattern in global business cycle. The graph of total dependency increases in value when global market experience financial and economic crisis, whereas decreases significantly during the periods of economic recovery and expansion.Fig. 5 Total time-varying connectedness using Diebold and Yilmaz (2012). Note: this figure shows the rolling-window version of total connectedness. The rolling-window size 260 days
Figure 6 presents total time-varying connectedness among our sample energy markets following Baruník and Křehlík (2018). The red color in graph presents long-run dependency whereas green color shows short-run dependency among the energy markets. Our results highlight an increase in the energy market dependency during different crisis periods like GFC (2008–09), ESDC (2012–14), and the recent COVID-19 pandemic both during the short- and long-run periods. However, the magnitude of dependency is relatively strong in the short run. These results support the earlier findings by Lin and Su (2021) that connectedness among the global energy markets increased significantly during the COVID-19 pandemic. These results suggest that the presence of turbulent market conditions affect dependence level between different energy markets more during the short-run and,therefore, carry implications for the short-run investments. Since the interdependency across energy markets remains consistent under normal market conditions, it increases significantly under periods when the global market experiences financial and economic crises. Therefore, the overall network dependency behaves in a cyclical pattern following the global business cycle. These results highlight limited diversification benefits during the crisis periods both during the short- and long-run periods; however, diversification opportunities increase during periods of expansion and recovery.Fig. 6 Total time-varying connectedness using Barunik and Krehlik (2018). Note: this shows the rolling-window version of short run (green) and long run (red) connectedness. The rolling-window size 260 days
Figure 7 presents network of return connectedness for our sample energy markets during the 2008–09 Global financial crisis period. Our results presented in Fig. 7a highlight strong dependency between energy markets during the GFC period. All the energy markets are highly connected within region and across different regions. Such increase in interdependency highlight that during the financially turbulent period, investing in energy markets provides limited diversification benefits, thus following contagion and therefore requires a careful placement of energy securities in a portfolio during such periods. Albulescu et al. (2020) report similar findings that returns coherence among different energy markets increases during crisis periods. In a next step, to get a simplified view of the network dependency among our sample energy markets during the GFC (2008–09) crisis period, we simplify the dependence network with a restricted number of edges by only capturing values which are larger than the average of top 100 individual pairwise connectedness. Our results (Fig. 7b) support the earlier findings that energy markets are connected both within and across other region’s energy markets. For instance, the energy market of SLO acts as a recipient of spillover from not only from the GRE (regional) but also from the energy markets in the Asia–Pacific region. Similarly, NOR energy market receives information from ITA (regional) as well as from the USA (cross-region) energy markets and, furthermore, transmits changes toward the COL (cross-region) energy market. The DEN energy market acts as a recipient of information from the TUR (regional), SIN, and PAK (cross-regional) energy markets whereas GER receive information from IND during the global financial crisis. In case of American Energy markets, BRA and COL act as recipient of changes from the European energy markets of SPN and NET, respectively. From the perspective of American energy markets, CAN transmits spillover towards SLO and US towards the NOR (European) and SAF (African) energy markets. It is worth mentioning that, American energy markets are not connected within the region during the 2008–09 global financial crisis which is quite from the Asia–Pacific energy markets where we witness both regional and cross-regional dependence during the global financial crisis. For example, energy markets of SRI, SIN, HKD, IND, and MAL act as recipient of change from their European counterparts whereas, SIN and SRI receive information from both regional as well as European energy markets. Such increase in interconnectedness during the crisis period within as well as across different regions limit opportunities for diversification. Therefore, investors need careful examination before placing energy securities in a portfolio during crises periods.Fig.7 The network of return connectedness using Diebold and Yilmaz (2012)—global financial crisis. (a) Without thresholding. (b) With thresholding. Note: this shows the connectedness among 51 sampled energy markets, classified by regions. In (b), we only keep the values larger than the average of the 100 largest individual pairwise connectedness
Figure 8a presents network of return connectedness under the short-run period during the 2008–09 Global financial crisis period following Baruník and Křehlík (2018). Our results highlight strong short-run interconnectedness between energy markets within and across different regions during the GFC period which limits the diversification opportunities for investors. In Fig. 8b, we simplify network with a restricted number of edges and only capture values which are larger than the average of top 100 individual pairwise connectedness. Our results support earlier findings regarding the regional and cross-regional connectedness between energy markets. Among the European Energy markets, SLO act as recipient of information from IRE, HUN, and GER (regional) along with the CAN (American) and PHI (Asia–Pacific) energy markets. The NOR energy market receives spillover from the FRA and GER (regional) as well as from USA and CAN (American) energy markets. Both GER and FRA (European markets) receive changes from the IND and AUS (Asia–Pacific markets), respectively. In the case of American energy markets, we only witness COL as spillover recipient from the NET (European), OMN, and AUS (Asia–Pacific) energy markets. However, the energy markets of US and CAN act as net transmitters of change towards other regions. Energy markets in Asia–Pacific are also integrated in the short-run with regional as well as with cross-regional energy markets. For example, energy markets in SRI, TAI, HKG, IND, MAL, NZL, and OMN receive spillover from their European counterparts whereas RUS and KOR act as recipient of change from CAN (American) and SAF (African) energy markets, respectively. Notably, the energy market of EGY act as recipient of information from the European energy markets whereas SAF receives changes from both USA and the European energy markets. On the other hand, MRC transmits change towards IRE (European) whereas SAF spillover towards the KOR (Asia–Pacific) energy market during the short-run period. Overall, a careful investigation about energy assets placements in a portfolio is required at regional as well as at international level under the short-run investment horizon.Fig.8 The network of return connectedness using Barunik and Krehlik (2018)—short run–global financial crisis. (a) Without thresholding. (b) With thresholding. Note: this shows the connectedness among 51 sampled energy markets, classified by regions. In (b), we only keep the values larger than the average of the 100 largest individual pairwise connectedness
Figure 9 presents network of return connectedness between energy markets during GFC under long-run period. Our results presented in Fig. 9a highlight strong dependence between energy markets in the long-run during the GFC period. The energy markets in all four regions are highly interconnected not only within the region but also across different regions. In addition, each energy market acts as a recipient as well as transmitter of spillover over the long-run. Such increase in coherence at regional and international level suggests limited diversification opportunities for investors under distressed financial situations. Our findings are consistent with the results by Rehman (2020) that integration among energy markets increased significantly during the GFC period (2008–09). Figure 8b again presents long-run network connectedness after simplifying the network with a restricted number of edges and only capturing values which are larger than the average of top 100 individual pairwise connectedness. Our results highlight that European energy markets receive changes from cross-regional energy markets more than transmitting changes towards other regions. For instance, SLO, POR, IRE, GER, GRE, DEN, and CRO from the Europe receive spillover from the Asia–Pacific energy markets whereas, IRE, GER, and DEN receive changes from the American energy markets. AUT energy market receives spillover from both EGY (African) and ARG (American) energy markets during the GFC period. Notably, energy markets in the American region do not exhibit dependence with each other; however, CHI and PER act as recipient of information from the Asia–Pacific energy markets. Similarly, SRI and IND (Asia–Pacific) receive changes from TUR and CRO (European) energy markets, respectively. JOR energy market is a net recipient of information from the ARG (American) energy market. On the contrary, African energy markets are neither connected within the region nor receive any spillover from any other energy market during the GFC. Nonetheless, EGY energy market acts as net transmitter of change towards SLO and AUT (European) energy markets in the long run. These results highlight regional diversification opportunities for investors holding portfolio of African energy markets.Fig.9 The network of return connectedness using Barunik and Krehlik (2018)—long run–global financial crisis. (a) Without thresholding. (b) With thresholding. Note: this shows the connectedness among 51 sampled energy markets, classified by regions. In (b), we only keep the values larger than the average of the 100 largest individual pairwise connectedness
Figure 10a plots dependency network of Diebold and Yilmaz (2012) for the sampled energy markets during the COVID-19 pandemic period. Our findings highlight strong presence of dependence between the energy markets within region as well as across other regions. Our results of such strong connectedness between different energy markets during the COVID-19 pandemic is consistent with the finding by Lin and Su (2021) who report a dramatic increase in total connectedness among energy markets in the beginning of COVID-19 crisis. We witness that each single market exhibits bidirectional spillover with other energy markets during the COVID-19 pandemic. This increase in dependency suggest limited diversification opportunities for investors during the pandemic. In order to get more clear view of network connectedness, Fig. 10b simplifies the network with a restricted number of edges and only capture values which are larger than the average of top 100 individual pairwise connectedness. Our results highlight that among the European energy markets, SLO acts as a net recipient of spillover from American (COL and CHI), African (SAF), and Asia–Pacific (RUS, NZL, JOR, and JPN) energy markets. These results are different from the ones reported by Singh et al. (2019) that the energy markets within the Asia–Pacific region are connected with the Russian energy markets which act as a major transmitter of spillover. In addition, NOR appears as the major recipient of information from the TUR and SWE energy markets during COVID-19 pandemic. On the other hand, American energy markets act as a net transmitter rather than the recipient of change from other energy markets. We witness that COL, CHI, and ARG from the American energy markets transmit spillover towards SLO (European) and PAK (Asia–Pacific) energy markets during the COVID-19 pandemic. In the case of Asia–Pacific energy markets, SRI acts as a recipient of change from European and energy markets within the region whereas PAK receives spillover from ARG during the pandemic. Among the African energy markets, only SAF transmit changes towards SLO (European) energy markets. Despite both regional and cross-regional interconnectedness among our sample energy markets, there exist few opportunities for diversification for investors both at regional as well as at international level even during the pandemic.Fig. 10 The network of return connectedness using Diebold and Yilmaz (2012)—COVID19. (a) Without thresholding. (b) With thresholding. Note: this shows the connectedness among 51 sampled energy markets, classified by regions. In panel (b), we only keep the values larger than the average of the 100 largest individual pairwise connectedness
Next, short-run dependency network across our sample energy markets during the COVID-19 pandemic is depicted in Fig. 11 following Baruník and Křehlík (2018). Figure 11a shows short-run dependency network among energy markets during the COVID-19 pandemic. Our results reveal that energy markets are highly dependent within and across other regions. Such increase in network dependency suggests limited opportunities for investors for portfolio diversification in the short run during the pandemic. To get a clearer view of the dependency network, we simplify network with a restricted number of edges and only capture values which are larger than the average of top 100 individual pairwise connectedness in Fig. 11b. Our results highlight that, among the European Energy markets, only CRO and ROM energy markets act as recipient of spillover from Asia–Pacific energy markets whereas BEL energy market is the major transmitter of change towards the SRI (Asia–Pacific) energy market. In case of American energy markets, we witness that in the short run, ARG energy market receives spillover from the CRO (European) and KUW (Asia–Pacific) energy markets during the COVID-19 pandemic whereas CHI receives change from the DEN (European) and CAN energy market (within the region). On the other hand, USA, BRA, and PER energy markets transmit change towards the energy market in other regions. Among the Asia–Pacific energy markets, SRI act as major recipient of spillover from the European and the American energy markets. PHI (Asia–Pacific) receives spillover from IRE (European) and BRA (American) energy markets. Likewise, PAK energy market acts as recipient of change from the ARG (American) energy market during the COVID-19 pandemic in the short run. Notably, majority of the Asia–Pacific energy markets are connected within a region implying limited benefits from diversification by investing only in the energy sector of Asia–Pacific region. These results are supported by the recent work of Akyildirim et al. (2022) that connectedness among the global energy markets increases significantly during the COVID-19 period. The case of African energy markets is similar to Asia–Pacific markets in terms of receiving spillover of change from both the European and the American energy markets. For instance, SAF energy market act as recipient of information from the IND and the PHI (Asia–Pacific) energy markets together with the IRE (European) energy market during the COVID-19 pandemic, whereas MRC receives information from NET (European) as well as from US and CAN (American) energy markets during the pandemic implying limited diversification benefits in the short run.Fig.11 The network of return connectedness using Barunik and Krehlik (2018)—short run–global financial crisis. (a) Without thresholding. (b) With thresholding. Note: this shows the connectedness among 51 sampled energy markets, classified by regions. In (b), we only keep the values larger than the average of the 100 largest individual pairwise connectedness
Long-run network of return connectedness across our sample energy markets during the COVID-19 pandemic is presented in Fig. 12 following Baruník and Křehlík (2018). Our results depicted in the Fig. 12a highlights strong long-run dependence between the energy markets during the COVID-19 pandemic. We witness that each single market exhibits bidirectional spillover in the long run during COVID-19 pandemic. Among the European energy markets, SLO, POL, and NOR act as major recipient of spillover from the energy markets in Asia–Pacific and the American region, while CAN among the American energy markets acts as a major recipient of spillover from the European and Asia–Pacific energy markets. Similarly, COL acts as a major transmitter of change towards the European and the Asia–Pacific energy markets in the long run during COVID-19 pandemic. From the perspective of Asia–Pacific energy markets, THI, SRI, SIN, PAK, JOR, JPN, and INS appear as a major recipient of information from the European energy markets during the pandemic. On the other hand, SAF and EGY exhibit bidirectional spillover towards the energy markets in other regions. In Fig. 12b, we present long-run network connectedness after simplifying the network with a restricted number of edges and only capturing values which are larger than the average of top 100 individual pairwise connectedness. Our results highlight that European energy markets receive spillover from the energy markets in other regions whereas transmits information only towards the SIN (Asia–Pacific) energy market. The SLO energy market acts a net recipient of spillover from many cross-region energy markets like Asia–Pacific, African, and American regions. Furthermore, the SLO energy market also receives spillover within region during the COVID-19 in the long run. Notably, all energy markets in the American region are sensitive to regional as well as cross-regional spillover except CAN which receive information from the JPN (Asia–Pacific). The COL energy market transmits information towards SLO and NOR (European) and SIN (Asia–Pacific) energy markets during COVID-19 period. Similarly, SIN, JPN, and NZL among the Asia–Pacific energy markets are connected with cross-regional energy markets in the long run whereas all other markets remain insensitive to changes in other energy markets during the COVID-19 pandemic. On the other hand, EGY among the African energy markets acts as net transmitter of information towards SLO (European) whereas SAF energy market transmits information towards SLO and POL (European) as well as towards the SIN (Asia–Pacific) energy market. Overall, though we find few traces of regional and cross-regional connectedness, our findings suggest diversification opportunities for within and cross-region-based energy portfolio during the COVID-19 pandemic in the long run.Fig. 12 The network of return connectedness using Barunik and Krehlik (2018)—long run–global financial crisis. (a) Without thresholding. (b) With thresholding. Note: this shows the connectedness among 51 sampled energy markets, classified by regions. In (b), we only keep the values larger than the average of the 100 largest individual pairwise connectedness
To ensure that our results discussed above are not sensitive to the choice of forecasting horizon (h) or the window length W, we change our baseline rolling window and forecast horizon and select all possible combinations from the following parameter sets: w ∈ {200; 260; 300} and h ∈ {75; 100; 125}. Figure 13 plots results from the nine possible combinations where all the forecasting horizons (h) or the window length W have comparable paths and, therefore, overlap most of the time. Furthermore, all the choices lead towards several boost points, including the crisis period of global financial crisis in 2008–09, Eurozone crisis in 2010–12, global oil crash in 2015, and the COVID-19 pandemic in 2019–20. Hence, our findings provide evidence that the results are not sensitive to the choice of forecasting horizon (h) or the window length W.Fig. 13 Robustness to the choice of rolling window and forecast horizon. Notes: this shows the results for each other combination of window-length w ∈ {200, 260, 300} and forecast-horizon h ∈ {75, 100, 125}
Conclusion
We examine the presence of dependence across different energy markets classified into regions, i.e., Africa, America, Asia–Pacific, and the Europe, covering period from Jan 2007 to June 2021. Our analysis period covers significant time period encompassing various financial and economic crisis periods, including the global financial crisis (2008–09) and the recent COVID-19 pandemic. To examine the presence of dependence across different energy markets, we apply normal and threshold dependence measures proposed by Diebold and Yilmaz (2012) and Baruník and Křehlík (2018). Our results highlight strong dependence between our sampled energy markets at both regional as well as across the region. We find that European and American energy markets are highly connected within the region over the long-run. Asia–Pacific (except RUS) and the African energy markets (except SAF) offer optimal diversification opportunities by highlighting low connectedness of energy returns within the region as well as across other regions. We also find that CHI and HKG among the Asia–Pacific and USA and CAN among the American energy markets are highly connected both in the short and long run. The magnitude of such dependence further intensifies during different crisis periods. We witness substantial increase in returns dependence across all the energy markets both within region and across the energy markets in other regions. Such increase in the dependence between different energy markets during the crisis periods limits chances of optimal portfolio returns using the diversification strategies. Results of threshold dependence measures support the presence of short- and long-run diversification opportunities which not only exist within region but also across other regions.
Our results carry important implications for the investment community. We examine the presence of dependence between energy markets individually within and across certain regions. Knowledge of dependence between the energy markets on country basis can help individual as well as institutional investors for investment purposes. However, presence of dependence on the country level can not only benefit investors but also policy makers. There are studies which examine the effectiveness of inter-regional against within region diversification (Ahmad et al. 2022; Narayan & Rehman 2021); so, our work also contributes in this aspect. Policy makers can analyze and assess market conditions across different regions in terms of efficiency to lure investment from international investors. Our findings imply a careful selection of energy securities in a portfolio for optimal returns. We witness a heterogeneous behavior of different energy markets with other energy securities in a single portfolio. There is no consistent behavior for any one single security together with other securities in a portfolio. One security may yield optimal returns in one combination but may not be appropriate in terms of portfolio returns with another combination. Therefore, the possibility of returns exists but the selection of portfolio should be based on the dependence structure between different securities. Another implication arising from this work is the behavior of energy securities structured within different regions. We witness many securities offering diversification benefits with the energy securities in one region but no benefits in another region. Likewise, the presence of heterogeneous dependence structure among securities within a single region rules out the possibility of regional diversification benefits. These benefit though may exist for some energy assets but a careful examination of their underlying dependence behavior is important. Finally, the contagion phenomena seem quite obvious during the crises periods, i.e., GFC and the COVID-19 periods. However, few markets offer diversification opportunities under these financially and economically stressed periods. We recommend directions for future research by expanding the scope of this study to include other asset classes along with the green energy market, for example, green energy bonds, conventional equities, socially responsible stocks. In this way, more implications can be generated for diversification in portfolio comprising of different assets. Because of the difference in asset classes, such combinations can result in optimal performance of portfolios. Another avenue of research could be to examine the energy markets on the regional level as well. Such an analysis can add robustness to results of this paper which sampled individual energy markets within a certain region.
Appendix
Appendix Table 2
Table 2 Analysis-oriented attribute table
Authors Sampling Method
Ahmad et al. (2022) Stocks markets of BRICS Panel cointegration and panel regression
Akyildirim et al. (2022) Global energy equity indexes Spillover approach of Antonakakis et al. (2020)
Benlagha and Omari (2022) Gold, oil and five leading stock markets Gabauer's (2020) DCC-GARCH connectedness approach
Luo et al. (2022) Grey energy market to the natural gas market Connectedness framework of Antonakakis et al. (2020)
Narayan and Rehman (2021) Stock markets Asia, Central and Eastern Europe (CEE), Latin America, or the Middle East and North Africa (MENA) Panel cointegration tests and vector autoregressive error-correction (VECM) models
Abadie (2021) Spanish electricity and natural gas prices Stochastic model with deterministic and stochastic parts
Albulescu et al. (2020) Energy, agriculture, and metal commodity markets Copula-based local Kendall’s tau approach
Baruník and Křehlík (2018) 11 major financial firms representing the financial sector of the U.S. economy Barunik and Krehlik (2018) spillover approach
Algieri and Leccadito (2017) Energy, food, and metal commodity markets Delta conditional value-at-risk (ΔCoVaR) approach based on quantile regression
Author contribution
Mobeen Ur Rehman: idea generation, initial write up, and discussion of results. Naeem Abubakr: data curation, software, and formal analysis. Nasir Ahmad: initial write up and discussion. Xuan Vinh Vo: idea, supervision, and editing.
Funding
This research is partly funded by the University of Economics Ho Chi Minh City, Vietnam.
Availability of data and materials
Data will be made available for request.
Declarations
Ethical approval
The paper does not have any ethical concern and does not contain any primary data.
Consent to participate
The paper is based on secondary data and therefore does not involve participation of any respondent.
Consent to publish
The authors give ESPR a right to publish this paper.
Competing interests
There are no competing results to declare.
1 These statistics are sourced from https://www.iea.org/reports/world-energy-investment, https://www.bloomberg.com/energy
2 These sampling in this work comprises of oil, gas and electricity markets.
3 The sampling countries include China, India, Japan, Korea, Malaysia, Thailand, Australia, South Africa, France, Italy, Netherlands, Norway, Poland, Russia, Spain, UK, Turkey, USA, Canada, Argentina, and Brazil.
4 China, India, Japan, Korea, Malaysia, Thailand, Australia, South Africa, France, Italy, Netherlands, Norway, Poland, Russia, Spain, UK, Turkey, USA, Canada, Argentina, and Brazil.
5 See among others, Naeem et al. (2020) and Wang et al. (2019) etc.
Highlights
• We examine the presence of returns dependence across 51 energy markets.
• We apply normal and threshold dependence measures proposed by Diebold and Yilmaz (2012) and Baruník and Křehlík (2018).
• We highlight the presence of strong dependence between the energy markets at both regional level and across other regions.
• We witness substantial increase in dependence across all the energy markets during different crisis periods.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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J Bionic Eng
J Bionic Eng
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10.1007/s42235-022-00316-8
Research Article
Improved Dwarf Mongoose Optimization for Constrained Engineering Design Problems
Agushaka Jeffrey O. [email protected]
12
Ezugwu Absalom E. [email protected]
13
Olaide Oyelade N. [email protected]
1
Akinola Olatunji [email protected]
1
Zitar Raed Abu [email protected]
4
http://orcid.org/0000-0002-2203-4549
Abualigah Laith [email protected]
5678
1 grid.16463.36 0000 0001 0723 4123 School of Mathematics, Statistics, and Computer Science, University of KwaZulu-Natal, King Edward Avenue, Pietermaritzburg Campus, Pietermaritzburg, 3201 KwaZulu-Natal South Africa
2 grid.459488.c 0000 0004 1788 8560 Department of Computer Science, Federal University of Lafia, Lafia, 950101 Nigeria
3 grid.25881.36 0000 0000 9769 2525 Unit for Data Science and Computing, North-West University, 11 Hoffman Street, Potchefstroom, 2520 South Africa
4 grid.449223.a 0000 0004 1754 9534 Sorbonne Center of Artificial Intelligence, Sorbonne University-Abu Dhabi, 38044 Abu Dhabi, United Arab Emirates
5 grid.116345.4 0000000406441915 Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman, 19328 Jordan
6 grid.449114.d 0000 0004 0457 5303 Faculty of Information Technology, Middle East University, Amman, 11831 Jordan
7 grid.411423.1 0000 0004 0622 534X Faculty of Information Technology, Applied Science Private University, Amman, 11931 Jordan
8 grid.11875.3a 0000 0001 2294 3534 School of Computer Sciences, Universiti Sains Malaysia, 11800 Pulau Pinang, Malaysia
13 12 2022
133
25 9 2022
26 11 2022
29 11 2022
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This paper proposes a modified version of the Dwarf Mongoose Optimization Algorithm (IDMO) for constrained engineering design problems. This optimization technique modifies the base algorithm (DMO) in three simple but effective ways. First, the alpha selection in IDMO differs from the DMO, where evaluating the probability value of each fitness is just a computational overhead and contributes nothing to the quality of the alpha or other group members. The fittest dwarf mongoose is selected as the alpha, and a new operator ω is introduced, which controls the alpha movement, thereby enhancing the exploration ability and exploitability of the IDMO. Second, the scout group movements are modified by randomization to introduce diversity in the search process and explore unvisited areas. Finally, the babysitter's exchange criterium is modified such that once the criterium is met, the babysitters that are exchanged interact with the dwarf mongoose exchanging them to gain information about food sources and sleeping mounds, which could result in better-fitted mongooses instead of initializing them afresh as done in DMO, then the counter is reset to zero. The proposed IDMO was used to solve the classical and CEC 2020 benchmark functions and 12 continuous/discrete engineering optimization problems. The performance of the IDMO, using different performance metrics and statistical analysis, is compared with the DMO and eight other existing algorithms. In most cases, the results show that solutions achieved by the IDMO are better than those obtained by the existing algorithms.
Keywords
Improved dwarf mongoose
Nature-inspired algorithms
Constrained optimization
Unconstrained optimization
Engineering design problems
==== Body
pmcIntroduction
The drive to better each circumstance or situation in human life is high. Optimization tries to find the best solution amongst a pool of other solutions. As such, optimization occurs naturally in many human endeavors and is deeply rooted in science, businesses, ecology, and manufacturing [1]. Basically, optimization is accomplished using either the mathematical or metaheuristic approach. The mathematical methods suffer from being gradient-dependent, time or computationally complex, and problem-dependent [2]. On the other hand, the metaheuristic approach does not guarantee that a better or optimal solution will be found; however, a near-optimal solution will be found. The trade-off of speed with the quality of the solution and associated drawbacks of the mathematical approach could be attributed to the surge in the rate at which researchers are proposing nature-inspired algorithms. Also, some attribute this surge to the ease of mimicking nature’s way of solving problems [3].
Another reason for this surge is the emergence of new application areas in various optimization domains and their attendant technology. These emerging real-life application areas require optimization of various components like speed, profit, risk, efficiency, or cost, often nonlinear and complex, requiring a robust and efficient metaheuristic optimization technique. Though the metaheuristic methods do not guarantee that it would find the optimal solution, its stochastic nature ensures at least a near-optimal solution in the shortest possible time. Also, the “No Free Lunch Theorem (NFLT)” stipulates that no one algorithm can optimally solve all optimization problems. No matter how robust an algorithm is, it can only solve that problem or problems for which its robustness is established. Therefore, there is a need to develop new algorithms, hybridize two or more existing algorithms, or improve existing algorithms to solve emerging optimization problems.
Many aspects of natural problem-solving techniques have been used for developing metaheuristic algorithms. One of the first approaches that use nature as a source of inspiration is the Genetic Algorithm (GA), whose source of inspiration is natural selection in the theory of evolution [4]. Another popular approach is Particle Swarm Optimization (PSO) which is inspired by the intelligent way birds flock together [5]. They have been used to solve problems in domains such as the traveling salesman problem [6], optimal control [7], and many more. These algorithms have recorded significant success in their respective areas of applications. However, some authors have criticized the over-reliance on the metaphor-based paradigm by the nature-inspired metaheuristic algorithms [8–10].
Nature-inspired metaheuristic algorithms imitate some aspects of the problem-solving technique in nature. They are stochastic and gradient-independent, and their parameters can be tuned depending on the problem to be solved [2]. Each nature-inspired metaheuristic algorithm has its unique way of searching the problem space for the optimal solution. Its robustness and efficiency are measured by how effective the search mechanism is under different problem landscapes and parameter uncertainty. Other desired features of these algorithms include implementation simplicity, flexibility, and robustness. The research efforts on nature-inspired metaheuristic algorithms are enormous, and impossible to review all the contributions except in a review study [11]. However, some selected nature-inspired metaheuristic algorithms proposed between 2019 and 2022 are summarized in Table 1Table 1 Some nature-inspired metaheuristic algorithms with their source of inspiration (2019–2021)
Acronym Name References
BO Butterfly Optimization Algorithm [47]
SSA Squirrel Search Algorithm [48]
DHOA Deer Hunting Optimization Algorithm [49]
EPC Emperor Penguins Colony [50]
HHO Harris Hawks Optimization [51]
SOA Seagull Optimization Algorithm [52]
ASO Atom Search Optimization [53]
NRO Nuclear Reaction Optimization [54]
HGSO Henry Gas Solubility Optimization [55]
BWO Black Window Optimization [56]
ChOA Chimp Optimization Algorithm [57]
MPA Marine Predators Algorithm [58]
MRFO Manta Ray Foraging Optimization [59]
AVOA African Vultures Optimization Algorithm [60]
GTO Artificial Gorilla Troop Optimizer [61]
RFO Red Fox Optimization Algorithm [62]
CHIO Coronavirus Herd Immunity Optimization [63]
RCM Red Colobuses Monkey [64]
GOA Gazelle Optimization Algorithm [65]
RHSO Red Hyraxes Swarm Optimizer [66]
PDO Prairie Dog Optimization [67]
EOSA Ebola Optimization Search Algorithm [68]
PPO Predator–Prey Optimization [69]
Aside from developing new nature-inspired algorithms, developers have also hybridized existing metaheuristic algorithms. The bibliographic diversity of hybridized approaches is enormous; therefore, a few examples of this approach involving the DMO are mentioned in this study. The DMO was hybridized with a Multi-Hop Routing Scheme (DMOSC-MHRS) and applied to solve the clustering problem [12]. The binary variant of DMO, the BDMO, was hybridized with a local search algorithm simulated annealing to tackle feature selection challenges of varying dimensional problems (BDMSAO) [13]. Moreover, in [14], the study proposed a Binary Dwarf Mongoose Optimizer (BDMO) and was applied to solve the multiclass high-dimensional feature selection problem. The success history-based adaptive differential evolution (SHADE) was hybridized with a modified Whale Optimization Algorithm (WOA) such that the two algorithms work stand-alone and only share information about the best-found solution [15].
These inspirational sources can be categorized into swarm-based, evolutionary-based, human, and physics-based, as in [16], and some further categorized them as system-based and bio-based, as can be found in [13]. The swarm-based category, also known as Swarm Intelligent (SI), derives their inspirations from the behavior or social interaction of animals, fish, birds and so on. This group has attracted much attention in the past decades as more methods were developed based on this inspirational point. The evolutionary-based are nature-based that commence their process by random generation of solutions’ population. The human-based category is based on the activities that humans perform. For example, the teaching–learning process involving students and teachers was used to form a popular algorithm in this group. Similarly, the physics-based is inspired by physics laws in nature. For example, nuclear reaction, atom search, and others.
The authors in [17] proposed a novel self-adaptive beneficial factor-based improved SOS (SaISOS), which improved the Symbiosis Organism Search (SOS) algorithm. Also, a modified Whale Optimization Algorithm (WOA) was developed for prediction using COVID-19 chest X-ray pictures [18]. The Quasi-Oppositional Based Learning (QOBL) strategy and Symbiosis Organisms Search (SOS) were incorporated to form a Quasi-Oppositional Symbiosis Organisms Search (QOSOS) algorithms for solving unconstrained global optimization problems [19]. The mLBOA, a new BOA variant, was proposed to solve the IEEE CEC 2017 benchmark suite [20]. The ensemble of Butterfly Optimization Algorithm (BOA) and Symbiosis Organism Search (SOS) called (h-BOASOS) was used to optimize the weight and cost of the cantilever retaining wall [21]. The authors [22] proposed a modified WOA called m-SDWOA by combining the WOA with the modified Symbiotic Organisms Search (SOS).
The DMO, a recently developed swarm-based metaheuristic algorithm, has received some attention as researchers have improved, modified, or hybridized it to solve various optimization problems. Shortly after its development, the DMO was employed to modify long short-time memory (LSTM) in predicting the effect of AI2O3 content of nanoparticle on the thermal expansion’s coefficient in Cu-AI2O3 nanocomposites which uses the in situ chemical method in its preparation [23]. Alumni nitrate was used to prepare the nanocomposite, which was added to a copper nitrate solution. After which the AI2O3 and CuO in powdered form were obtained, and removal of the leftover liquid was done by thermal treatment for 1 h at 850° C. The study investigated the impact of AI2O3 content of the Cu-AI2O3 nanocomposite. The machine learning model proposed could predict the thermal expansion coefficient (TEC), which was evaluated using various temperature rates, achieving an accuracy of up to 99%, as reported by the researchers.
The DMO was also applied to the clustering problem in [12], where a novel DMO-secure-based clustering combined with a multi-hop scheme of routing (DMOSC-MHRS) was developed in the internet of drones arena. Moreover, in [14] the study proposed a binary dwarf mongoose optimizer (BDMO) and was applied to solve the multiclass high-dimensional feature selection problem. The proposed method used 18 high-dimensional feature selection datasets and was compared against 10 state-of-the-art feature selection techniques. The method produced higher validation accuracy on 15 of the 18 datasets utilized. Afterward, the BDMO was hybridized with a local search Algorithm Simulated Annealing (SA) known as BDMSAO [13] to tackle feature selection challenges of varying dimensional problems. The proposed hybrid method yielded the highest classification accuracy obtainable on 50% of the 18 datasets employed for validation. It was compared with other popular methods in the literature with promising results.
This algorithm has been gaining ground in other application areas. For example, in [47] work, a parameter estimation of an autoregressive exogenous (ARX) model was developed based on the DMO. In [24], a new method was developed that incorporated the Dwarf Mongoose Optimization Algorithm (DMOA), generalized normal distribution (GNF), and opposition-based learning strategy (OBL), which is abbreviated as GNDDMOA. The proposed method was evaluated using 8 data clustering and 23 test functions and was compared with other popular techniques. This proposed GNDDMOA yielded the best results when employed to solve data clustering applications. Finally, the DMO was modeled with machine learning-driven ransomware detection called DWOML-RWD [25]. The method was majorly proposed to recognize and classify ransomware. This study first carried out the pre-processing stage of feature selection with a Krill Herd Optimization (EKHO) using dynamic oppositional-based learning (QOBL).
The proposed optimization technique (IDMO) modifies the base algorithm (DMO) in three simple but effective ways. First, the alpha selection in IDMO differs from the DMO, where evaluating the probability value of each fitness is just a computational overhead and contributes nothing to the quality of the alpha or other group members. The fittest dwarf mongoose is selected as the alpha, and a new operator ω is introduced, which controls the alpha movement, thereby enhancing the exploration ability and exploitability of the IDMO. Second, the scout group movements are modified by randomization to introduce diversity in the search process and explore unvisited areas. Finally, the babysitter's exchange criterium is modified such that once the criterium is met, the babysitters that are exchanged interact with the dwarf mongoose exchanging them to gain information about food sources and sleeping mounds, which could result in better-fitted mongooses instead of initializing them afresh as done in DMO, then the counter is reset to zero. The proposed improved algorithm is used to solve benchmark test functions and twelve (12) different optimization problems in the engineering domain. The major contributions of this study can be summarized as follows:The alpha selection in IDMO differs from the DMO, where evaluating the probability value of each fitness is just a computational overhead and contributes nothing to the quality of the alpha or other group members. The fittest dwarf mongoose is selected as the alpha.
A new operator ω is introduced, which controls the alpha movement, thereby enhancing the exploration ability and exploitability of the IDMO.
The scout group movements are modified by randomization to introduce diversity in the search process and explore unvisited areas.
The babysitter's exchange criterium is modified such that once the criterium is met, the babysitters that are exchanged interact with the dwarf mongoose exchanging them to gain information about food sources and sleeping mounds, which could result in better-fitted mongooses instead of initializing them afresh as done in DMO, then the counter is reset to zero.
The rest of the paper is organized as follows: Sect. 2 presents the dwarf mongoose optimization algorithm (DMO). Section 3 presents the improved dwarf mongoose optimization algorithm (IDMO). The experimental setup, results, and detailed discussion are presented in Sect. 4. Finally, the conclusion and future work is presented in Sect. 5.
The Dwarf Mongoose Optimization Algorithm (DMO)
This section presents the base algorithm, namely the dwarf mongoose optimization (DM) algorithm. First, the nature-derived inspiration which motivated the design of the novel DMO is described to allow for the understanding of the conceptualization of the flow of the algorithm. This study justified and provided a linkage of the real-life activities or phenomena in the domain of consideration to further buttress the optimization process inherent among dwarf mongoose creatures. The second sub-section is focused on presenting a summary of the mathematical and procedural models of the DMO algorithm. Then the section is concluded by drawing up the gap in the existing implementation of DMO with respect to the natural phenomenon in the domain. This is aimed at providing a ground for a new variant.
Inspiration
The behavioral pattern of an organism is an embodiment of its natural disposition to the demand of survival and evolvement strategy. This strategy allows the organism to adapt to its environment, evolve into a bigger specie, develop a fitness mechanism to wade off predators, source food, and build a social system with related and non-related organisms. When the population of such an organism is considered, their combined behavioral pattern demonstrates a great system with natural phenomena typical of providing computational solution patterns. A careful understudy of the dwarf mongoose population revealed that an interesting and useful natural phenomenon is inherent in their existential strategy. One of the fundamental attributes of the dwarf mongoose, peculiar to the Helogale specie, is the ability to cohabit in groups—a natural disposition that reflects a complete optimization process.
A group of dwarf mongoose lives in a territory that is demarcated using anal secretion, a behavioral approach for wading off competing groups or predators, and for keeping group members within the territory size. The secretion is made on horizontal objects within the territory using secretion from anal or checks glands. The smell of the secretion, which may remain detectable between 20 and 25 days, serves two purposes: reassures group members of safety within the territory and puts predators to flight [26] [27]. Unlike other organisms, which expand their population size for the benefit of resource enrichment, the dwarf mongoose prefers to shrink its population size to allow for the sustainability of available resources for the group. This resource control strategy is one of the group survival strategies in addition to the anti-predation strategy. Whereas the former supports foraging and nutrition needs, the latter ensures that the group members are kept from an intruder's reach.
In fact, compared to secretion measure for wading off an enemy, the dwarf mongoose has an aggressive skull-crush attack, a bite aimed at their prey's eyes—an approach that allows for adaptation and disallows intruding dwarf mongoose from depleting their group resources. The prey hunted down serves as a food source, which any individual extensively and intensively searches for within the group to have a full meal. This food search has characterized the dwarf mongoose with a seminomadic lifestyle, allowing a group to forage for food intensively from the current location and extensively over a long distance. This foraging behavior promotes relocation of the group's territory, referred to as a mound, to allow for searching for a new mound where the groups pitch their territory and sleep. This sleeping mound is reported to change almost every night [28]. Meanwhile, while the group moves about during the foraging activity, cohesion of the entire group members is achieved using a peep vocalization to alert members of the presence of a predator or intruder [29].
The group of dwarf mongooses maintains a caste structure that delineates members into subgroups. These subgroups include the alpha (male and female), juvenile, scout, and babysitters. The task of vocalization associated with foraging activity is reserved for the alpha female. Meanwhile, even the call for the group members to move out of their mound for foraging activity, the direction of the journey, and the distance covered, are imitated through the vocalization of this same alpha female. Furthermore, the alpha female is the only member who can and should birth, rare, and raise young dwarf mongooses. An attempt by other female subgroup members will be fought harshly and considered an act of insubordination [30], which group members will aggressively fight and most likely lead to the offender's departure from the group or such young, birthed ones being killed. In fact, to prevent such an extreme reaction, the alpha female prevents the subordinate males from mating with subordinate females.
Meanwhile, babysitters are elected from among the subordinates to keep watch on the babies of the alpha females since such young ones are prevented from foraging with the group. However, their mothers may carry them during mound relocation. This carrying capacity of the young dwarf mongoose often limits the distance covered when relocating to another mound. This presents an advantage to the young ones since the dwarf mongooses attack all enemies as a closed group [31]. This attack on an enemy—which could also mean another group of dwarf mongoose—is led by the alpha male, and the alpha female comes in the rear, considering they might be carrying the young ones. The numerical strength of a group determines if it will win the fight. Unfortunately, while the group may win against a ground predator, they are known to be weak in dealing with predator launching from an aerial position. Group territoriality determines the optimization of group size, which optimizes an individual’s fitness and impacts the cost/benefit relationship in the group. Considering the rich foraging, anti-predation, and group territory sustenance strategy of the dwarf mongoose, the DMO algorithm was designed and implemented to solve real-life optimization problems. In the next subsection, we present the algorithmic and mathematical models of the DMO.
The DMO Model
Motivated by the natural phenomena of the dwarf mongoose, the design of the DMO [32] algorithm is discussed in the following paragraph. The authors model all subgroups identified with the dwarf mongoose population by incorporating the alpha (male and female), scouts, and babysitter subgroups. The adaptive nature of the animals in their environment concerning predation and foraging was also simulated and applied in the design phase. In Fig. 1, the complete optimization process of the dwarf mongoose is represented. First, the scouting group moves out to source food while those designated for babysitting are allowed to remain in the mound. It is assumed that the procedure for looking out for food, known as foraging, demonstrates the exploration phase of the optimization process. Moreover, since the location of a new food source allows for a group of dwarf mongoose to settle down in a mound, the DMO models that as the exploitation or intensification phase. Meanwhile, the algorithm also simulated the discovery of new mounds resulting from the exploration process. The figure also showed that the design for the exchange of babysitters among the scout group is provisioned.Fig. 1 The optimization procedures of the DMO
The representation of a group of dwarf mongooses, which also represents the entire population, is modeled using Eq. (1). Since the population of the dwarf mongoose is often composed of the alpha groups, juvenile group, and scout (including babysitters), we derive the alpha group from the population to allow for allocating the remaining individuals in the population for the other two subgroups. Meanwhile, considering the role of the alpha female (α) in the population, they applied Eq. (2) to compute this special subgroup of alphas. This is made possible by first evaluating the fitness fit of the entire group and as well an individual fitness to know what individuals are characterized and suitable for the alpha female (α).1 X=x1,1x1,2⋯x1,d-1x1,dx2,1x2,2⋯x2,d-1x2,d⋮⋮xi,j⋮⋮xn,1xn,2⋯xn,d-1xn,d,
2 α=fiti∑i=1nfiti.
Similarly, the scout groups, which represent the workforce of the dwarf mongoose population, are computed and extracted from the entire population. To achieve this, they developed Eq. (3) to represent this derivation process, allowing for the foraging activity and searching for new sleeping mounds simultaneously [31].3 Xi+1=Xi-CF∗phi∗rand∗[Xi-M→]ifφi+1>φiXi+CF∗phi∗rand∗[Xi-M→]else,
where rand is a random number between 0,1 and CF=1-iterMaxiter2iterMaxiter is the collective-volatile movement control parameter and M→=∑i=1nXi×smiXi determines the movement of the mongoose to the new sleeping mound, and φ=∑i=1nsmin.
The predatory and foraging activities within a mound of dwarf mongoose require that individuals move from one location to another. This will often require that an update mechanism be applied for computing each group member's position. They leverage the vocalization peep facility of the alpha female (α) in addition to a randomly generated variable phi, in the range of [−1,1] to compute the current position of an individual. Using Eq. (4), the position update model is described.4 Xi+1=Xi+phi∗peep.
Another important milestone characterized by predatory and foraging activities is the discovery of a new sleeping mound. This new mound is assumed to change during the iterative process of optimization. To model the discovery of the sleeping mound (sm), Eq. (5) is applied for computing this, and Eq. (6) allows for averaging φ the sleeping mound values.5 smi=fiti+1-fitimax{fiti+1,fiti}.
The procedure for the application of mathematical models described in this section is encoded in the following listing:Initialize all control parameters
The population of the dwarf mongoose is first generated
Subgrouping the entire population into alpha (male and female), scouts, and babysitters
Determine the available number of search agents by subtracting the babysitters from the entire population
Set the rate of exchange for babysitting tasks as L
While the termination condition is not satisfied, do the following:i. Compute the fitness of the mongoose population/group
ii. Activate and set the time counter
iii. Apply Eq. (2) to deduce the size of the alpha female
iv. Update the position of a potential food source using Eq. (4)
v. Iterate over each individual and compute the fitness of Xi
vi. Derive the sleeping mound for the population using Eq. (5)
vii. Determine the movement vector M→
viii. Exchange the babysitters
ix. Compute the scout group using Eq. (3)
x. Update the solution so far
Return the best solution
The procedure described above was translated into a pseudocode, and then implemented as the DMO algorithm. Although the DMO demonstrates some measure of novelty, a further study of the domain revealed that some important component of the optimization process derivable from the natural existence and co-existence among the dwarf mongoose presents an opportunity for advancing the algorithm. The inclusion of these phenomena is necessitated by enhancing performance and balancing the exploration and exploitation stages. The next section presents a detailed design and discussion of the improved dwarf mongoose optimization algorithm.
The pseudocode for the algorithm is given in algorithm listing 1.
The Improved Dwarf Mongoose Optimization Algorithm (IDMO) Model
The section presents the improved dwarf mongoose optimization algorithm (IDMO).
The IDMO Model
The IDMO is proposed to enhance the exploration and exploitation of the DMO. This limitation is evident in the solution returned by DMO for F9, F15, and F17, which shows how DMO could not find the optimal solution. This optimization technique modifies the base algorithm (DMO) in three simple but effective ways. First, the alpha selection in IDMO differs from the DMO, where evaluating the probability value of each fitness is just a computational overhead and contributes nothing to the quality of the alpha or other group members. The fittest dwarf mongoose is selected as the alpha, and a new operator ω is introduced, which controls the alpha movement, thereby enhancing the exploration ability and exploitability of the IDMO. Second, the scout group movements are modified by randomization to introduce diversity in the search process and explore unvisited areas. Finally, the babysitter's exchange criterium is modified such that once the criterium is met, the babysitters that are exchanged interact with the dwarf mongoose exchanging them to gain information about food sources and sleeping mounds, which could result in better-fitted mongooses instead of initializing them afresh as done in DMO, then the counter is reset to zero.
The proposed IDMO achieves optimization in three phases, as shown in Fig. 2. This model shows how the scouting activity is separated from the foraging, which is not the case in DMO, where the scouting and foraging are the same activity. The individual dwarf mongooses are the search agents as modeled as a n×d matrix shown in Eq. 6. At the exploration phase, the modified alpha (Eq. 8) leads the group to uncharted territories using steps modeled in Eq. 9. Equation 10 models a new operator ω, which controls the alpha movement, thereby enhancing the exploration ability and exploitability of the IDMO. As shown in Eq. 11, the scout group movements are modified by randomization to introduce diversity in the search process and explore unvisited areas. The exploitation is achieved after the babysitter exchange criterium is met and babysitters are exchanged, as shown in Eq. 12. This phase refines the obtained solution toward the optimal solution.Fig. 2 The model of the proposed IDMO
Population Initialization
The IDMO population is initialized stochastically as a matrix of candidate dwarf mongooses (X), as shown in Eq. (6). The population vector ranges between the upper bound (U) and lower bound (L) of the optimization problem6 X=x1,1x1,2⋯x1,d-1x1,dx2,1x2,2⋯x2,d-1x2,d⋮⋮xi,j⋮⋮xn,1xn,2⋯xn,d-1xn,d,
where n is the number of dwarf mongoose in a mound, xi,j denotes the position of the jth dimension of the ith population and each xi,j is defined in Eq. (7).7 xi,j=rand×U-L+L.
Alpha Group
The population size of this group is modeled by subtracting the number of babysitters from the total number of dwarf mongooses. The alpha female (α) leads this group, and the fittest dwarf mongoose is selected as the alpha female, as given in Eq. 8. The alpha selection in IDMO differs from the DMO, where evaluating the probability value of each fitness is just a computational overhead and contributes nothing to the quality of the alpha or other members.8 α=min(fit1,fit2,⋯,fitn).
The alpha female keeps the group together using vocalization modeled by peep.
The IDMO searches the problem space moving around as defined in Eq. 9. Initially defined as the fittest dwarf mongoose, it drags the other family members toward a potential food source. This scenario is a clear departure from the DMO, where only the alpha’s vocalization is used to influence the position of the other dwarf mongoose. In IDMO, the position of the alpha is used to set the position of the other mongoose and a new operator ω, defined in Eq. 10, which controls the alpha movement, thereby enhancing the exploration ability and exploitability of the IDMO9 Xi+1=α+phi∗rand∗(Xi-Xk),
10 ω=e-4∗(Citer/Maxiter)2,
where phi=peep2∗rand∗ω, Xi is the previous dwarf position, rand is a uniformly distributed random number [−1,1]. Xk is a randomly selected dwarf mongoose.
Scout Group
The responsibility of the scouts is to look for a suitable sleeping mound since the dwarf mongooses are known to be seminomadic, never returning to the previous sleeping mound. The IDMO models the scout group scouting for the next sleeping mound after foraging activities. The scouts’ fitness is considered a potential sleeping mound since the dwarf mongooses are known to stay around abundant food sources, and the fittest scout is considered the selected sleeping mound. The scouts are modeled as given in Eq. 11.11 Xi+1=α+phi∗rand∗(Xk-Xh)/2,
where rand is a random number between0,1, and Xk,Xh are randomly selected dwarf mongooses.
The Babysitters
The babysitter’s exchange criterium is given in Eq. 12. Once the criterium is met, the exchanged babysitters interact with the dwarf mongooses to gain information about food sources and the next sleeping mound, which could result in better-fitted mongooses instead of initializing them afresh as done in DMO, then the counter is reset to zero. This improvement is modeled in Eq. 13, where the dwarf mongooses to replace the babysitters are randomly selected, and their information is passed to the babysitters as shown. If L gets to zero, it is reset by multiplying it with the current iteration and CF.12 L=Roundup0.6∗n∗dim∗1Citer,L∗Citer∗CFwhenL<0
13 Xi+1=(Xj+rand∗α-(Xk+Xh)/2∗br,
where CF=1-CiterMaxiter2CiterMaxiter controls the collective-volitive movement of the dwarf mongooses, Xj,Xk,Xh are randomly selected dwarf mongooses to replace the babysitters, and br is the birthrate.
The computation complexity of the IDMO is significantly reduced because it simplifies the overhead of alpha selection. The intuitive and detailed process of IDMO is shown in Fig. 3. The optimization process starts when the dwarf mongooses forage, led by the alpha female. A select few are left behind, called the babysitters, to tend the nest. The search for abundant food sources simulates the exploration phase of the IDMO. At midday, the babysitters are exchanged so they can feed since the dwarf mongooses are not known to bring food for the young or others. When this change occurs, the return to already known food sources to enable the exchanged babysitters to feed quickly before new food sources or sleeping mounds are found. This scenario simulates the exploitation phase of the IDMO. The scouting for a sleeping mound at the end of the day further explores and exploits the search space. Like the DMO, the IDMO algorithm has only one specific parameter to be fine-tuned (the number of babysitters.Fig. 3 The flowchart of the proposed IDMO
Conceptual Advantage of the IDMO
The superiority of the proposed IDMO can be theoretically attributed to the fact that the IDMO processes are stochastic in all ramifications. Starting with the population generation and the updating steps of the alpha and scout groups. The selection of the babysitters and dwarf mongooses to exchange them is entirely stochastic, which improves these solutions using enhanced exploratory and exploitation. The IDMO has only one parameter that can be tuned, and its implementation is simple and flexible.
As listed in Algorithm 2, the following algorithm reflects the mathematical model and procedural listing for the IDMO model.
Results and Discussion
The proposed improvements of the IDMO were tested to establish performance using 31 benchmark functions (classical and CEC2020 benchmark functions [33, 34], twelve (12) engineering benchmark problems, and real-world feature selection problems. The results of IDMO for benchmark functions were compared with that of DMO and eight existing population-based metaheuristic algorithms, namely differential evolution (DE), arithmetic optimization algorithm (AOA), particle swarm optimization (PSO), constriction-coefficient-based (PSO) and GSA (CPSOGSA), salp swarm algorithm (SSA), grey wolf optimizer (GWO), biogeography-based optimization (BBO), sine cosine algorithm (SCA). All the algorithms and optimization problems considered were implemented using MATLAB R2020b, and Table 2 presents the different algorithm control parameters used for the experiments. The population size and the maximum number of iterations used for all algorithms are 50 and 1000, respectively. Windows 10 OS environment, Intel Core [email protected] GHz CPU, and 16G RAM were used to conduct the experiments. The results of 30 independent runs of each algorithm are collated using the “best, worst, average, and SD” performance indicators. Further statistical analysis was carried out using mean, standard deviation, and Friedman and Wilcoxon tests.Table 2 Algorithm control parameters
Algorithm References Name of the parameter Value of the parameter
AOA [70] α 5
μ 0.05
PSO [5] C1, C2 2
Wmax 0.9
Wmin 0.2
CPSOGSA [71] φ1,φ2 2.05
GWO [72] A [0,2]
r1f r2 [0,1]
SCA [73] a 2
SSA [74] c2, c3 [0,1]
BBO [75] nKeep 0.2
Pmutation 0.9
DE [76] Lower bound of scaling factor 0.2
Upper bound of scaling factor 0.8
PCR 0.8
Benchmark Test Function
The results of all the algorithms used in this study are presented in Table 3. The exploitation ability of the IDMO was tested using the unimodal, separable, and non-separable benchmark functions (F1-F9). Clearly, the IDMO, AOA, and GWO found the global minimum solution for F1 and F2. However, the DMO, CPSOGSA, PSO, DE, SSA, and SCA found near-optimal solutions, and the BBO could not find the optimal solution. All the algorithms failed to find the global minimum for F5 and showed promising results for F6-F9. In most cases, the IDMO outperformed the DMO and performed competitively with GWO. The result confirms the exploitative capability of IDMO.Table 3 Result of classical benchmark functions
Function Dim Global Value IDMO DMO AOA CPSOGSA PSO BBO DE SSA SCA GWO
F1 50 0 Best 0.00E + 00 2.00E−07 0.00E + 00 0.00E + 00 6.49E−05 1.07E + 01 2.36E−05 2.88E−08 3.83E−02 0.00E + 00
Worst 0.00E + 00 6.81E−07 0.00E + 00 1.00E + 04 4.52E−03 1.78E + 01 6.72E−05 5.86E−08 2.12E + 02 0.00E + 00
Average 0.00E + 00 3.87E−07 0.00E + 00 5.00E + 02 8.00E−04 1.38E + 01 3.89E−05 4.30E−08 4.52E + 01 0.00E + 00
SD 0.00E + 00 1.13E−07 0.00E + 00 2.24E + 03 1.15E−03 1.68E + 00 1.00E−05 7.40E−09 7.45E + 01 0.00E + 00
F2 50 0 Best 0.00E + 00 1.64E−04 0.00E + 00 1.41E-08 1.59E−03 1.36E + 00 4.43E−04 7.24E−02 9.04E−06 0.00E + 00
Worst 0.00E + 00 4.28E−04 0.00E + 00 7.31E + 01 3.59E + 01 1.81E + 00 8.23E−04 5.28E + 00 3.36E−02 0.00E + 00
Average 0.00E + 00 2.80E−04 0.00E + 00 5.87E + 00 2.00E + 00 1.57E + 00 5.88E−04 2.04E + 00 5.38E−03 0.00E + 00
SD 0.00E + 00 8.60E−05 0.00E + 00 1.60E + 01 7.99E + 00 1.15E−01 1.04E−04 1.33E + 00 7.76E−03 0.00E + 00
F3 50 0 Best 0.00E + 00 1.23E−01 0.00E + 00 5.46E + 03 2.17E + 03 8.61E + 02 7.18E + 04 4.84E + 02 9.10E + 03 0.00E + 00
Worst 6.95E + 00 8.64E−01 3.10E−01 2.33E + 04 5.45E + 03 1.63E + 03 1.07E + 05 7.73E + 03 5.56E + 04 3.45E−08
Average 3.55E−01 4.14E−01 5.15E−02 1.33E + 04 4.04E + 03 1.20E + 03 9.15E + 04 2.05E + 03 2.46E + 04 3.31E−09
SD 1.55E + 00 2.02E-01 7.07E−02 5.91E + 03 9.77E + 02 2.11E + 02 9.99E + 03 1.67E + 03 1.07E + 04 8.82E−09
F4 50 0 Best 0.00E + 00 8.53E−01 3.85E−02 3.83E + 01 7.20E + 00 1.77E + 00 1.94E + 01 7.62E + 00 3.50E + 01 0.00E + 00
Worst 1.06E−03 9.38E−01 7.60E−02 9.35E + 01 1.42E + 01 2.33E + 00 2.60E + 01 1.77E + 01 7.23E + 01 0.00E + 00
Average 5.32E−05 9.03E−01 4.92E−02 7.52E + 01 9.84E + 00 2.10E + 00 2.23E + 01 1.29E + 01 5.61E + 01 0.00E + 00
SD 2.38E−04 1.92E−02 9.13E−03 1.98E + 01 1.70E + 00 1.36E−01 2.19E + 00 2.33E + 00 8.88E + 00 0.00E + 00
F5 50 0 Best 4.36E + 01 1.08E + 00 4.77E + 01 4.46E + 01 4.64E + 01 2.44E + 02 7.59E + 01 4.55E + 01 3.99E + 02 4.59E + 01
Worst 4.59E + 01 6.12E + 00 4.89E + 01 3.05E + 02 2.07E + 02 1.37E + 03 2.76E + 02 8.13E + 02 1.26E + 06 4.84E + 01
Average 4.45E + 01 3.40E + 00 4.85E + 01 8.00E + 01 1.31E + 02 3.98E + 02 1.82E + 02 1.55E + 02 3.05E + 05 4.68E + 01
SD 5.60E−01 1.56E + 00 3.01E−01 7.06E + 01 3.95E + 01 2.44E + 02 7.13E + 01 2.23E + 02 4.11E + 05 6.95E−01
F6 50 0 Best 1.70E−02 2.17E−07 5.39E + 00 0.00E + 00 1.90E−05 1.03E + 01 1.50E−05 3.48E−08 8.35E + 00 7.11E−01
Worst 7.79E−01 6.96E−07 6.88E + 00 7.89E−01 4.33E−03 1.87E + 01 7.00E−05 6.35E−08 6.41E + 02 2.50E + 00
Average 4.76E−01 4.05E−07 6.23E + 00 4.81E−02 7.00E−04 1.26E + 01 3.89E−05 4.37E−08 7.24E + 01 1.51E + 00
SD 2.30E−01 1.47E−07 4.01E−01 1.76E−01 1.01E−03 1.93E + 00 1.36E−05 7.17E−09 1.43E + 02 4.46E−01
F7 50 0 Best 4.14E−04 3.43E−02 1.04E−06 8.22E−02 3.01E−02 5.71E−03 5.92E−02 5.10E−02 2.19E−02 1.32E−04
Worst 5.58E−03 8.82E−02 5.14E−05 2.10E−01 7.77E−02 1.42E−02 9.32E−02 2.70E−01 2.50E + 00 2.20E−03
Average 1.83E−03 5.76E−02 1.76E−05 1.31E−01 4.80E−02 9.38E−03 7.47E−02 1.76E−01 3.65E−01 7.48E−04
SD 1.48E−03 1.25E−02 1.42E−05 3.79E−02 1.36E−02 2.96E−03 1.02E−02 5.41E−02 5.58E−01 4.68E−04
F8 50 −20,949 Best −1.40E + 04 −6.60E + 03 −8.83E + 03 −1.40E + 04 −1.44E + 04 −1.42E + 04 −1.40E + 04 −1.46E + 04 −5.94E + 03 −1.12E + 04
Worst −1.02E + 04 −5.38E + 03 −7.19E + 03 −1.07E + 04 −1.12E + 04 −1.15E + 04 −1.27E + 04 −1.05E + 04 −4.80E + 03 −5.71E + 03
Average −1.16E + 04 −6.00E + 03 −7.93E + 03 −1.22E + 04 −1.27E + 04 −1.27E + 04 −1.33E + 04 −1.23E + 04 −5.27E + 03 −9.07E + 03
SD 1.06E + 03 3.30E + 02 5.25E + 02 7.85E + 02 7.06E + 02 6.93E + 02 3.75E + 02 1.07E + 03 3.40E + 02 1.19E + 03
F9 50 0 Best 0.00E + 00 8.28E−01 0.00E + 00 1.23E + 02 1.62E + 02 5.63E + 01 1.81E + 02 4.28E + 01 8.46E−01 0.00E + 00
Worst 1.87E + 01 1.13E + 00 0.00E + 00 3.15E + 02 2.96E + 02 1.16E + 02 2.24E + 02 1.41E + 02 2.07E + 02 1.02E + 01
Average 1.61E + 00 1.01E + 00 0.00E + 00 2.05E + 02 2.14E + 02 7.33E + 01 2.00E + 02 8.02E + 01 7.51E + 01 6.85E−01
SD 5.03E + 00 7.39E−02 0.00E + 00 4.96E + 01 3.64E + 01 1.69E + 01 1.01E + 01 2.43E + 01 6.17E + 01 2.38E + 00
F10 50 0 Best 0.00E + 00 4.32E−04 0.00E + 00 0.00E + 00 1.68E−03 9.22E−01 8.21E−04 1.27E + 00 8.37E−01 0.00E + 00
Worst 0.00E + 00 1.54E−03 0.00E + 00 1.91E + 01 1.47E + 00 1.49E + 00 1.74E−03 3.67E + 00 2.05E + 01 0.00E + 00
Average 0.00E + 00 7.31E−04 0.00E + 00 7.64E + 00 4.29E−01 1.18E + 00 1.34E−03 2.46E + 00 1.84E + 01 0.00E + 00
SD 0.00E + 00 2.56E−04 0.00E + 00 8.72E + 00 5.63E−01 1.18E−01 2.29E−04 6.08E−01 5.08E + 00 0.00E + 00
F11 50 0 Best 0.00E + 00 3.59E−06 9.76E−02 1.27E + 00 9.93E−05 1.08E + 00 2.35E−05 9.60E−07 1.50E−01 0.00E + 00
Worst 0.00E + 00 6.24E−03 7.64E−01 9.22E + 01 5.88E−02 1.17E + 00 2.93E−04 3.94E−02 3.47E + 00 1.88E−02
Average 0.00E + 00 8.27E−04 3.89E−01 2.17E + 01 1.06E−02 1.12E + 00 9.31E−05 7.31E−03 1.29E + 00 1.63E−03
SD 0.00E + 00 1.46E−03 1.79E−01 3.58E + 01 1.65E−02 2.21E−02 6.69E−05 9.82E−03 7.62E−01 5.08E−03
F12 50 0 Best 3.25E−05 1.03E + 00 5.01E−01 4.77E + 00 2.61E−06 1.36E−02 7.08E−06 3.07E + 00 2.21E + 00 2.29E−02
Worst 1.83E−02 4.44E + 00 6.59E−01 1.10E + 01 7.58E−01 2.87E−02 4.50E−05 1.35E + 01 6.61E + 06 8.12E−02
Average 7.47E−03 2.48E + 00 5.96E−01 7.54E + 00 1.44E−01 2.11E−02 2.12E−05 7.48E + 00 6.31E + 05 4.71E−02
SD 5.59E−03 1.04E + 00 3.35E−02 2.07E + 00 2.24E−01 4.27E−03 9.94E−06 2.25E + 00 1.54E + 06 1.70E−02
F13 50 0 Best 3.89E−03 6.80E−01 4.60E + 00 1.10E−02 4.25E−04 4.55E−01 3.83E−05 1.10E−02 7.71E + 00 1.03E + 00
Worst 5.78E−01 3.83E + 00 4.95E + 00 4.95E + 01 2.34E−01 7.56E−01 1.79E−04 7.93E + 01 5.49E + 07 2.19E + 00
Average 3.27E−01 1.50E + 00 4.82E + 00 2.31E + 01 5.43E-02 5.85E−01 1.04E−04 3.58E + 01 4.42E + 06 1.55E + 00
SD 1.51E−01 7.69E−01 1.04E−01 1.38E + 01 7.41E−02 7.84E−02 3.44E−05 2.67E + 01 1.23E + 07 2.98E−01
F14 2 1 Best 9.98E−01 4.00E−03 9.98E−01 9.98E−01 9.98E−01 9.98E−01 9.98E−01 9.98E−01 9.98E−01 9.98E−01
Worst 9.98E−01 1.94E−02 1.27E + 01 1.27E + 01 9.98E−01 1.55E + 01 9.98E−01 9.98E−01 1.00E + 00 1.27E + 01
Average 9.98E−01 7.61E−03 8.22E + 00 2.97E + 00 9.98E−01 4.58E + 00 9.98E−01 9.98E−01 9.98E−01 2.76E + 00
SD 5.09E−17 4.11E−03 4.68E + 00 2.90E + 00 0.00E + 00 3.68E + 00 0.00E + 00 1.53E−16 1.17E−03 3.51E + 00
F15 4 0.003 Best 3.07E−04 1.94E−06 3.86E−04 3.07E−04 3.07E−04 5.27E−04 4.37E−04 3.74E−04 3.96E−04 3.07E−04
Worst 3.07E−04 6.35E−04 8.00E−02 2.04E−02 2.04E−02 1.38E−03 7.63E−04 1.22E−03 1.35E−03 3.08E−04
Average 3.07E−04 3.61E−04 1.08E−02 4.62E−03 1.82E−03 6.64E−04 6.11E−04 7.26E−04 8.55E−04 3.07E−04
SD 2.76E−13 1.75E−04 1.84E−02 8.08E−03 4.39E−03 1.78E−04 1.01E−04 2.54E−04 3.46E−04 7.80E−09
F16 2 3 Best 3.00E + 00 4.86E−04 3.00E + 00 3.00E + 00 3.00E + 00 3.00E + 00 3.00E + 00 3.00E + 00 3.00E + 00 3.00E + 00
Worst 3.00E + 00 5.55E−02 3.00E + 01 3.00E + 00 3.00E + 00 3.00E + 01 3.00E + 00 3.00E + 00 3.00E + 00 3.00E + 00
Average 3.00E + 00 1.24E−02 4.35E + 00 3.00E + 00 3.00E + 00 4.35E + 00 3.00E + 00 3.00E + 00 3.00E + 00 3.00E + 00
SD 9.34E−16 1.41E−02 6.04E + 00 1.25E−15 2.70E−16 6.04E + 00 6.52E−16 6.18E−14 1.42E−05 3.45E−06
F17 3 −3.86 Best −3.86E + 00 −3.86E + 00 −3.86E + 00 −3.86E + 00 −3.86E + 00 −3.86E + 00 −3.86E + 00 −3.86E + 00 −3.86E + 00 −3.86E + 00
Worst −3.86E + 00 −3.86E + 00 −3.85E + 00 −3.86E + 00 −3.86E + 00 −3.86E + 00 −3.86E + 00 −3.86E + 00 −3.85E + 00 −3.85E + 00
Average −3.86E + 00 −3.86E + 00 −3.85E + 00 −3.86E + 00 −3.86E + 00 −3.86E + 00 -3.86E + 00 −3.86E + 00 −3.86E + 00 −3.86E + 00
SD 2.28E−15 2.28E−15 3.96E−03 2.05E−15 2.28E−15 1.86E−15 2.28E−15 1.11E−14 2.50E−03 2.83E−03
F18 6 −3.32 Best −3.32E + 00 −3.32E + 00 −3.23E + 00 −3.32E + 00 −3.32E + 00 −3.32E + 00 −3.32E + 00 −3.32E + 00 −3.20E + 00 −3.32E + 00
Worst −3.32E + 00 −3.32E + 00 −2.93E + 00 −3.20E + 00 −3.20E + 00 −3.20E + 00 −3.32E + 00 −3.20E + 00 −2.59E + 00 −3.08E + 00
Average −3.32E + 00 −3.32E + 00 −3.12E + 00 −3.22E + 00 −3.27E + 00 −3.28E + 00 −3.32E + 00 −3.23E + 00 −3.02E + 00 −3.26E + 00
SD 5.61E−12 4.89E−16 5.86E−02 4.36E−02 6.07E−02 5.82E−02 4.05E−05 4.90E−02 1.55E−01 7.27E−02
F19 4 −10.1532 Best −1.02E + 01 −1.02E + 01 −6.59E + 00 −1.02E + 01 −1.02E + 01 −1.02E + 01 −1.02E + 01 −1.02E + 01 −6.47E + 00 −1.02E + 01
Worst −1.02E + 01 -1.02E + 01 −2.77E + 00 −2.63E + 00 −2.63E + 00 −2.63E + 00 −1.02E + 01 −2.63E + 00 −4.97E−01 −5.06E + 00
Average −1.02E + 01 −1.02E + 01 −4.45E + 00 −5.89E + 00 −7.89E + 00 −7.14E + 00 -1.02E + 01 −8.90E + 00 −4.06E + 00 −9.90E + 00
SD 6.17E−15 1.03E−11 9.60E−01 3.36E + 00 3.25E + 00 3.50E + 00 2.21E−05 2.64E + 00 1.85E + 00 1.14E + 00
F20 4 −10.4028 Best −1.04E + 01 −1.04E + 01 −8.22E + 00 −1.04E + 01 −1.04E + 01 −1.04E + 01 −1.04E + 01 −1.04E + 01 −8.09E + 00 −1.04E + 01
Worst −1.04E + 01 −1.04E + 01 −2.79E + 00 −2.75E + 00 −2.77E + 00 −1.84E + 00 −1.04E + 01 −5.09E + 00 −9.07E−01 −1.04E + 01
Average −1.04E + 01 −1.04E + 01 −4.74E + 00 −8.44E + 00 −8.19E + 00 −5.87E + 00 −1.04E + 01 −9.87E + 00 −4.15E + 00 −1.04E + 01
SD 3.67E−15 3.42E−03 1.38E + 00 3.12E + 00 3.17E + 00 3.50E + 00 5.81E−05 1.63E + 00 2.28E + 00 1.61E−04
F21 4 −10.5363 Best −1.05E + 01 −1.05E + 01 −6.02E + 00 −1.05E + 01 −1.05E + 01 −1.05E + 01 −1.05E + 01 −1.05E + 01 −8.34E + 00 −1.05E + 01
Worst −1.05E + 01 −1.05E + 01 −2.17E + 00 −2.42E + 00 −2.42E + 00 −2.42E + 00 −1.05E + 01 −2.43E + 00 −9.47E−01 −1.05E + 01
Average −1.05E + 01 −1.05E + 01 −4.30E + 00 −8.06E + 00 −9.72E + 00 −7.16E + 00 −1.05E + 01 −8.56E + 00 −4.96E + 00 −1.05E + 01
SD 5.04E−15 1.06E−04 1.01E + 00 3.53E + 00 2.50E + 00 3.85E + 00 4.99E−13 3.18E + 00 1.66E + 00 1.65E−04
Mean rank 2.88 3.64 6.17 7.67 5.64 6.21 4.29 5.98 8.76 3.76
Rank 1 2 7 9 5 8 4 6 10 3
The study used the multimodal, separable, and non-separable benchmark functions (F10-F21) to test the exploration ability of the IDMO. The algorithms seem to perform relatively well, finding optimal or near-optimal solutions. The IDMO, however, returned the best solution for most of the functions and performed competitively for others. The null hypothesis of related-samples Friedman's test assumed that the distributions of IDMO, DMO, CPSOGSA, AOA, GWO, DE, BBO, SCA, SSA, and PSO are the same. The test results are summarized in Table 4; a p value of 0.000 is returned by the test, which is far less than the significant tolerance level of 0.05, so the hypothesis is rejected. The lowest mean rank is returned by the IDMO, as shown in Fig. 4, which means it ranked first for all the 21 benchmark functions.Table 4 Summary of Friedman’s test
Total N 21
Test statistic 75.228
Degree of freedom 9
Asymptotic Sig. (two-sided test) 0.000
Fig. 4 Mean ranking of the 10 algorithms used
The Wilcoxon Signed Ranks Test on classical benchmark test functions shown in Table 5 confirmed the superiority of the optimization capability of IDMO. The IDMO has higher R + values in 7 out of 9 cases, and the number of R − and ties combined is more for the remaining two cases. This outcome implies that IDMO significantly outperforms DMO, AOA, CPSOGSA, PSO, BBO, DE, SSA, SCA, and GWO for all of the classical benchmark test functions. Their respective p-values returned by Wilcoxon's test at tolerance level, α = 0.05, show a significant difference in the performance of the algorithms in 7 out of 9 cases, which means that IDMO significantly outperforms 7 out of 9 algorithms on all classical test functions.Table 5 Wilcoxon signed ranks test for classical benchmark functions
Algorithms N Mean rank Sum of ranks Z Asymp. Sig. (two-tailed)
DMO–IDMO Negative ranks 5 12.40 62.00 −0.686b 0.492
Positive ranks 12 7.58 91.00
Ties 4
Total 21
AOA–IDMO Negative ranks 3 5.67 17.00 −2.983b 0.003
Positive ranks 15 10.27 154.00
Ties 3
Total 21
CPSOGSA–IDMO Negative ranks 2 11.00 22.00 −2.938b .003
Positive ranks 17 9.88 168.00
Ties 2
Total 21
PSO–IDMO Negative ranks 3 11.00 33.00 −2.286b .022
Positive ranks 15 9.20 138.00
Ties 3
Total 21
BBO–IDMO Negative ranks 1 19.00 19.00 −3.211b .001
Positive ranks 19 10.05 191.00
Ties 1
Total 21
DE–IDMO Negative ranks 4 9.00 36.00 −1.036b .300
Positive ranks 10 6.90 69.00
Ties 7
Total 21
SSA–IDMO Negative ranks 2 11.50 23.00 −2.722b .006
Positive ranks 16 9.25 148.00
Ties 3
Total 21
SCA–IDMO Negative ranks 0 .00 .00 −3.920b < ,001
Positive ranks 20 10.50 210.00
Ties 1
Total 21
GWO–IDMO Negative ranks 4 5.00 20.00 −2.040b .041
Positive ranks 10 8.50 85.00
Ties 7
Total 21
bBased on negative ranks
Also, the IDMO returned smaller values for the standard deviation than the other exiting algorithms, which translates to IDMO being a more stable algorithm. The convergence rate comparison in Fig. 5 confirms this assertion and reveals that IDMO converges toward the best solution early in the iteration process. This convergence can be attributed to the alpha effectively pulling the other population members toward the optimal solution early in the iteration. In some cases (F2-F4), this effect is seen in the middle of the iteration. In the case of F8, IDMO converged toward the optimal solution late in the iteration process.Fig. 5 Convergence rate comparison for classical and CEC2020 benchmark functions
The CEC2020 Test Functions
The robustness and stability of the proposed IDMO were further tested using all the functions found in CEC 2020 benchmark test suite. The results of these tests are presented in Table 6. Clearly, the IDMO returned better solutions than other algorithms because it could find the global optimum for F22, F23, F25, F27, and F29. The IDMO performed competitively for the rest of the functions, returning solutions very close to optimal ones. The solutions returned by the AOA, GWO, and CPSOGSA are also competitive. Friedman’s test was used to carry out a non-parametric test on the results, as presented in Table 7. The IDMO also returned the lowest mean ranks of these comparisons, ranking first amongst all the algorithms compared, as shown in Fig. 6. The convergence rate comparison for the CEC 2020 is also shown in Fig. 5. The IDMO, closely followed by AOA, GWO, and CPSOGSA, provided the best convergence.Table 6 Results of CEC2020 test functions
Function Global Opt Value IDMO DMO AOA CPSOGSA PSO BBO DE SSA SCA GWO
F22 100 Best 100.07 409.33 1.31E + 09 103.32 107.58 101.45 326.91 18,406,000 2.06E + 08 4132.3
Worst 101.43 22,626 1.34E + 10 12,616 5618 9479.3 5794.6 12,320 1.38E + 09 4.81E + 08
Average 100.33 5538.9 5.06E + 09 4335.2 1676.6 2057.6 1992.1 2825.4 6.75E + 08 1.96E + 07
SD 0.27695 6041.8 2.40E + 09 3972 1566.3 2482.6 1501.2 2797.2 2.97E + 08 8.75E + 07
F23 1100 Best 1108.1 1499.5 1506.9 1347.8 1115.1 1250.5 1308.2 1482.1 1738.8 1116.8
Worst 1507 2439.7 2621.8 2859.8 1905.4 2390.9 1754.7 2526.7 2785.6 1876.5
Average 1242.2 2064.3 2018.7 2188.3 1466.3 1783.9 1552.7 1916.5 2301.3 1524.2
SD 97.941 206.86 310.98 358.44 187.56 263.22 111.6 300.71 250.68 210.7
F24 700 Best 713.47 724.85 766.97 729.55 712.76 714.08 716.08 733.85 762.11 717.17
Worst 727.11 744.13 828.09 821.18 732.39 729.92 727.08 751.65 796.07 746.98
Average 718.36 733.3 801 759.03 721.39 720.9 722.16 731.28 775.54 730.58
SD 3.2551 4.6801 15.2 23.211 4.9189 4.36 2.245 10.17 9.1564 10.56
F25 1900 Best 1900.6 1900.5 3854.5 1900.7 1900.5 1900.1 1900.8 1903 1909.1 1900.5
Worst 1901.8 1902.7 186,740 1936.5 1901.9 1904.6 1901.9 1903.6 2082.2 1903.5
Average 1901.3 1901.3 62,921 1902.8 1901.1 1901.7 1901.6 1901.7 1923.9 1901.9
SD 0.30019 0.56783 52,820 6.4186 0.37742 0.94168 0.28284 0.7055 30.854 0.79346
F26 1700 Best 1719.8 2689.5 34,413 2180.1 2261.1 2208 4677.1 2951.6 5195.9 3109.4
Worst 1814.9 9413.5 369,980 61,662 8108.7 121,810 98,655 17,343 69,371 352,510
Average 1759.8 4343.8 170,260 12,593 4208 25,290 27,794 5886.3 19,164 65,047
SD 21.325 1491.5 92,783 14,552 1651.5 33,507 19,248 3862.2 14,917 128,330
F27 1600 Best 1600.5 1600.6 1600.5 1600.5 1600.5 1600.5 1600.5 1600.7 1601 1600.5
Worst 1600.5 1601.1 1630.8 1660.7 1659 1619.3 1600.9 1603.1 1602.4 1622.2
Average 1600.5 1600.9 1615.2 1616.6 1612.9 1603.3 1600.7 1601.1 1601.5 1603.2
SD 0.00086963 0.12188 8.8082 22.669 11.984 5.9223 0.083246 0.49274 0.29381 5.9343
F28 2100 Best 2103.6 2360 2707.9 2527.5 2134.6 2125.9 2239.1 3520 3206.3 2533
Worst 2125.1 2968.9 57,694 23,244 4599.7 22,806 5027.4 19,475 26,612 17,583
Average 2109.2 2579.1 8043.3 8128.1 2701.9 8606.8 3169.1 6999.2 10,094 8628.2
SD 4.4189 134.97 9733.1 6196.7 537.8 7009.3 790.72 4990.2 5331.4 4655.6
F29 2200 Best 2200.1 2239.3 2417.6 2246.9 2200 2300.6 2274.2 2311.5 2273.1 2301.5
Worst 2303.2 2303.5 3346.4 3376.6 2304.8 2309.7 2301.6 2309.3 2424.6 2321.4
Average 2279.3 2287.8 2791.4 2336.5 2298.7 2302.6 2299.9 2296 2368.4 2307.9
SD 42.131 19.046 254.97 196.71 18.67 1.6989 4.9212 22.805 31.759 4.9224
F30 2400 Best 2416.3 2500 2688.9 2500 2500 2500 2560.5 2503.2 2534.2 2729.5
Worst 2736.9 2614.1 2975.6 2824.4 2764.2 2767.4 2753.8 2768.8 2801.5 2771
Average 2539.7 2522.1 2827.1 2758.7 2723.9 2715.7 2725.6 2747.5 2768.2 2748.3
SD 65.097 29.925 70.872 72.626 55.138 86.578 44.927 8.3183 55.568 12.484
F31 2500 Best 2601.8 2898 2950.8 2898.1 2600.1 2897.8 2899.9 2904.7 2923.3 2900.2
Worst 2898.1 2940.7 3445.1 3024.2 2948 2949.4 2947.5 2950.6 2971.2 2949.9
Average 2887.9 2903.9 3149.9 2940.4 2907.5 2932.1 2913.9 2925.7 2956.8 2934.3
SD 54.03 9.8305 106.65 37.844 62.419 22.393 13.589 23.926 14.119 17.203
Mean rank 1.25 3.75 9.2 7.70 3.20 5.35 4.30 4.95 8.50 5.80
Rank 1 3 10 8 2 6 4 5 9 7
Table 7 Summary of Friedman’s test
Total N 10
Test statistic 62.694
Degree of freedom 9
Asymptotic sig. (2−sided test) .000
Fig. 6 Mean ranking for CEC functions
A further Wilcoxon Signed Ranks Test for CEC 2020 test functions is presented in Table 8. A p value less than the 0.05 significance level indicates that the obtained results for IDMO significantly outperform the other algorithms considered in this study. Also, this assertion is further confirmed by the IDMO obtaining higher R + values than R − or ties in all the cases. The implication is that the IDMO significantly outperforms all the algorithms used in the comparison for all the CEC 2020 test functions. Thus, it can be concluded that the efficiency, searchability, and robustness of IDMO are better than the other state-of-the-art algorithms used in this study.Table 8 Wilcoxon signed ranks test for CEC 2020 test functions
Algorithm N Mean rank Sum of ranks Z Asymp. sig. (two-tailed)
DMO—IDMO Negative ranks 1 5.00 5.00 −2.073b 0.038
Positive ranks 8 5.00 40.00
Ties 1
Total 10
AOA—IDMO Negative ranks 0 0.00 0.00 −2.803b 0.005
Positive ranks 10 5.50 55.00
Ties 0
Total 10
CPSOGSA—IDMO Negative ranks 0 0.00 0.00 −2.803b 0.005
Positive ranks 10 5.50 55.00
Ties 0
Total 10
PSO—IDMO Negative ranks 1 1.00 1.00 −2.701b 0.007
Positive ranks 9 6.00 54.00
Ties 0
Total 10
BBO—IDMO Negative ranks 0 0.00 0.00 −2.803b 0.005
Positive ranks 10 5.50 55.00
Ties 0
Total 10
DE—IDMO Negative ranks 0 0.00 0.00 −2.803b 0.005
Positive ranks 10 5.50 55.00
Ties 0
Total 10
SSA—IDMO Negative ranks 0 0.00 0.00 −2.803b 0.005
Positive ranks 10 5.50 55.00
Ties 0
Total 10
SCA—IDMO Negative ranks 0 0.00 0.00 −2.803b 0.005
Positive ranks 10 5.50 55.00
Ties 0
Total 10
GWO—IDMO Negative ranks 0 0.00 0.00 −2.803b 0.005
Positive ranks 10 5.50 55.00
Ties 0
Total 10
bBased on negative ranks
Engineering Problems
This section presents the results of experiments conducted using the IDMO to optimize twelve (12) benchmark problems in different engineering domains. The population size and the maximum number of iterations used for IDMO, DMO, and AOA are 50 and 1000, respectively. The results for the remaining comparative algorithms are obtained from their respective literature. The number of function evaluations (FEs) is set at populationsize×maximumiterations. Windows 10 OS environment, Intel Core [email protected] GHz CPU, and 16G RAM were used to conduct the experiments. The results of 30 independent runs of each algorithm are collated using the “best, worst, average, and SD” performance indicators. Further statistical analysis was carried out using mean, standard deviation, and Friedman and Wilcoxon tests. The details about the 12 engineering problems can be found at the following:The welded beam design problem [35, 36]
The compression spring design problem (CSD) [37]
The pressure vessel design problem (PVD) [38]
The speed reducer design problem (SRD) [39]
The three-bar truss design problem (3-BTD) [40]
The gear train design problem (GTD) [41]
The cantilever beam design problem (CBD) [42]
The optimal design of I-shaped beam (IBD) [43]
The tubular column design (TCD) [44]
The piston lever design problem (PLD) [43]
The corrugated bulkhead design problem (Cbhd) [45]
The reinforced concrete beam design problem (RCB) [46]
Results of the Welded Beam Design Problem (WBD)
The results and statistical analysis of optimizing the WBD using IDMO and other existing results in the literature are presented in Table 9. The IDMO found the least minimum cost, and Fig. 7 shows that this value was found at the 400th iteration. This means the results were achieved within 20,000 function evaluations (FEs). The least minimum cost for IDMO was achieved within the desired combination of the four (4) problem design variables, as shown in Table 9. The IDMO also returned the minor standard deviation and average values, thereby confirming the stability and robustness of the IDMOin solving the WBD problem.Table 9 The comparative results of WBD
Algorithm h l t b Best Worst Average SD FEs
IDMO 0.200952683 3.353311664 9.036343673 0.20574711 1.6952 1.781 1.7192 0.021464 20,000
DMO [32] 0.205234326 3.26225324 9.037040824 0.205730354 1.6953 1.6991 1.6961 0.00097687 35,000
AOA [70] 0.247498553 2.536812819 10 0.250284392 1.831 2.928 2.3579 0.27284 40,000
BBO [77] 0.185486 4.3129 8.439903 0.235902 1.918055 3.606933 2.630412 4.11E—01 50,000
PSO [77] 0.219292 3.430416 8.433559 0.236204 1.85272 3.841845 2.613785 4.71E—01 50,000
ICA [77] 0.205799 3.469634 9.03495 0.205806 1.725135 2.237755 1.79433 1.10E—01 50,000
WCA [78] 0.205728 3.470522 9.03662 0.205729 1.724856 1.744697 1.726427 4.29E—03 46,500
ABC [79] 0.20573 3.470489 9.036624 0.20573 1.724852 NA 1.741913 3.10E—02 30,000
EO [80] 0.2057 3.4705 9.0366 0.2057 1.724853 1.736725 1.726482 3.26E—03 15,000
TEO [81] 0.205681 3.472305 9.035133 0.205796 1.725284 1.931161 1.76804 5.82E—02 NA
SSA [74] 0.2057 3.4714 9.0366 0.2057 2.246638 1.725886 1.823426 1.28E—01 50,000
WSA [77] 0.20573 3.470489 9.036624 0.20573 1.724852 1.725068 1.724908 4.15E—05 50,000
GWO [77] 0.205677 3.470894 9.038558 0.205739 1.728487 1.725232 1.72631 7.71E—04 50,000
SHO [82] 0.205563 3.474846 9.035799 0.205811 1.725661 1.726064 1.725828 2.87E—04 NA
WOA [83] 0.205396 3.484293 9.037426 0.206276 1.730499 NA 1.732 0.0226 9900
SNS [84] 0.2057296 3.4704887 9.0366239 0.2057296 1.724852 1.725051 1.72488 5.18E—05 9000
Fig. 7 Convergence rate graph for WBD
Results of the Compression Spring Design Problem (CSD)
The results of optimizing the CSD with IDMO and other existing results are presented in Table 10. The IDMO failed to return the least cost of the objective function. However, its result is better than that of the DMO and AOA. The IDMO needed 20 iterations, corresponding to 1,000 FEs, as shown in Fig. 8.Table 10 Summary of comparative results for CSD
Algorithm d D N Best Worst Mean SD NFEs
IDMO 0.13914 1.3 11.88923 3.6619 3.6923 3.6632 0.005662 1,000
DMO [32] 0.13915 1.3 11.89243 3.6619 3.6619 3.6619 1.57E−15 20,000
AOA [70] 0.148317 1.3 15 4.3133 6.585 6.0337 0.52677 50,000
CPSO [85] 0.051728 0.357644 11.244543 0.0126747 0.012924 0.01273 5.20E—05 200,000
HPSO [86] NA NA NA 0.0126652 0.0127191 0.0127072 1.58E—05 81,000
CDE [87] 0.051689 0.356718 11.288968 0.0126702 0.01279 0.012703 2.70E—05 204,800
PSO [77] 0.05169 0.356737 11.28885 0.012857 0.071802 0.019555 1.17E—02 20,000
QPSO [77] 0.0518 0.359 11.279 0.012669 0.018127 0.013854 1.34E—03 20,000
G−QPSO [77] NA NA NA 0.012666 0.015869 0.012996 6.28E—04 20,000
WCA [88] 0.05168 0.3565 11.3004 0.012665 0.012952 0.012746 8.06E—05 11,750
ABC [79] 0.051749 0.358179 11.203763 0.012665 NA 0.012709 1.28E—02 30,000
APSO [89] 0.052588 0.378343 10.138862 0.0127 0.014937 0.013297 6.85E—04 120,000
IAPSO [89] 0.051685 0.356629 11.294175 0.01266523 0.01782864 0.01367653 1.57E—03 20,000
WOA [83] 0.0512 0.3452 12.004 0.0126763 NA 0.0127 3.00E—04 4410
MCEO [90] 0.051994 0.364109 10.868421 0.01266051 0.01350901 0.0127196 3.79E—05 2000
EO [80] 0.051207 0.345215 12.004032 0.012666 0.013997 0.013017 3.91E—04 15,000
SNS [84] 0.051587 0.354268 11.434058 0.01266525 0.01276587 0.01268472 2.39E—05 9000
Fig. 8 Convergence rate graph for CSD
Result of the Pressure Vessel Design Problem (PVD)
Similarly, Table 11 presents the comparative results and statistical analysis of the IDMO and several other existing optimization algorithms. The IDMO returned the least cost of the design problem, achieved at the 20th iteration, equivalent to 1,000 FEs, as shown in Fig. 9. Similarly, the stability of the IDMO is confirmed by returning the least value of the average and standard deviation performance indicators.Table 11 Summary of the comparative results for PVD
Algorithm Ts Th R L Best Worst Average SD FEs
IDMO 0.5479 0.2469 43.4967 160.0482 4527.2 5106.1 4533.2 279.92 1000
DMO [32] 0.4611 0.2401 40.3196 200 4527.3 4527.3 4527.3 2.96E−11 5000
AOA [70] 0.3764 0.3945 40.6441 200 4739.3 6763.9 5592.3 549.35 45,000
SAP [91] 0.8125 0.4375 40.3239 200 6288.8 6308.2 6293.8 7.41E + 00 3000
HPSO [85] 0.8125 0.4375 42.0984 176.6366 6059.7 6288.7 6099.9 8.62E + 01 81,000
CDE [87] 0.8125 0.4375 42.0984 176.6376 6371.1 6059.7 6085.2 4.30E + 01 204,800
CPSO [85] 0.8125 0.4375 42.0913 176.7465 6061.1 6363.8 6147.1 8.65E + 01 200,000
PSO [92] 0.8125 0.4375 42.0984 176.6366 6693.7 14,076.3 8756.7 1.49E + 03 8000
QPSO [92] 0.8125 0.4375 42.0984 176.6374 6059.7 8017.3 6839.9 4.79E + 02 8000
G−QPSO [92] 0.8125 0.4375 42.0984 176.6372 6059.7 7544.5 6440.4 4.48E + 02 8000
ABC [79] 0.8125 0.4375 42.0985 176.6366 6059.7 NA 6245.3 2.05E + 02 30,000
CS [93] 0.8125 0.4375 42.0985 176.6366 6059.7 6495.4 6447.7 5.03E + 02 15,000
WOA [83] 0.8125 0.4375 42.0983 176.639 6059.7 NA 6068.05 6.57E + 01 6300
APSO [89] 0.8125 0.4375 42.0984 176.6374 6059.7 7544.5 6470.7 3.27E + 02 200,000
EO [80] 0.8125 0.4375 42.0985 176.6366 6059.7 7544.5 6668.1 5.66E + 02 15,000
CGO [94] 0.8125 0.4345 42.0892 176.7587 6247.7 6331 6251 1.07E + 01 100,000
SNS [84] 0.8125 0.4375 42.0985 176.6366 6059.7 6410.1 6097.1 9.28E + 01 6000
Fig. 9 Convergence rate graph for PVD
Results of the Speed Reducer Design Problem (SRD)
The best and statistical results of optimizing the SRD with IDMO compared with other existing methods are presented in Table 12. It can be seen that the IDMO returned the least cost of the objective function. The “average and standard deviation” values returned by the IDMO confirm its stability and robustness. The required number of function evaluations (FEs) for the IDMO algorithm is 500, which is equivalent to the 10th iteration, as shown in Fig. 10, which is much lower than that of other algorithms.Table 12 Summary of comparative results for SRD
Algorithm × 1 × 2 × 3 × 4 × 5 × 6 × 7 Best Worst Average SD FEs
IDMO 3.5 0.7 17 7.3 7.8 3.4 5.3 2993.7 3007.3 2998.2 3.2165 500
DMO [32] 3.5 0.7 17 7.3 7.7 3.4 5.3 2993.6 2993.6 2993.6 4.63E−13 10,000
AOA [32] 3.6 0.7 17 7.5 8.3 3.6 5.3 3059.2 3222.5 3119.1 32.434 40,000
CS [93] 3.5 0.7 17 7.6 7.8 3.3 5.3 3001 3009 3007.2 4.96E + 00 250,000
ABC [79] 3.5 0.7 17 7.3 7.8 3.4 5.3 2997.1 NA 2997.1 0.00E + 00 30,000
WCA [78] 3.5 0.7 17 7.3 7.7 3.4 5.3 2994.5 2994.5 2994.5 7.40E—03 15,150
APSO [89] 3.5 0.7 18 8.1 8.0 3.4 5.3 3187.6 4443.0 3822.6 3.66E + 02 30,000
SHO [82] 3.5 0.7 17 7.3 7.8 3.4 5.3 2998.6 3003.9 2999.6 1.93E + 00 NA
SSA [74] 3.5 0.7 17 7.3 7.7 3.4 5.3 2996.0 3015.7 3005.6 4.63E + 00 NA
WOA [83] NA NA NA NA NA NA NA 2996.6 3233.6 3042.9 4.08E + 01 NA
CSS [93] NA NA NA NA NA NA NA 2996.5 3106.2 3005.7 4.86E + 00 NA
CGO [94] NA NA NA NA NA NA NA 2994.4 2995.5 2994.5 0.110282 100,000
FACSS [95] NA NA NA NA NA NA NA 2996.4 3006.4 2999.4 4.82E + 00 NA
SNS [84] 3.5 0.7 17 7.3 7.7 3.4 5.3 2994.5 2994.5 2994.5 7.00E—06 3750
Fig. 10 Convergence rate graph for SRD
Results of the Three-Bar Truss Design Problem (3-BTD)
The best results and statical analysis of optimizing the 3-BTD with IDMO and several other existing algorithms are presented in Table 13. The best objective value returned by the IDMO is the least and better than that of other algorithms. This was achieved within the 5th iteration (250 FEs), as shown in Fig. 11.Table 13 Summary of comparative results for 3−BTD
Algorithm × 1 × 2 Best Worst Average SD FEs
IDMO 0.219498 0.188424 106.93 106.93 106.93 4.85E−05 250
DMO [32] 0.219515 0.188373 106.93 106.93 106.93 3.01E−14 500
AOA [32] 0.224256 0.192452 106.93 107.16 106.97 0.045939 45,000
GA [77] 0.788915 0.407569 263.89589 264.82081 263.96804 1.66862E—01 50,000
PSO [77] 0.788669 0.408265 263.89584 264.5849 263.95741 1.36897E—01 50,000
ICA [77] 0.788625 0.408389 263.89585 263.91413 263.89933 4.11693E—03 50,000
CS [93] 0.78867 0.40902 263.97156 NA 264.0669 9.00000E—05 15,000
WCA [78] 0.788651 0.408316 263.89584 263.8962 263.8959 8.71000E—05 5250
GWO [77] 0.788648 0.408325 263.89601 263.90422 263.89796 1.61422E—03 50,000
WSA [77] 0.788683 0.408227 263.89584 263.89743 263.89607 3.11960E—04 50,000
CGO [94] NA NA 263.89584 263.89601 263.89585 2.51E—05 100,000
AOS [96] NA NA 263.89584 263.89585 263.89584 8.26E—09 100,000
SNS [84] 0.7886847 0.4082211 263.89584 263.89586 263.89585 3.31056E—06 4800
Fig. 11 Convergence rate graph for 3-BTD
Results of the Gear Train Design Problem (GTD)
The best results and statical analysis of optimizing the GTD with IDMO and several other existing algorithms are presented in Table 14. Though all the algorithms found the global optimum solution as the ‘best’ value, the IDMO returned the least value for the standard deviation and average values, indicating a more stable and robust optimization. Also, this was achieved within the minimum number of 5,000 function evaluations, as shown in Fig. 12.Table 14 Comparative result for GTD
Algorithm × 1 × 2 × 3 × 4 Best Worst Average SD FEs
IDMO 48 17 22 54 2.70E−12 2.36E−09 1.22E−09 6.16E−10 5,000
DMO [32] 49 19 16 43 2.70E−12 2.31E−11 8.81E−12 9.50E−12 20,000
AOA [32] 55 14 34 60 2.31E−11 2.73E−08 1.28E−08 1.14E−08 45,000
GA [77] 49 19 16 43 2.70E−12 1.5247E−08 1.6212E−09 3.2174E−09 50,000
PSO [77] 34 13 20 53 2.31E−11 1.0222E−06 7.9383E−08 1.8147E−07 50,000
ICA [77] 43 16 19 49 2.70E−12 2.3576E−09 8.0417E−10 7.7862E−10 50,000
CS [93] 43 16 19 49 2.70E−12 6.51E−09 9.6633E−10 6.4529E−10 50,000
ABC [79] 49 16 19 43 2.70E−12 1.3616E−09 1.6800E−10 4.5748E−09 50,000
MSFWA [97] 49 19 16 43 2.70E−12 1.36165E−09 1.68012E−10 7.2953E−08 50,000
SNS [84] 43 19 16 49 2.70E−12 1.36165E−09 1.68012E−10 3.74894E−10 25,000
Fig. 12 Convergence rate for GTD
Results of the Cantilever Beam Design Problem (CBD)
The best results and statical analysis of optimizing the CBD with IDMO and several other existing algorithms are presented in Table 15. It can be observed that the best solution for solving the CBD problem obtained is IDMO, which returned the optimal values for the five (5) design variables within the 80th iteration or 4000 FEs as shown in Fig. 13. Furthermore, the superiority and robustness of IDMO are shown by the least “average and standard deviation” values it returned.Table 15 Comparative result for CBD
Algorithm × 1 × 2 × 3 × 4 × 5 Best Worst Average SD FEs
IDMO 5.689588 5.020755 4.261692 3.312994 2.040863 1.3004 1.3005 1.3004 1.31E−05 4,000
DMO [32] 5.694297 5.025255 4.253986 3.314226 2.037547 1.3004 1.3004 1.3004 2.26E−16 15,000
AOA [32] 6.322849 4.41889 4.119345 7.754706 1.46564 1.3847 3.2824 1.9122 0.52199 45,000
SOS [98] 6.01878 5.30344 4.49587 3.49896 2.15564 1.33996 NA 1.33997 1.1E—5 15,000
CGO [94] 6.01513 5.3093 4.495 3.50142 2.15278 1.33997 1.340602 1.340052 1.23E—04 100,000
AOS [96] NA NA NA NA NA 1.339957 1.491711 1.351954 0.0249974 100,000
MGA [99] NA NA NA NA NA 1.3399756 1.3402011 1.3400526 6.99E—05 100,000
SNS [84] 6.01545 5.31066 4.488 3.50528 2.15428 1.3399576 1.3399576 1.3399576 1.1102E—15 12,000
Fig. 13 Convergence rate for CBD
Results of the Optimal Design of I-Shaped Beam (IBD)
The best results and statical analysis of optimizing the IBD with IDMO and several other existing algorithms are presented in Table 16. All the algorithms could find optimal solutions, and the least standard deviation was returned by the IDMO. This result confirms the IDMO's stability and superiority. Also, the results were achieved within the smallest possible function evaluations (150), as can be seen in Fig. 14.Table 16 Summary of comparative results for IBD
Algorithm × 1 × 2 × 3 × 4 Best Worst Average SD FEs
IDMO 80 50 0.9 2.321795 0.013074 0.013078 0.013075 8.8592E−07 150
DMO [32] 80 50 0.9 2.321793 0.013074 0.013074 0.013074 1.523E−13 2,500
AOA [32] 80 50 0.9 2.321547 0.013074 0.013161 0.013089 1.6536E−05 4,000
GWO [100] 80 50 0.9 2.3217 0.0131 NA NA NA NA
EMGO-FCR [100] 80 50 0.9 2.32 0.0131 NA NA NA NA
CS [93] 80 50 0.9 2.3216 0.0130747 0.01353646 0.0132165 0.0001345 5000
SOS [98] 80 50 0.9 2.3217 0.0130741 NA 0.0130884 4.0E−5 5000
AOS [96] NA NA NA NA 0.0130741 0.013814 0.0131788 1.555E−04 100,000
SNS [84] 80 50 0.9 2.3217 0.0130741 0.0130764 0.0130743 4.313E−07 3600
Fig. 14 Convergence rate for IBD
Results of the Tubular Column Design (TCD)
The TCD problem has been previously solved using various optimizers, and some of the best results obtained by these optimizers and IDMO are presented in Table 17. The number of function evaluations needed to obtain the results and statistical analysis of some optimizers is reported. It can be seen from Fig. 15 that the IDMO obtained this result in the 10th iteration or 500 FEs.Table 17 Summary of comparative results for TCD
Algorithm × 1 × 2 Best Worst Average SD FEs
IDMO 6.182678144 0.2 24.615 2.46E + 01 24.615 1.95E−06 500
DMO [32] 6.182683216 0.2 24.615 2.46E + 01 24.615 1.81E−14 4,000
AOA [32] 6.179782123 0.2 24.615 2.47E + 01 24.631 0.021115 25,000
ISA [101] 5.45115623 0.29196547 2.65E + 01 26.531 NA 3000
CS [93] 5.45139 0.29196 26.53217 26.53972 26.53504 1.93E—03 15,000
FA [102] NA NA 26.52 NA 28.74 2.08 3000
AOS [96] NA NA 26.531378 26.608314 26.531614 1.0300E—03 100,000
SNS [84] 5.45115623 0.29196547 26.486361 26.486371 26.486362 2.2160E—06 1250
Fig. 15 Convergence rate for TCD
The Piston Lever Design Problem (PLD)
The best results and statical analysis of optimizing the PLD with IDMO and several other existing algorithms are presented in Table 18. It can be seen that the results returned by the IDMO, DMO, and AOA are relatively small compared to those of CS, ISA, CGO, AOS, MGA, and SNS. Figure 16 shows that the result for IDMO was obtained at the 60th iteration or 3000 FEs.Table 18 Comparative result for PLD
Algorithm × 1 × 2 × 3 × 4 Best Worst Average SD FEs
IDMO 0.05 0.144897318 4.11572157 120 4.695 167.87 10.136 29.791 3000
DMO [32] 0.05 0.125073578 4.116042166 120 4.6949 4.7006 4.6987 0.0027386 5000
AOA [32] 500 500 2.578147082 120 7.532 488.42 320.17 115.54 35,000
PSO [103] 133.3 2.44 117.14 4.75 122 294 166 51.7 50,000
DE [103] 129.4 2.43 119.8 4.75 159 199 187 14.2 50,000
GA [103] 250 3.96 60.03 5.91 161 216 185 18.2 50,000
HPSO [103] 135.5 2.48 116.62 4.75 162 197 187 13.4 50,000
HPSO with Q-learning [103] NA NA NA NA 129 168 151 13.4 50,000
CS [93] 0.05 2.043 120 4.085 8.4271 168.592 40.2319 59.0552 50,000
ISA [101] NA NA NA NA 8.4 610.6 226.5 111.2 12,500
CGO [94] NA NA NA NA 8.41281381 167.472809 45.04866 67.24763 100,000
AOS [96] NA NA NA NA 8.41914274 167.664986 33.741276 93.46674724 100,000
MGA [ [99] NA NA NA NA 8.41340665 167.473213 32.468893 29.96370439 100,000
SNS [84] 0.05 2.042 120 4.083 8.41269835 167.472775 24.318974 47.71792646 5000
Fig. 16 Convergence rate for PLD
Results of the Corrugated Bulkhead Design Problem (CBHD)
The best results and statical analysis of optimizing the CBhD with IDMO and several other existing algorithms are presented in Table 19. The results showed the IDMO returned the least value for the objective function within the least possible function evaluations, as shown in Fig. 17.Table 19 Summary of comparative result for CBhD)
× 1 × 2 × 3 × 4 Best Worst Average SD FEs
IDMO 48.31 54.78 61.93 0.43 4.6972 1.548 4.6693 4.3569 2500
DMO [32] 48.14 5.45E + 01 62.04 0.43 4.8201 4.6699 4.5407 0.70271 20,000
AOA [32] 43.46 74.92 100 0.39 5.002 5.9617 5.031 0.99549 40,000
FA [102] 37.12 33.04 37.19 0.73 7.21 NA 10.23 1.95 12,000
LF−FA [102] 57.69 34.15 57.69 1.05 6.95 NA 8.83 1.26 12,000
LS−LF−FA [102] 57.69 34.13 57.55 1.05 6.86 NA 7.44 0.67 12,000
AD−IFA [102] NA NA NA NA 6.84 NA 7.21 0.58 12,000
AOS [96] NA NA NA NA 6.843 7.0669 7.0608 6.49E – 04 100,000
SNS [84] 57.69 34.15 57.69 1.05 6.843 6.8431 6.843 2.09E—05 3125
Fig. 17 Convergence rate for CBhD
Results of the Reinforced Concrete Beam Design Problem (RCB)
The best results and statical analysis of optimizing the IBD with IDMO and several other existing algorithms are presented in Table 20. It can be seen that values returned by the IDMO, DMO, and AOA are relatively small compared to FA, CS, AOS, and SNS. There is a significant improvement in the results available in the literature. It is important to note that this improvement was achieved within the least possible function evaluations (100) or 2nd iteration, as shown in Fig. 18.Table 20 Comparative result for RCB
Algorithm × 1 × 2 × 3 Best Worst Average SD Fes
IDMO 6.16 28 5 357.5 357.6 357.55 1.12E−06 100
DMO [32] 6 33 5 357.6 357.6 357.6 1.17E−13 150
AOA [32] 8.4 28 5 357.6 357.6 357.6 0 200
FA [104] 6.32 34 8.5 359.208 669.15 460.706 80.7387 25,000
CS [93] 6.32 34 8.5 359.208 NA NA NA 5000
AOS [96] 6.32 34 8.5 359.208 362.2535 359.3306872 0.596149 100,000
SNS [84] 6.32 34 8.5 359.208 362.634 359.3222001 0.6149858 1000
Fig. 18 Convergence rate for RCB
Summary of Results
This study proposes a modified version of the dwarf mongoose optimization algorithm (IDMO) for constrained engineering design problems. This optimization technique modifies the base algorithm (DMO) in three simple but effective ways. The proposed method solved 21 classical, 10 CEC2020, and 12 constrained benchmark engineering optimization problems at a relatively low computational cost. This section summarizes the obtained results.
The unimodal test functions provide a good tool to test the exploitation capabilities of IDMO. The results of these experiments show that IDMO effectively exploited the search regions and returned the optimal or near-optimal solution compared to the DMO and eight other algorithms. This scenario can be attributed to the newly introduced operator ω, which controls the alpha movement ensuring continuous neighborhood searching during exploitation and stops when the next phase is activated. Similarly, the results of IDMO on multimodal test functions, which are excellent tools for measuring the exploration ability of algorithms, were superior compared to the other algorithms used. Hence, it can be concluded that IDMO has very good exploration capabilities.
The IDMO demonstrated high optimization capabilities while solving the 12 engineering benchmark problems. It returned superior results for almost all the 12 engineering problems, as seen from the results. Also, the convergence analysis for the benchmark and engineering problems further confirms the superiority of the IDMO. As seen from the convergence figure, the IDMO found quality solutions early in the iteration process and converged steadily toward the optimal solution. Further statistical analysis of the obtained results using Friedman’s test showed that IDMO ranked first in the final ranking of all algorithms based on their general performance. A conclusion can be made that the proposed algorithm could perform real-world optimization tasks efficiently.
Conclusion and Future Work
This study proposes a modified version of the dwarf mongoose optimization algorithm (IDMO) for constrained engineering design problems. This optimization technique modifies the base algorithm (DMO) in three simple but effective ways. Firstly, the alpha selection in IDMO differs from the DMO, where evaluating the probability value of each fitness is just a computational overhead and contributes nothing to the quality of the alpha or other group members. The fittest dwarf mongoose is selected as the alpha, and a new operator ω is introduced, which controls the alpha movement, thereby enhancing the exploration ability and exploitability of the IDMO. Secondly, the scout group movements are modified by randomization to introduce diversity in the search process and explore unvisited areas. Finally, the babysitter's exchange criterium is modified such that once the criterium is met, the babysitters that are exchanged interact with the dwarf mongoose exchanging them to gain information about food sources and sleeping mound, which could result in better-fitted mongooses instead of initializing them afresh as done in DMO, then the counter is reset to zero.
The proposed method solved 21 classical, 10 CEC2020, and 12 constrained benchmark engineering optimization problems at a relatively low computational cost. The results and further statistical analysis showed that the IDMO is an effective tool for optimizing the selected optimization problems. A comparison with DMO and other state-of-the-art algorithms further solidifies the superiority of the IDMO. The IDMO achieved more balanced exploitation and exploration due to introducing a new operator ω, which controls the alpha movement. Also, the randomization of the scout group and babysitters' updating steps greatly influenced the performance of the IDMO.
While this study greatly improved the exploration and exploitation capabilities of the DMO, the overall effect or influence of the alpha female persists. Though the randomization of the updating steps prevents the IDMO from being trapped in local minima, the alpha size could still prevent effective exploitation. In the future, efforts could be made to address the issues mentioned above. Also, the capability of the IDMO could be tested on CEC 2011, CEC 2014, and CEC 2017 benchmark functions and other complex real-world optimization problems such as feature selection and classification using deep learning models.
Data availability statement
All data generated or analyzed during this study are included in this article.
Declarations
Conflict of interest
The authors declare that there is no conflict of interest with regard to the publication of this paper.
Publisher's Note
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| 0 | PMC9745293 | NO-CC CODE | 2022-12-15 00:02:24 | no | J Bionic Eng. 2022 Dec 13;:1-33 | utf-8 | J Bionic Eng | 2,022 | 10.1007/s42235-022-00316-8 | oa_other |
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Curr Oncol Rep
Curr Oncol Rep
Current Oncology Reports
1523-3790
1534-6269
Springer US New York
1342
10.1007/s11912-022-01342-9
Anesthesiology and Critical Care (JP Cata, Section Editor)
Influence of Perioperative Anesthesia on Cancer Recurrence: from Basic Science to Clinical Practice
Xia Sun-hui
Zhou Di
Ge Feng
Sun Minli
Chen Xiangyuan
Zhang Hao [email protected]
Miao Changhong [email protected]
grid.413087.9 0000 0004 1755 3939 Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
13 12 2022
119
2 8 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Purposeof Review
In this review, we will summarize the effects of these perioperative anesthetics and anesthetic interventions on the immune system and tumorigenesis as well as address the related clinical evidence on cancer-related mortality and recurrence.
Recent Findings
Cancer remains a leading cause of morbidity and mortality worldwide. For many solid tumors, surgery is one of the major therapies. Unfortunately, surgery promotes angiogenesis, shedding of circulating cancer cells, and suppresses immunity. Hence, the perioperative period has a close relationship with cancer metastases or recurrence. In the perioperative period, patients require multiple anesthetic management including anesthetics, anesthetic techniques, and body temperature control. Preclinical and retrospective studies have found that these anesthetic agents and interventions have complex effects on cancer outcomes. Therefore, well-planned, prospective, randomized controlled trials are required to explore the effects of different anesthetics and techniques on long-term outcomes after cancer surgery.
Summary
Due to the conflicting effects of anesthetic management on cancer recurrence, further preclinical and clinical trials are required and beneficial to the development of systemic cancer therapies.
Keywords
Surgery
Anesthesia
Perioperative period
Cancer recurrence
Immune system
http://dx.doi.org/10.13039/100007452 Wu Jieping Medical Foundation 320.6750.2020-21-19 Miao Changhong the Yangfan Plan of Shanghai Science and Technology Commission22YF1439600 Xia Sun-hui http://dx.doi.org/10.13039/501100010031 Postdoctoral Research Foundation of China China Postdoctoral Science Foundation Xia Sun-hui
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pmcIntroduction
Cancer is a major contributor to global morbidity and mortality despite advances in prevention, diagnosis, and treatment. According to the World Health Organization and the American Medical Association, cancer is becoming a major global health concern since it is the second leading cause of death after cardiovascular disease, resulting in 10 million deaths in 2020 [1], and the overall incidence of new cancer cases is almost 19.3 million worldwide [2]. Moreover, many patients experienced delayed diagnosis and treatment (including surgery) because of the unprecedented impacts of the COVID-19 pandemic on public health care systems. These delays may have a significant effect on cancer prognosis.
Despite advances in chemotherapy, radiotherapy, and immunotherapy, surgery (under anesthesia) is still an important component of modern cancer treatment that helps millions of people live healthier, more productive lives. However, the relationship between anesthesia and cancer recurrence remains a controversial issue because surgical stress and intraoperative anesthesia can impair the host immune system [3]. A number of theories explain how the surgical procedure may promote cancer recurrence after excision and the adverse impact of surgical stress on the body’s innate tumor defense mechanisms [4, 5] and the inadvertent seeding of tumor cells during the perioperative period [6, 7••, 8]. Anesthetics can also suppress the immune response by directly affecting cell-mediated immunity (CMI) or by activating the hypothalamic–pituitary–adrenal axis (HPA) and the sympathetic nervous system (SNS) [9]. The impairment of CMI may reactivate micrometastases that are already disseminated at the time of surgery [10], increasing the frequencies of cancer recurrence and distant metastasis. The stimulation of the HPA induces the release of neuroendocrine mediators, such as catecholamines, prostaglandin E2 (PGE2), cytokines, and cortisol, which in turn attenuate the activity of immune cells [11•]. Other neuroendocrine mediators, such as IL-6 and matrix metalloproteinases (MMPs), are also secreted and play critical roles in the regulation of tumor growth and angiogenesis [10].
The role of anesthesia in cancer recurrence has received considerable attention in recent decades, and there have been a number of retrospective studies and much preclinical research into this topic. An increasing number of preclinical findings suggest that general anesthetics have the potential to influence critical hallmarks of cancer that are involved in tumorigenesis and metastasis [12]. For example, intravenous anesthetics, such as propofol, and inhalational volatile anesthetics, such as sevoflurane, are two major classes of general anesthetics often utilized in clinical practice. Sevoflurane has been demonstrated to promote proliferation, migration, invasion, and angiogenesis in a variety of cancer cell types, whereas propofol may antagonize these same pathways [13–15]. Several retrospective studies have demonstrated an association between inhalational anesthesia and lower rates of recurrence-free survival in cancer patients who undergo elective surgery than in those who receive propofol-based anesthesia [16, 17]. Additionally, perioperative anesthetic management, including different anesthetic techniques and body temperature management, also has a close relationship with cancer prognosis [18•, 19••]. Based on current preclinical findings, every component of these procedures has a possible link to the development of immune dysfunctions that influence cancer metastasis and recurrence. However, only some small-scale retrospective studies have investigated the association between perioperative anesthetic management and cancer recurrence, which highlights the need for further prospective and randomized controlled trials (RCTs).
With the aim of optimizing the current clinical strategy and unraveling the controversial findings on exactly how surgery/anesthetics/anesthetic intervention-induced immunosuppression leads to an increase in cancer-related recurrence during the perioperative period, we provide a comprehensive review of the important role of the perioperative period in cancer treatment and the profound influence of anesthesia on cancer recurrence.
Effects of the Immune System on Cancer Recurrence
To understand the effects of surgery and anesthetics on cancer recurrence, the first step is to understand the basics of cancer biology. The microenvironment of tumors consists of cancer cells, different kinds of inflammatory cells, and inflammatory mediators. Both tumor and inflammatory cells secrete a complex array of chemical and protein signaling molecules that promote cancer development and metastasis in both an autocrine and paracrine manner. It should be emphasized that the immune cells that have been recruited may not have the typical protective response that leads to tumor cell eradication. The secretion of proinflammatory cytokines by these immune cells and the tumor itself may shift the balance in favor of tumor progression [20]. As a result, a tumor can be viewed as an organism that establishes its own complex physical and chemical connections with the host immune system. The majority of the molecular and cellular processes involved in this process remain to be fully elucidated.
Both the regression and development of cancer cells are influenced by the immune system. The innate and adaptive systems form the functional and effective immune system. Epithelial barriers, granulocytes, macrophages, natural killer (NK) cells, and dendritic cells make up the innate immune system, which is the first-line defense against invading organisms and tumor cells. The adaptive immune system serves to eliminate threats that have evaded the innate immune system. It comprises humoral immunity, antibody-mediated response, and CMI [21]. CMI, which is mediated by numerous kinds of T cells, is the principal defense against tumor cell invasion among these three components of immunity. Activated T cells are categorized by the cytokines that they secrete. The cytokines released by T-helper (Th) 1 cells promote inflammation, stimulate B cells, activate macrophages, and promote the development of cytotoxic T cells. IgE production and eosinophil are both stimulated by the cytokines that are secreted by Th2 cells [22]. Another important proinflammatory cytokine is IL-1, which is generated mostly by monocytes and macrophages. It is also a key regulator of inflammation and immune responses [23].
It has long been recognized that cancer can occur at sites of inflammation and injury caused by surgery, and it is known that inflammatory cells and mediators play a key role in cancer recurrence. Inflammatory cells, including leukocytes (neutrophils, monocytes, eosinophils, and basophils) and lymphocytes (T cells, B cells, and NK cells), are present early in the neoplastic process and play an important role in the tumor microenvironment by secreting an array of cytokines and chemokines, including IL-6, TNF-α, IL-1β, and PGE2. During the “elimination phase,” when a cancer-free state should be achieved, they are the essential players in recognizing and eliminating cancer cells [24••]. If tumor cells survive after the “elimination phase,” they may enter an “equilibrium” state, in which the host’s adaptive immune response keeps them dormant and prevents further tumor progression. In the final stage, called the “escape phase,” tumor cells exhibit apparent clinical growth as they evade the control of the host’s immunity and its capacity to create an immunosuppressive state by producing various cytokines, such as vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β) [25]. Moreover, DNA damage and somatic mutations may lead to cancer formation, which is a process that has been termed “initiation”; this process can persist in cells indefinitely until a second injury or “trigger” occurs. Inflammation, injury, irritants, or a host of other exposures may all act as “triggers.” This kind of “trigger”-related process results in the recruitment of inflammatory cells and finally constitutes a positive feedback loop, which leads to decreased cellular proliferation [26•].
The Perioperative Period as a Critical Window for Cancer Recurrence
The perioperative period is divided into three phases: the preoperative period (a few preoperative hours), the intraoperative period, and the postoperative period (several days after surgery). During the intraoperative period, general anesthesia consists of the administration of intravenous anesthetics (e.g., thiopental or propofol) for induction, followed by muscle relaxants and endotracheal intubation, then volatile anesthetics (e.g., sevoflurane) and opioids, which are applied for maintenance and pain control. The perioperative period triggers significant physiologic disruptions because it is a time of maximum vulnerability for patients with cancer. In the setting of perioperative inflammation, immunosuppression, and increased concentrations of catecholamines and angiogenesis, the seeding of circulating cancer cells in distant organs, as well as the growth of dormant tumors and micrometastasis, can be facilitated [27].
Given the critical role of the perioperative period of surgery, it is necessary to clarify its impact on cancer recurrence. It was first hypothesized a century ago that surgery promotes local recurrence and the distant spread of cancer [28]. Several theories have been proposed to explain this phenomenon, the most notable of which involve minimal levels of residual disease, the dissemination of tumor cells at the time of surgery, and, possibly, a switch from tumor dormancy to proliferation [29, 30]. Recent studies have investigated the possible influence of the metabolic, neuroendocrine, inflammatory, and immunological changes that occur perioperatively and are connected to or induced by anesthesia. Indeed, there is some evidence that anesthetics and other perioperative factors have the potential to affect long-term outcomes after cancer surgery [31]. According to these findings, general anesthetics, except propofol, can impair various immune functions of macrophages, dendritic cells, T lymphocytes, and NK cells [32]. Additionally, although opioid analgesia is the foundation of cancer pain relief, it can also promote tumor growth by inhibiting immune function and increasing angiogenesis [33]. As a result, opioid-sparing analgesia may be used to maintain the normal function of NK cells and reduce the metastatic spread of cancer [34]. As regional anesthesia (RA)/analgesia can block both afferent neural transmissions from the central nervous system and the descending efferent signals, it may attenuate surgery-stimulated adverse effects by minimizing the neuroendocrine stress response induced by SNS activation. Furthermore, regional analgesia inhibits the release of endogenous opioids; thus, the occurrence of opioid-induced immune suppression may be reduced [35]. With the combination of regional and general anesthesia (GA)/analgesia, the amount of general anesthetics required can be significantly reduced, which is probably accompanied by reduced immunosuppression as well as lower requirements for the use of opioids for postoperative pain relief [3]. However, further RCTs are required to substantially verify this theory.
Mechanisms of Cancer Recurrence in the Perioperative Period
The mechanisms underlying postsurgical cancer recurrence are complicated and poorly understood. Following the intended curative surgical resection of a primary tumor, cancer may recur at several sites due to a variety of mechanisms [18•]. There are four possible mechanisms that can cause cancer recurrence. The first is local recurrence at the tumor resection site, which occurs due to the proliferation of residual cells. The second is lymph node metastasis caused by the release of tumor cells into the lymphatic system before or during the procedure. The third method involves the seeding of distant organs by circulating tumor cells (CTCs) released before or during the procedure. The last involves seeding within a body cavity (e.g., peritoneal spread) [36].
The risk that individual cancer cells will seed in tissue and that the cancer will progress to a clinically significant metastatic disease is partly influenced by intraoperative dissemination, potentially by anesthesia and other perioperative events [37]. To survive in the hostile circulatory system by avoiding detection and elimination by marginalized leukocytes, few CTCs exist in the “slow circulation points” of the pulmonary and hepatic capillaries so that a complex tissue microenvironment involving the interrelations of surrounding noncancerous stromal cells, immune system cells, extracellular matrix, chemokines, cytokines, and myriad other factors may be established [38, 39]. Once immune escape is accomplished, inflammatory mediators can boost the efficiency of local colonization by aiding in the destruction of the endothelial glycocalyx, combined with endothelial denudation resulting in the formation of a premetastatic niche [40]. This precursor state comprises clusters of bone marrow-derived cells that populate and precondition the extracellular environment, allowing subsequent CTC infiltration and colony expansion [41]. Hypoxic environments established at the surgical resection sites, as well as the activation of platelets that release chemokines that attract bone marrow-derived cells, may also aid in the development of the premetastatic niche [42]. These pathological changes can drive the process known as “epithelial-to-mesenchymal transition,” whereby epithelial cancer cells develop a mesenchymal phenotype facilitating cellular motility and thus triggering angiogenic and metastatic cascades [43]. Therefore, dissemination, immune escape, and angiogenesis form an entire pathological process that finally induces cancer recurrence. We will further discuss each process below.
Intraoperative Dissemination: a Trigger for Cancer Recurrence
The intraoperative dissemination of tumor cells can occur through the lymphatic, hematogenous, and/or transcoelomic (a route of tumor metastasis across a body cavity or organ surface including the pleural or peritoneal surfaces) routes. CTCs are detectable in the majority of patients with solid tumors [44], and an increased number of CTCs has been confirmed to be linked with a poor prognosis in patients with a variety of tumor types [45, 46]. In particular, it has been demonstrated that CTC numbers increase following surgery for breast [47], lung [48], and colorectal [49] cancers. Thus, although the evidence that high numbers of CTCs correlate with inferior patient outcomes across all tumor types is currently inconclusive [50], there are reasonable concerns that tumor cell release after surgery leads to metastatic colonization.
Even after the removal of the primary tumor, disseminated cancer cells may survive and retain the ability to invade via lymphatic vessels because of surgical disruption, which has been observed by real-time fluorescence imaging [51]. For example, the number of CTCs was detected to increase fourfold on average in the sentinel lymph nodes of a cohort of 414 patients following breast cancer surgery [52]. By analyzing mouse models and tissue samples from patients with pancreatic ductal adenocarcinoma, it was shown that dormant disseminated cancer cells that lacked a cell surface molecule that elicits T-cell-mediated attacks account for both quiescence and resistance to immune elimination since they are unable to relieve endoplasmic reticulum stress [53•]. Accordingly, the outgrowth of disseminated cells into macrometastases requires not only high levels of surgical stress but also the suppression of systemic immunity [53•]. Additionally, the dissemination of tumor cells can be induced directly by surgical procedures. For example, the use of laparoscopic ports can result in port-site recurrences that may cause intra-abdominal spread. This phenomenon has been reported following surgery for gastrointestinal [41], gynecological [54], urological [55], and thoracic [56] malignancies and, alarmingly, was reported to occur in more than 10% of patients following the resection of incidentally diagnosed gall bladder cancer [57].
Anesthetics used during surgery also have a potential role in promoting metastatic dissemination. In murine models of breast cancer, sevoflurane led to significantly more lung metastasis than propofol [58]. Interestingly, sevoflurane can increase IL-6 levels, which in turn leads to the activation of signal transducer and activator of transcription (STAT)-3 as well as the subsequent infiltration of myeloid cells into the lung [58]. According to this finding, anesthetics can promote cancer metastasis by altering the tumor microenvironment through cytokines [59].
Immune Escape: a Maladaptive Immune Response for Cancer Recurrence
A number of studies in both preclinical models and patient samples have converged on the theme that primary cancers and metastases apply a range of strategies to avoid detection and destruction by the immune system, and the majority of which are activated in the aftermath of surgery. Tissue damage is usually accompanied by localized inflammation, hypoxia, and acidosis, which can also influence infiltrating immune cells by promoting the activity of protumor M2-like macrophages and by suppressing antitumor immune responses [60] under the influence of inflammatory mediators, such as PGE2. PGE2 is a lipid mediator, and its action is mediated by PGE2 receptors (EP1-4). Both EP2 and EP4 are Gs-coupled receptors that signal through adenylate cyclase-dependent cAMP/PKA/CREB pathways [61]. The effects of PGE2 related to immunosuppression include the inhibition of neutrophil, NK, and T-cell mitogenesis [62]. Tumor cells can shed cell surface ligands to evade recognition by immune cells, including NK cells, with the consequent impairment of NK-cell-mediated cytolytic activity [63]. Such mechanisms reveal the temporary development of a tumor-promoting milieu surrounding the surgical wound or at sites of micrometastases that might increase the risk of recurrence [64, 65].
Following surgery, there is a protracted period of immunosuppression. This counterbalancing phenomenon, referred to as the resolution phase of inflammation, has evolved to contain the intensity of the acute inflammatory response but might also contribute to perioperative vulnerability to cancer recurrence. Accordingly, a compensatory anti-inflammatory response aroused by the surgical response can also lead to the dysregulation of CMI with subsequent immunosuppression [66]. Furthermore, prostaglandin signaling regulates lymphatic vessel dilatation and, therefore, may enable cancer metastasis [67]. This cytokine-mediated imbalance results in a shift toward the protumoral Th2 profile, which favors tumor growth by disrupting CMI [68].
The secretion of cortisol and catecholamines is also a major trigger caused by surgical stress and anesthetics [69]. The action of cortisol is to diffuse through the cellular membrane to bind the intracellular glucocorticoid receptor. This complex translocates into the cell nucleus, where it interacts with glucocorticoid-responsive elements to transcribe different factors, such as NF-κB, which enable cortisol to inhibit or promote the production of inflammatory cytokines directly [70]. β-adrenoreceptors have been found in breast, prostate, lung, esophageal, and liver cancer cells [71–75]. Once epinephrine or norepinephrine activates β-adrenergic signaling, the intracellular concentration of cyclic adenosine monophosphate (cAMP) is increased to directly modulate cancer cell growth, proliferation, invasiveness, angiogenesis, and metastasis [76]. One critical characteristic of cancer cells is the formation of invadopodia, which are used to degrade and facilitate migration through the extracellular matrix [77]. The activation of β-adrenoreceptors promotes an increase in the number of invadopodia, which correlates with enhanced tumor invasion in breast cancer models [78]. Hence, minimizing surgical stress and limiting subsequent immunosuppression might reduce patient vulnerability and hamper cancer metastasis after surgery.
Epithelial-to-Mesenchymal Transition: a Major Cellular Mechanism of Cancer Recurrence
It has been shown that metastatic cancer cells migrate individually both in vivo and in vitro [79]. In humans, it is believed that seeding requires the joint action of a cluster of tumor cells moving together [80], which involves epithelial-mesenchymal transition (EMT). EMT is the transdifferentiation process through which transformed epithelial cells obtain the capacity to invade, resist stress, and disseminate [81]. Specifically, cancer cell clusters can retain and require epithelial gene expression and can transition between distinct epithelial differentiation states to accomplish the proliferative versus migratory components of metastasis. The transition from one state to another is governed by several kinds of growth factors [82] and signaling pathways [83]. Spontaneous EMT in primary tumor cells shifts among different intermediate stages with different invasive, metastatic, and differentiation characteristics [84]. Tumor cells with a combination of epithelial and mesenchymal phenotypes are more effective in circulation and colonization at the secondary site, which favors the development of metastasis [84].
The initiation of the EMT process is considered responsive to specific environmental stimuli during cancer surgery [85]. Moreover, recent studies have implicated that using anesthetics can induce EMT and facilitate tumor metastasis during the perioperative period. Ischemia/reperfusion injury (IRI) often occurs during surgeries involving hepatocellular carcinoma (HCC) and liver transplantation [86, 87]. Hypoxia and inflammation can upregulate lipocalin2 (LCN2) levels to induce EMT in many cancers, which promotes tumor cell survival, proliferation, and metastasis [88, 89]. Latent EMT programs can be activated through the crosstalk that occurs between various immune cells that accumulate during the surgery and neighboring carcinoma cells. For example, CD8 + cytotoxic T cells are typically involved in the immunosurveillance and immunoediting of carcinomas. Moreover, pancreatic ductal epithelial cells lose the expression of E-cadherin following coculture with activated T cells in vitro, resulting in a spindle-shaped mesenchymal morphology accompanied by the expression of vimentin and ZEB1 [90]. In cancer patients, EMT programs are important for tissue regeneration and repair during wound healing after surgery. With the help of EMT, nonmotile epithelial cells are able to migrate across a wound site, proliferate, and then revert to the epithelial state to restore the integrity of the epithelial barrier as part of a process known as “re-epithelialization” [91, 92]. However, when the deregulated activity of EMT is induced by the overexpression of SLUG in human keratinocytes in vitro, it can cause the increased levels of desmosomal disruption and tumor spreading that are typically observed during local recurrence [93]. Regarding anesthetics, propofol was found to normalize EMT by inhibiting SLUG expression, resulting in an increase in the occurrence of apoptosis and a reduction in the growth and invasion of pancreatic cancer cells [94•].
The Perioperative Effects of Anesthetics on Cancer Recurrence
Inhalational Anesthetics
Volatile anesthetics are widely used during oncological surgery. Preclinical research suggests that volatile agents can promote cancer progression by direct and indirect mechanisms. First, volatile anesthetics can directly modify intracellular signals involved in key aspects of cancer cell behavior, including proliferation, invasion, migration, and sensitivity to chemotherapeutic agents. For example, isoflurane at 1.2% has been found to promote proliferation and migration while reducing levels of apoptosis in glioblastoma stem cells by promoting the overexpression of hypoxia-inducible factor (HIF) [95••, 96]. In non-small cell lung cancer, isoflurane (at 1%, 2%, and 3%) promoted proliferation in a concentration-dependent manner and invasion and invasiveness via Akt-mTOR signaling [97]. Desflurane at 10.3% induces EMT and metastasis through dysregulation of a well-known tumor suppressor called the miR-34/LOXL3 axis in a colorectal cancer cell line [98]. Using 2% sevoflurane for 6 h in vitro can increase the survival of breast cancer cells via modulation of intracellular Ca2 + homeostasis [99]. Second, sevoflurane can suppress CMI, which indirectly promotes tumor cell proliferation and angiogenesis. Sevoflurane, isoflurane, and desflurane induce the apoptosis of T lymphocytes and upregulate the expression of HIF-1α both in vitro and in vivo [100, 101]. It has also been shown that sevoflurane increases the levels of MMP-3 and MMP-9 in patients undergoing breast cancer surgery [102]. Third, inhalation anesthetics may cause distant metastasis by the activation of the HPA axis and the SNS by releasing neuroendocrine mediators, such as cortisol, catecholamines, and PGE2 [103].
In addition to these preclinical findings cited above, retrospective clinical studies have also widely discussed the effects of volatile and propofol-based anesthesia on cancer outcomes. Nevertheless, these studies have either shown that inhalational anesthetics are associated with an increased risk of cancer recurrence and the decreased overall survival (OS) or have shown no difference in different cancer outcomes between the two groups that were analyzed [16, 17, 104, 105•, 106, 107].
In summary, volatile anesthetics regulate important functions of cancer cells. The conflicting results of the pro and antitumoral effects on cancer cells might be explained by differences in experimental conditions, such as type of cell line, incubation time (range from 30 min to 6 h), type, and especially the concentration of volatile anesthetics (range between 0.5 and 10%). For instance, some studies treated cancer cells with extremely high concentrations that are unlikely to be employed in clinical practice, and perhaps, the “antitumortumoural” effect is related to the use of toxic concentrations of volatile anesthetics [108].
Intravenous Anesthetics
Similar to inhaled anesthetics, propofol is hypothesized to have both antitumor and tumor-promoting effects [109, 110]. Propofol inhibits the invasion and migration of breast tumors directly by altering the expression of MMPs, which are enzymes that play important roles in the degradation of extracellular proteins and EMT [111], by inhibiting the NF-κB pathway in vitro [112]. In another in vitro study, propofol inhibited the migration, but not the proliferation, of both ER-positive and ER-negative breast cancer cells mediated by decreasing the expression of neuroepithelial transforming gene-1, which is important for enhanced migration [113]. Tumor endothelial cells (TECs) [114], which are located in the inner surface of the blood vessels of the tumor stroma, have close associations with tumor progression in angiogenesis, metastasis, and colonization [115]. Propofol can reduce the expression of adhesion molecules (E-selectin, ICAM-1, and VCAM-1) and glycolysis proteins (GLUT1, HK2, and LDHA) in TECs, leading to an inhibitory effect on tumor metastasis [116]. It has also been found that aerobic glycolysis in colorectal cancer cells can be directly disrupted by propofol via inactivation of the NMDAR-CAMKII-ERK pathway [117]. The antitumoral effects of propofol on cancer progression also entail indirect mechanisms underlying immunosuppression, such as the potentiation of NK-cell cytotoxicity and reduced activation of the inflammatory response. For instance, in the peripheral blood of patients with colon cancer, propofol increased the expression levels of activated p30 and p44 in NK cells, which can promote the activation and proliferation of NK cells [118]. Additionally, in the peripheral blood of patients with esophageal squamous cell carcinoma, propofol enhanced the expression of cytotoxic effector molecules, such as granzyme B and IFN-γ, indicating enhanced NK cytotoxicity [119]. Regarding the cytokine profile, propofol downregulates the levels of proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α [120], and inhibits PGE2 and COX activity [121]. Surprisingly, propofol can decrease NET formation through the inhibition of p-ERK without disrupting neutrophil killing capacity [122, 123].
Regarding tumor-promoting effects, in vitro studies have shown that propofol significantly promotes apoptosis in breast cancer cells followed by the downregulation of miR-24 expression, upregulation of p27 expression, and cleaved caspase-3 expression [124]. The expression levels of pro-apoptotic proteins, such as Bax, Bak, and cytochrome C, are increased, followed by the activation of the caspase cascades via an intrinsic apoptotic signaling pathway induced by propofol [125]. In addition, HIF-1 activation and the activation of related downstream genes, such as VEGF, were suppressed by propofol in an in vitro study using macrophage cells. This process is expected to inhibit the systemic inflammatory response to surgery [126]. In particular, propofol has a causal link with breast cancer recurrence. Propofol can accelerate the migration of breast cancer cells in association with the activation of the GABAA receptor [127] and promote the proliferation of human breast cancer cells related to the inhibition of p53 and activation of nuclear factor E2-related factor-2 in vitro [128].
Consistent with these preclinical data, the findings of retrospective studies that are presented in Table 1 are contradictory. However, recently, an increasing number of retrospective studies have shown that improved survival associated with propofol anesthesia is more pronounced in gastric cancer surgery. Nevertheless, further large-scale, high-quality RCTs are warranted to confirm the relationship between different anesthetic choices and cancer outcomes. Recent basic and clinical evidence raises the possibility that total intravenous anesthesia with propofol is appropriate for use as the standard anesthetic agent for all cancer surgeries.Table 1 Summary of clinical studies comparing TIVA vs. inhalational anesthesia with respect to cancer outcomes
Ref Year Study type Cancer type Patients Outcomes
[214] 2022 Retrospective Oral n = 1347 No difference in RFS (HR 1.11, 95% CI 0.85–1.45, p = 0.439) or OS (HR 1.10, 95% CI 0.84–1.45, p = 0.527)
[215] 2021 Retrospective Gastric n = 2827 Increased OS (HR 0.65; 95% CI 0.46–0.94, p < 0.01) in TIVA group
[216] 2021 Retrospective Glioblastoma n = 50 Increased OS (HR 0.51; 95% CI 0.30–0.85, p = 0.011) and decreased recurrence (HR 0.60; 95% CI 0.37–0.98, p = 0.040) in TIVA group
[217] 2020 Retrospective Digestive n = 196,303 No difference in RFS (HR 0.99, 95% CI 0.96–1.03, p = 0.59) or OS (HR 1.02, 95% CI 0.98–1.07, p = 0.28)
[218] 2020 Retrospective Gastric n = 408 Increased OS (HR 0.56; 95% CI 0.41–0.78, p < 0.001) in TIVA group
[219] 2020 Retrospective Bladder n = 231 Increased RFS (HR 3.4; 95% CI 1.5–7.7, p < 0.01) in TIVA group
[220] 2020 Retrospective Pancreatic n = 68 Increased OS (HR 0.63; 95% CI 0.40–0.97, p = 0.037) and decreased recurrence (HR 0.55; 95% CI 0.34–0.90, p = 0.028) in TIVA group
[221] 2020 MA Breast, gastric, colon, liver, glioma, lung n = 23,489 Increased OS (HR 0.79; 95% CI 0.66–0.94, p = 0.008) in TIVA group. No difference in RFS (HR 0.81; 95% CI 0.61–1.07, p = 0.137)
[197••] 2019 RCT Breast n = 2108 No difference in cancer recurrence (HR 0.97, 95% CI 0.74–1.28; p = 0.84)
[222] 2019 Retrospective Appendiceal n = 373 No difference in RFS (HR 1.45, 95% CI 0.94–2.22, p = 0.093) or OS (HR 1.66, 95% CI 0.86–3.20, p = 0.128)
[223] 2019 Retrospective Cholangiocarcinoma n = 70 Increased OS (HR 0.51; 95% CI 0.28–0.94, p = 0.032) and decreased metastasis (HR 0.36; 95% CI 0.15–0.88, p = 0.025) in TIVA group. No difference in cancer recurrence (HR 1.17, 95% CI 0.46–2.93; p = 0.746)
[224] 2019 Retrospective Gastric n = 1538 No difference in RFS (HR 0.91, 95% CI 0.5–1.67, p = 0.764) or OS (HR 0.92, 95% CI 0.52–1.64, p = 0.774)
[225] 2019 Retrospective Breast n = 5331 No difference in RFS (HR 0.96; 95% CI 0.69–1.32, p = 0.782) or OS (HR 0.96, 95% CI 0.69–1.33, p = 0.805)
[226] 2019 Retrospective Liver n = 492 Increased OS (HR 0.47; 95% CI 0.38–0.59, p < 0.001) and decreased local recurrence (HR 0.31; 95% CI 0.26–0.37, p < 0.001) and distant metastasis (HR 0.13; 95% CI 0.08–0.20, p < 0.001) in TIVA group
[227] 2019 Retrospective Breast, gastric, colon, liver, lung n = 2496 No difference in OS (HR 1.26, 95% CI 0.88–1.79, p = 0.21)
[228] 2019 MA Breast, esophageal, lung n = 18,778 Increased OS (HR 0.76; 95% CI 0.63–0.92, p < 0.01) and RFS (HR 0.78; 95% CI 0.65–0.94, p < 0.01) in TIVA group
[229] 2018 RCT (not powered for RFS and OS) Breast n = 8 No difference in RFS and OS
[230] 2018 Retrospective Gastric n = 2856 Increased OS (HR 0.63; 95% CI 0.56–0.70, p < 0.001) in TIVA group
[105•] 2018 Retrospective Colorectal n = 1363 Increased OS (HR 0.27; 95% CI 0.22–0.35, p < 0.001) in TIVA group
[231] 2018 Retrospective Lung n = 943 No difference in RFS (HR 1.31, 95% CI 0.84–2.04, p = 0.233) or OS (HR 0.90, 95% CI 0.64–1.27, p = 0.551)
[17] 2017 Retrospective Esophageal n = 922 Increased OS (HR 1.58; 95% CI 1.24–2.01, p < 0.001) and RFS (HR 1.42; 95% CI 1.11–1.89, p = 0.006) in TIVA group
[232] 2017 Retrospective Glioblastoma n = 378 No difference in RFS (HR 1.07, 95% CI 0.85–1.37, p = 0.531) or OS (HR 1.13, 95% CI 0.86–1.48, p = 0.531)
[233] 2017 RCT (not powered for RFS and OS) Lung n = 120 No difference in RFS and OS
RCT, randomized controlled trial; TIVA, total intravenous anesthesia; OS, overall survival; RFS, recurrence-free survival; MA, meta-analysis; HR, hazard ratio
Opioids
Opioid analgesics, as the fundamental pain relief approach, are commonly used within the perioperative period to supplement general anesthetic agents in both the induction and maintenance of anesthesia. There is some conflicting evidence from experimental studies investigating the role of opioids in tumor growth and metastasis. Most animal studies have found that certain opioids cause immunosuppression and, in turn, increase tumor recurrence postoperatively. In particular, morphine has largely been shown to suppress NK-cell cytotoxicity and T-cell proliferation [129, 130]. Similarly, it has been shown that fentanyl suppresses the activity of NK cells and promotes the apoptosis of lymphocytes and macrophages [131, 132]. However, other studies resulted in contradictory findings and instead proposed the effects of morphine on resistance to tumor metastasis by the downregulation of the reciprocal proangiogenic interaction between macrophages and breast cancer cells [133, 134]. A recent retrospective cohort clinical study of 1679 patients with stage I–III colorectal cancer showed no association between fentanyl use and oncological recurrence [135]. Alternatively, tramadol has been shown to have immunostimulatory properties by enhancing NK-cell cytotoxicity [136].
The mu-opioid receptors (MORs) are the major subtype of opioid receptors. MORs have been shown to be overexpressed in certain cancers. Mathew and colleagues in their report supported the fact that MOR is linked with tumor metastasis and found that there was less growth progression of lung carcinoma in MOR knockout mice [137]. Morphine has been found to not stimulate tumor initiation; however, it was found to stimulate the growth of existing breast tumors via MOPs in an experimental study [138]. Furthermore, the investigators concluded that patients who were given propofol anesthesia had a higher level of NK-cell expression than patients given general anesthesia with opioid analgesia. Conclusively, this report implies that opioids may modulate immune function mediated by MORs in breast cancer tissue [139]. Previous clinical evidence shows that the expression of MOR is associated with tumor grade and prognosis. Prostate cancer tissue exhibits more intense expression of MOR during staining, and in turn, patients with higher expression have worse oncologic outcomes [140]. MOR is also expressed at low levels in patients with low-grade (G1, G2) or low-stage (T1, T2) hepatocellular carcinoma [141], which is consistent with the results of a long-term retrospective study [142•]. Therefore, it is reasonable that there are several retrospective and prospective studies showing that intraoperative administration of high-dose opioids, including morphine and sufentanil, significantly reduced the survival rate and the median survival length in prostate cancer patients [143–145].
Local Anesthetics (LAs)
Several theories regarding the possible mechanisms of the observed potential beneficial effects of the LA results are stated below. First, it is well known that using RAs and LAs can reduce the use of opioids or volatile anesthetics during the perioperative period [146], which indirectly prevents the possible negative effects of general anesthetics on cancer recurrence. Second, there is strong evidence that LAs and RAs are able to reduce perioperative inflammation and the stress response induced by surgery [147, 148] and preserve the function of NK cells as one of the most important factors for the detection and destruction of CTCs [149, 150]. This systemic effect of the LA has a possible positive impact on perioperative processes leading to antitumor micrometastases by reducing the levels of CTCs in peripheral circulation, thus allowing prolonged (at least recurrence-free) survival. Third, lidocaine, bupivacaine, and ropivacaine, as usually used in LA, have been found to reduce mesenchymal stem cell proliferation in vitro, and the activation of transcription pathways related to the initiation of neoplasia and metastasis was also found to be inhibited [151]. It has been shown that the cytotoxic effects of T-lymphoma cells can be regulated by LAs in vitro, which is correlated with their lipophilicity and potency [152]. Apoptosis was also observed at lower concentrations of LAs, while necrosis was seen at higher concentrations. LAs have also been reported to alter the DNA methylation status of certain cancer cell types in a time- and dose-dependent manner to eventually reactivate tumor suppressor genes [153].
Recently, a systematic review showed that LAs, including lidocaine, ropivacaine, and levobupivacaine, present promising and consistent results regarding the anticancer influence of LAs on breast cancer [154•]. Therefore, regardless of the LA applied to avoid the possible pro-tumor effects of surgical stress response and general anesthesia, they can also reduce cancer recurrence involving the prevention of cancer cell proliferation, migration, and invasion. The etiology of these effects is likely multifactorial. In vitro and in vivo studies have proposed numerous mechanisms centered on NaV1.5 channels [155], Ras homolog gene family member A [156, 157], the cell cycle [158], endothelial growth factor receptor [159], calcium influx [160, 161], microRNA and mitochondria, in combination with hyperthermia and transient receptor potential melastatin 7 channels [162, 163]. Lidocaine has a shorter half-life than other LAs and is less toxic. As a result, it is the only amide LA compatible with intravenous administration. Interestingly, some findings in laboratory conditions have raised the possibility that intravenous infusion of lidocaine may be a safe and inexpensive way to provide significant benefits in long-term cancer outcomes [164]. It can potentially affect multiple biological pathways to act as an anti-inflammatory agent, immune cell modulator, and/or direct inhibitor of cancer cells [164]. Based on the promising laboratory data, accumulating prospective and retrospective clinical trials also support the beneficial anticancer effects of perioperative lidocaine treatment. In a recent retrospective study of 2239 patients undergoing resection of pancreatic carcinomas conducted by Zhang et al., those who received perioperative i.v. lidocaine exhibited significantly better OS at 1 and 3 years, while disease-free survival was unaffected [165••].
Others
Although intravenous and inhalational anesthetics have profound effects on cancer outcomes, we cannot ignore the effects of some perioperative anesthetic adjuvants. Ketamine is an NMDA receptor antagonist widely used in cancer treatment during the perioperative period due to its strong analgesic effects at subanesthetic doses. Increasing numbers of findings indicate that ketamine can modulate immune function through three major mechanisms [166]. First, ketamine has anti-inflammatory effects mediated by the inhibition of the expression of proinflammatory cytokines, such as IL-6 and TNF-α, during the early postoperative period [167]. Second, similar to other analgesics, ketamine significantly interferes with NK-cell cytotoxicity, thus increasing the susceptibility to tumor metastasis [14]. Third, ketamine can disrupt the balance of different T-cell populations, which inhibits antitumor immune function and is associated with cancer recurrence and poor survival in a dose-dependent manner [168]. A retrospective study also showed that ketamine is not associated with improved oncological outcomes [169].
Given that nonsteroidal anti-inflammatory drugs (NSAIDs) have opioid-sparing properties, they are another important adjuvant frequently administered in the perioperative period for analgesia. As COX inhibitors, NSAIDs decrease the expression of both cyclooxygenase-1 (COX-1) and COX-2 enzymes. Therefore, the overexpression of COX-2 increases the amount of PGE2, which further upregulates the expression levels of immunosuppressive IL-10. Similar to other oncogenes, COX-2 is overexpressed in colorectal carcinomas and adenomas as well as mammary tumors and plays a carcinogenic role [170, 171]. Indeed, COX-2 inhibitors are actively used in breast cancer [172], and overexpression of COX-2 favors breast tumor growth and increases the risk of cancer relapse by stimulating epithelial cell proliferation, inhibiting apoptosis, stimulating angiogenesis, suppressing immunity, and increasing the production of mutagens [173]. Three clinical studies have indicated that the use of NSAIDs may decrease the risk of cancer recurrence and increase disease-free survival. In a retrospective study of 327 women, a lower cancer recurrence rate was shown when ketorolac was given before cancer surgery than when other opioid-based analgesics were used [169]. In a follow-up study of the same patient population, it was found that the use of ketorolac could extend disease-free survival in the first few years after surgery with nearly no occurrence of relapse within the early months [174]. In another retrospective study of 720 breast cancer patients from a single-center cohort, the intraoperative use of NSAIDs (ketorolac or diclofenac) was associated with improved disease-free survival and overall survival [175]. As a result, the favorable antitumor effects of NSAIDs suggest their broader application to cancer treatment.
Dexmedetomidine (DEX) is becoming widely used to attenuate the stress response and reduce opioid requirements. DEX is a highly selective α2 adrenoreceptor agonist and has multiple pharmacologic effects, including hypnosis, analgesia, sedation, and anxiolysis. α2 adrenergic receptors are expressed on both immune cells and tumors, which indicates that DEX may affect the balance of the immune system and tumorigenesis [176, 177]. According to a meta-analysis of patient studies by Wang et al., the intraoperative use of DEX infusion increases the numbers of NK cells, B cells, and CD4 + T cells and the ratios of CD4 + /CD8 + and Th1/Th2 cells, while the number of CD8 + T cells is significantly decreased [178]. These data indicated that DEX can protect the immune function of surgical patients. This indication corroborates a previous study, which showed that DEX did not significantly inhibit T-cell proliferation or IL-2 production [179]. A recent study also showed that perioperative DEX had no favorable impacts on NK-cell activity or inflammatory responses in uterine cancer surgery patients [180]. However, Levon et al. tested the effects of DEX on tumor growth and found that the size of breast, lung, and colon cancer was significantly larger in mice that received DEX [181, 182•, 183]. Consistent with the animal study, the study of 1404 patients by Cata et al. showed that intraoperative dexmedetomidine administration was associated with worsened overall survival after surgery for non-small cell lung cancer [184]. However, a randomized controlled study should be conducted to confirm the results of these studies.
Tramadol is an atypical opioid analgesic that has shown antitumor effects in breast cancer cells in vitro and in vivo [185•, 186]. The mechanism by which tramadol exerts these effects involves suppression of colony formation, cell cycle arrest, and the induction of apoptosis via extracellular signal-regulated kinases by decreasing 5-hydroxytryptamine 2B receptor and transient receptor potential vanilloid-1 expression, as demonstrated by in vitro experiments [185•]. In vivo, tramadol administration decreased the expression of inflammatory cytokines, such as IL-6 and TNF-α, which are involved in tumor growth and invasion [186]. Additionally, tramadol functions similarly to morphine but may produce the opposite effect and instead increase the activation of NK cells in patients undergoing surgical tumor resection [33, 187]. Furthermore, a retrospective analysis of 2588 patients showed that tramadol use was associated with decreased rates of breast cancer recurrence and improved survival after breast cancer surgery [185•].
The Effects of Anesthetic Techniques on Cancer Recurrence
Whether anesthetic techniques during potentially curative intraoperative periods influence cancer recurrence is a question that needs to be addressed to reveal the associations between different anesthetic managements and cancer outcomes. There are two major anesthetic approaches that may potentially affect cancer recurrence risk: (1) the use of RA, including neuraxial (epidural or spinal) and paravertebral blocks, and (2) the use of general anesthesia, including intravenous and inhalation anesthesia. Over the past decade, RA has been hypothesized to lower the surgical stress response and immunosuppression, reduce the need for volatile anesthesia, and minimize pain and opioid needs in the perioperative period, hence decreasing the activation of pro-tumor pathways and enhancing long-term oncological outcomes. Additionally, RA preserves the function of the immune system and has a direct inhibitory effect on cancer cells [188, 189]. For example, when comparing the use of regional techniques with the use of general anesthesia in cancer patients in RCTs, substantially lower levels of NK-cell and T-cell activity were observed in those who received both than in individuals who only received general anesthesia [190, 191]. As a result, several retrospective studies and meta-analyses have shown that the application of RA to supplement GA is closely associated with better OS than the use of GA plus opioid analgesia, at least during the treatment of certain types of cancer, such as breast, colon, lung, and prostate cancers [192–196].
In this review, we summarized over 5 years of clinical evidence regarding the effects of various RAs on cancer outcomes. This review is almost exclusively from retrospective studies (Table 2). Interpretation of retrospective analyses should be inherently cautious because of potential selection bias. According to this summary, retrospective findings are not enough to prove the positive effects of RA due to conflicting results, while all the RCTs have reached similar conclusions. Specifically, some RCTs investigating RA and cancer recurrence enrolled more than 2100 women with primary breast cancer. Patients were randomly assigned to receive either RA (preferentially paravertebral block) with propofol sedation or sevoflurane/opioid-based general anesthesia. It has been shown that there is no difference in disease-free survival or cancer recurrence [197••]. The effect of combined epidural-general was also investigated in a large multicenter RCT including patients (n = 1712) with major noncardiac thoracic or abdominal surgery. The median follow-up time was after 5 years, and the combined epidural-general anesthesia and general anesthesia group had similar rates of mortality, cancer-specific survival, and relapse-free survival (RFS) [198]. The most recent RCT included 400 patients who were undergoing video-assisted thoracoscopic lung cancer resection and compared the effects of the use of combination epidural-general anesthesia against the use of general anesthesia alone. The primary outcome was RFS. Secondary outcomes were OS and cancer-specific survival. The median follow-up time was 32 months. The results indicated that the use of epidural anesthesia during major lung surgery did not result in better RFS, cancer-specific survival, or OS than the use of general anesthesia alone [199]. Other RCTs focusing on the effects of RA on colon and prostate cancer surgery also failed to demonstrate any benefits in cancer outcomes [200, 201]. Given that these studies are appropriately powered and the results seem compelling, the influence of RA on cancer recurrence might be negligible or not existent. It can be speculated that RA probably fails to produce a robust immunomodulatory or anti-inflammatory effect or that the concentrations of LAs in micrometastatic niches are too low to produce significant antitumor effects [102, 202]. Although there is insufficient evidence to support the use of regional techniques at this time for their perceived benefit in terms of cancer recurrence, RA continues to play a fundamental role in the developing subspecialty of oncology anesthesia, which is focused on individualized, perioperative management in an attempt to minimize morbidity, accelerate recovery, and promote the progression to the next stage of oncological therapy.Table 2 Summary of clinical studies assessing the effects of different regional anesthetic techniques on cancer outcomes
Ref Year Study type Intervention Cancer type Patients Outcomes
[199] 2021 RCT Epidural Lung n = 400 No difference in RFS (HR 0.9, 95% CI 0.60–1.35, p = 0.61) or OS (HR 1.12, 95% CI 0.64–1.96, p = 0.70)
[234] 2021 RCT Epidural Thoracic, Abdominal n = 1802 No difference in RFS (HR 0.97, 95% CI 0.84–1.12, p = 0.69) or OS (HR 1.09, 95% CI 0.93–1.28, p = 0.29)
[197••] 2019 RCT PVB Breast n = 2132 No difference in cancer recurrence (HR 0.97, 95% CI 0.74–1.28, p = 0.84)
[235] 2019 Retrospective Epidural Colon n = 225 Decreased RFS (HR 0.73; 95% CI 0.54–0.99, p = 0.028) in epidural group
[236] 2018 Retrospective Epidural Colon n = 999 No difference in RFS (HR 1.06, 95% CI 0.87–1.29, p = 0.92) or OS (HR 0.9, 95% CI 0.68–1.20, p = 0.48)
[237] 2018 Retrospective Spinal Bladder n = 231 Increased cancer recurrence (HR 2.06, 95% CI 1.14–3.74, p = 0.017) in GA group. No difference in OS
[238] 2018 Retrospective Epidural Ovarian n = 648 Increased OS (HR 1.67; 95% CI 1.36–2.04, p < 0.001) and RFS (HR 1.33; 95% CI 1.11–1.59, p = 0.021) in epidural group
[239] 2018 Retrospective Scalp block Glioblastoma n = 808 No difference in RFS (HR 0.98, 95% CI 0.80–1.20, p = 0.89) or OS (HR 1.02, 95% CI 0.82–1.26, p = 0.85)
[240] 2017 RCT PVB Breast n = 180 No difference in metastasis (HR 0.79, 95% CI 0.21–2.96, p = 0.88) or OS (HR 0.66, 95% CI 0.11–3.97, p = 0.15)
[241] 2017 Retrospective Epidural Gastrectomy n = 4218 Improved OS in epidural group (HR 0.65, 95% CI 0.58–0.73, p < 0.001)
[242] 2017 Retrospective Spinal Bladder n = 876 Decreased cancer recurrence (HR 0.636, p < 0.001) in spinal group
[243] 2017 Retrospective PVB Lung n = 1729 Increased OS (HR 0.60; 95% CI 0.45–0.79, p = 0.002) in PVB group. No difference in RFS
[244] 2017 Retrospective Scalp block Glioblastoma n = 119 Increased RFS (HR 0.31; 95% CI 0.07–0.21, p < 0.001) in scalp block group
RCT, randomized controlled trial; PVB, paravertebral block; OS, overall survival; RFS, recurrence-free survival; HR, hazard ratio
The Effects of Perioperative Body Temperature on Cancer Recurrence
Body temperature is a sensitive indicator of whether the internal environment of the body is in a stable state. Body temperature acts as a critical regulator to influence the response to cancer. However, the mechanisms have only recently been investigated. Increasing in vitro and in vivo studies found that elevated temperatures can generally promote the activation, function, and delivery of immune cells, while reduced temperatures inhibit these processes [203]. In particular, adaptive immunity can be modulated by temperature, including antigen-presenting cells and CD4 + /CD8 + T cells [203]. Moreover, in patients undergoing open surgery for gastric cancer, Yi Yang et al. found that maintaining a body temperature close to normal could preserve immune functions [204]. Accordingly, the picture that is emerging is that temperature can have varying impacts on cancer outcomes. Given that perioperative systemic hypothermia is commonly encountered and even a few degrees of perioperative hypothermia can have immunosuppressive consequences, it is necessary to explore the association between hypothermia and cancer recurrence. In a rat model of colon cancer, tumor retention was found to be promoted by perioperative hypothermia [205], and severe hypothermia (3–7 °C decrease from the normal body temperature) markedly suppressed NK-cell activity and jeopardized host resistance to experimental mammary metastasis [206]. However, these results have not been replicated in human studies. In a reanalysis of data from a previous cohort of 852 patients, where intraoperative core body temperature was defined as a median intraoperative temperature of < 36 °C, consistent with the existing consensus definition [207], there was no significant increase in the incidence of cancer recurrence or death from metastasis following radical cystectomy. Yucel et al. also drew a similar conclusion [208•]. However, there are several conflicting findings that demonstrate the causal relationship between hypothermia and cancer prognosis. For example, intraoperative hypothermia may be a significant predictor of recurrence and survival in muscle-invasive bladder cancer [209] and rectal cancer [210].
According to a clinical study by Zheng et al. of stage III gastric cancer patients, a high postoperative body temperature could significantly reduce the 5-year disease-free survival [211]. Therefore, treating hyperthermia (also called thermal therapy or thermotherapy) is becoming one of the cancer treatment methods used to reduce cancer recurrence. Indeed, accumulating evidence indicates that physiological responses to high body temperature can enhance the microenvironment’s ability to resist tumors through temperature-sensitive checkpoints that regulate tumor vascular perfusion and metabolism [212]. In contrast to prior research, a recent in vitro study indicated that cancer cells can resist higher temperatures than normal cells by not activating caspase 3 [213]. As a result, the influence of thermal stimuli on the tumor environment and the antitumor immune response remain incompletely understood.
Conclusion and Future Perspectives
Recently, many of the retrospective clinical trials highlighted in this review have definitively demonstrated the profound impacts of perioperative events on cancer recurrence. For example, most retrospective trials have found that TIVA is a better anesthetic choice for cancer surgery according to the increased OS and RFS. However, several RCTs have shown that epidural and paravertebral nerve blocks are unable to modify cancer prognosis. For other anesthetic agents/techniques, there is still a critical lack of clinical evidence confirming the association with cancer recurrence during the perioperative period. The preclinical and clinical studies provided in this review exhibited conflicting findings on the effects of anesthesia on the immune response and cancer growth. Therefore, large-cohort prospective clinical trials are required to explore the effects of different anesthetics and techniques on long-term outcomes after cancer surgery. Furthermore, such trials will be beneficial to the development of systemic cancer therapies, which will enable us to optimize perioperative cancer treatment.
Author Contribution
All authors wrote, revised, and finalized the manuscripts for publication.
Funding
This research was supported by the Wu Jieping Medical Foundation (No. 320.6750.2020–21-19), the Yangfan Plan of Shanghai Science and Technology Commission (No. 22YF1439600), and the China Postdoctoral Science Foundation (No. 2022M710771).
Declarations
Conflict of Interest
The authors declare no competing interests.
This article is part of the Topical collection on Anesthesiology and Critical Care
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Sun-hui Xia, Di Zhou, and Feng Ge contributed equally to this work.
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| 36512273 | PMC9745294 | NO-CC CODE | 2022-12-15 00:02:24 | no | Curr Oncol Rep. 2022 Dec 13;:1-19 | utf-8 | Curr Oncol Rep | 2,022 | 10.1007/s11912-022-01342-9 | oa_other |
==== Front
Comput Human Behav
Comput Human Behav
Computers in Human Behavior
0747-5632
0747-5632
Published by Elsevier Ltd.
S0747-5632(22)00429-0
10.1016/j.chb.2022.107609
107609
Article
Community-oriented Motivational Interviewing (MI): A novel framework extending MI to address COVID-19 vaccine misinformation in online social media platforms
Scales David ab∗
Gorman Jack M. b
DiCaprio Peter b
Hurth Lindsay b
Radhnakrishan Malavika b
Windham Savannah b
Akunne Azubuike b
Florman Julia b
Leininger Lindsey c
Starks Tyrel J. de
a Section of Hospital Medicine, Division of General Internal Medicine, Department of Medicine, Weill Cornell Medicine, USA
b Bronx, NY, USA
c Tuck School of Business, Dartmouth University, Hanover, NH, USA
d Department of Psychology, Hunter College of the City University of New York, New York, NY, USA
e Doctoral Program in Health Psychology and Clinical Science, Graduate Center of the City University of New York, New York, NY, USA
∗ Corresponding author. 525 East 68th Street, New York, NY, 10068, USA.
13 12 2022
13 12 2022
10760922 7 2022
30 11 2022
11 12 2022
© 2022 Published by Elsevier Ltd.
2022
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Researchers have linked circulating misinformation in online platforms to low COVID-19 vaccine uptake. Two disparate literatures provide relevant initial guidance to address the problem. Motivational Interviewing (MI) effectively reduces vaccine hesitancy in clinical environments; meanwhile, social scientists note inoculation, rebuttal, and appeals to accuracy are persuasive in digital contexts. A tension is inherent in these approaches. MI in digital forums may induce an ‘illusory truth effect,’ wherein falsehoods appear more accurate through repetition. Yet, rebutting misinformation directly may elicit backfire or reactance effects, motivating some to amplify their presentation of misinformation. Building on Identity Process Theory, we propose a theoretical framework for conducting MI-based infodemiology interventions among digital communities that conceptualizes the community in toto (rather than one specific person) as the unit of focus. Case examples from interventions on public Facebook posts illustrate three processes unique to such interventions: 1) Navigating tension between addressing commenters and “bystanders”; 2) Activating pro-vaccine bystanders; and 3) Reframing uncertainty or information individuals might find concerning or threatening according to implied collective values. This paper suggests community-oriented MI can maximize persuasive effects on bystanders while minimizing potential reactance from those with committed beliefs, thereby guiding community-oriented public health messaging interventions enacted in digital environments.
Infodemiologist: @1 I understand how you can be worried about the vaccines. While they seem new, mRNA vaccine technology has been studied since the 2000's. Covid vaccine-related data is closely monitored so that plus data from other vaccines means the likelihood of long term side effects from COVID vaccine is very low. These vaccines have been well studied. Hydroxychloroquine does not really help improve covid outcomes. [NIH link] Thalidomide was a tragedy, and doesn't compare here because safety concerns were ignored for years. Covid vaccines are well researched and the data is publicly available. This link gives details of vaccines authorized in the US: they describe the trials and results from each phase. [CDC link and disclaimer].
Keywords
Digital information environment
Vaccine hesitancy
Infodemiology
Identity process theory
Motivational interviewing
Bystander
Psychological reactance
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pmc1 Introduction
COVID-19 vaccination is a critical component of the US public health campaign to address the impact of the SARS-COV-2 virus. While alternative treatments to vaccination are available (e.g., corticosteroids, monoclonal antibodies, remdesivir, tocilizumab (Nhean et al., 2021), nirmatrelvir-ritonavir (aka Paxlovid) or molnupiravir (Saravolatz et al., 2022)), vaccination continues to substantially reduce the risk of serious chronic illness, infection, hospitalization, and mortality (Mohammed et al., 2022; UKHSA COVID-19 Evidence Team, 2022). Estimates range from 234,000 (Amin et al., 2022) to 318,000 (Brown University & Microsoft AI Health, 2022) deaths in the US could have been prevented through higher vaccination rates.
Rates of vaccination rose rapidly in the first half of 2021 after they became widely available. Unfortunately, vaccination progress at the population level has slowed dramatically in more recent months (Johns Hopkins Coronavirus Resource Center, 2022). As of August 2022, approximately two thirds of people in the US have received at least one dose of the COVID-19 vaccine. Rates vary widely by state, with approximately 50% vaccinated in Wyoming to nearly 85% in Rhode Island.
1.1 Medical misinformation and social media: implications for COVID-19 vaccination motivation
There is increasing evidence that exposure to false or inaccurate information and the misrepresentation of legitimate health research is specifically associated with reduced COVID-19 vaccination rates (Loomba et al., 2021; S. R. Neely et al., 2022). The distribution of misinformation is particularly problematic in internet-enabled communication platforms (e.g., “social media,” peer-to-peer encrypted messaging, etc.). Information consumers have morphed into information producers, allowing information and misinformation to propagate rapidly through horizontal, decentralized networks (Kümpel, 2021; Young & Miller, 2021). The more incorrect information is repeated and the longer it is allowed to persist without challenge, the more likely it is to influence actual health behaviors, a phenomenon termed the “illusory truth effect” (Brashier et al., 2021; Walter & Tukachinsky, 2020). Encountering inaccurate information can be confusing and lead to hesitation or doubt even in those with robust prior knowledge (Rapp & Salovich, 2018).
The consequences of online misinformation have been particularly evident during the COVID-19 pandemic. Even after the WHO's pandemic declaration, US residents relied more on social media for health-related information than on health authorities like the US Centers for Disease Control and Prevention (CDC) (Neely et al., 2021). Belief in COVID-19-related misinformation and conspiracies has been linked to erroneous beliefs about the virus itself (e.g., risk of infection or modality of transmission), the effectiveness of behavioral risk mitigation (e.g., masks or social distancing), as well as the safety and efficacy of COVID-19 vaccines (Hornik et al., 2021; Neely et al., 2022; Romer & Jamieson, 2020; 2021; van Mulukom et al., 2022).
The effect of misinformation propagated through social media cannot be adequately countered by traditional health information campaigns. Accurate information is insufficient to counteract codified false beliefs and attitudes (Roozenbeek & van der Linden, 2022; van der Linden, 2022; Walter & Murphy, 2018), especially when those beliefs are intertwined with someone's identity (Kahan, 2017b). Existing research has tested a range of intervention techniques designed to influence opinion in online spaces, including: inoculation (van der Linden, 2022), warnings/labels (Morrow et al., 2022), and promoting critical thinking or media literacy (Ecker et al., 2022), as well as debunking, refuting or rebutting misinformation (Chan et al., 2017; Walter & Murphy, 2018). However, the effect sizes of successful online interventions are often modest and rapidly decay (Maertens et al., 2021; Mourali & Drake, 2022). A full review of this literature is outside the scope of this paper; see Scales et al., 2021 or Ecker et al., 2022 for more details.
1.2 Motivational interviewing and the potential to develop online, social-media delivered intervention strategies to address medical misinformation and increase COVID-19 vaccination uptake
Motivational interviewing (MI) is a “directive, client-centered counseling style for working collaboratively with clients to enact a behavior change” (Magill & Hallgren, 2019). The principles of MI were inductively established through treating patients with substance use disorder by clinical psychologists William Miller and Stephen Rollnick in the 1980s (Miller & Rollnick, 2012). While scholars continue to debate the mechanism by which MI appears to be effective (Magill & Hallgren, 2019), it has a decades-long track-record of success in facilitating change across a wide spectrum of health behaviors (Lundahl et al., 2013; Palacio et al., 2016; Smedslund et al., 2011). Of particular relevance, studies indicate MI-based interventions increased the likelihood that parents would consent to vaccinate their children (Gagneur et al., 2018, 2019; Lemaitre et al., 2019) and have shown promise to promote uptake of vaccines against human papilloma virus (Brewer et al., 2020; O'Leary et al., 2017; Reno et al., 2018, 2019). Unlike psychoeducational strategies, MI is “a collaborative conversational style for strengthening a person's own motivation for and commitment to change” (Miller & Rollnick, 2012, p. 12). In the context of a working alliance characterized by empathy, curiosity, and compassion, the MI provider uses a core set of counseling skills (open questions, affirmations, reflections, and summary statements) to engage individuals, arrive at a shared goal or focus for the interaction, evoke motivation for change, and, if appropriate, create plans for accomplishing identified goals.
Three specific aspects of MI suggest an adapted intervention might be effectively deployed in an online context to enhance motivation for health-related behavior change, countering medical misinformation in general, and increasing vaccine confidence, particularly for COVID-19 vaccines, even when simultaneously faced with misinformation presented by online commenters. First, MI was developed to address ambivalence and explore and amplify personal motivation especially in those not necessarily aware of nor interested in the need for change. Online environments, replete with “echo chambers” and “epistemic bubbles” (Thi Nguyen, 2020), are populated by commenters with particular beliefs influenced by medical misinformation, including those who are prejudiced against vaccination and equipped with arguments against it characterized by misleading information and falsehoods. It is precisely this population that is considered particularly challenging to persuade, yet MI provides a starting point to develop principles for engaging such commenters productively. Second, eliciting someone's perspective on a target behavior and how they might go about change is a central component of MI. Third, the concept of supporting personal autonomy (i.e. the right to self-determination) and enhancing self-efficacy (i.e., someone's belief in their own capacity to enact behavior change) by drawing out and acknowledging an individual's strengths and resilience is central to MI. Critically, self-efficacy has also been shown to be an important element in counteracting misinformation (Seo et al., 2021).
As MI was initially developed as an individual intervention, it received critique for insufficiently factoring in social context (Stanton, 2010). It has since been adapted to cultural contexts that exhibit more collectivist and less individualistic cultural values (Self et al., 2022) and extended for use with counseling groups (Velasquez et al., 2006; Wagner et al., 2012) and couples (Starks et al., 2018, 2020, 2022). In each of these instances, the expansion of MI was facilitated by the integration of theoretical concepts that informed counselors' capacity to respond to contextual factors. Self et al. (2022) reviewed several studies each incorporating values, customs, and traditions reflecting cultural uniqueness to achieve higher values alignment and greater MI efficacy. Velasquez et al. (2006) drew upon theories of group process to balance the need to emphasize group cohesiveness and homogeneity amidst the MI process of drawing out individual heterogeneity. Starks (2022) drew upon interdependence theory to position individual decision making in the context of relationship functioning and the formation of joint goals shared by both partners in a couple.
Unfortunately, these existing innovations in MI practice with more than one person are not fully equipped to directly assess COVID-19 vaccination in an online, social-media setting. There, stakeholders are diverse with respect to their beliefs and activity level (whether they comment spontaneously, only in response to others, or merely observe) as well as their attitude towards the health behavior (e.g., COVID-19 vaccination). The person delivering an MI intervention has little or no control over the composition of the stakeholders in attendance and must deliver or engage in the intervention in a manner visible to the group at large. In short, a community-oriented framework for the delivery of MI is needed to facilitate implementation in online spaces.
1.3 Conceptualizing the challenges to implementing MI in social media spaces: the composition of stakeholders in online forums
In their work on group-based MI, Wagner et al. (2012) specifically discussed the influence of the counselor on group composition. In some instances, groups are selected to be homogenous with respect to readiness for behavior change. In others, group members may be selected so that those who have achieved some degree of behavior change may serve as peer models of potential change for those who might be in the initial stages of consideration. Unfortunately, interventionists in online social media spaces are unable to exercise control over the composition of stakeholders active in that space. They therefore need a theoretical framework that can inform practice strategies in the absence of such control.
Stakeholders in online forums may vary in the frequency with which they post comments, yet those who comment actively often have the most committed beliefs (Duggan & Smith, 2016). Their opinions and behaviors are also the most difficult to impact (Kahan, 2017a). As a result, those exerting the greatest influence on dialogue in online forums may represent the group least-responsive to intervention. Others, referred to as “bystanders,” may observe in these forums but may be reticent to participate. Previous research on hate speech and cyberbullying has examined “cyberbystanders” or “bystanders,” defined in that literature as those who witness anti-normative behavior but are reluctant to intervene (Wang, 2021). We identify two forms of ‘bystanders’: silent observers (passive bystanders) and those who join the conversation (active bystanders). Active bystanders differ from original posters or commenters in that they post only in reaction to comments made by others (whereas original posters and commenters post spontaneously and intentionally initiate exchanges). To maximize impact and minimize psychological reactance (i.e., a backfire effect), communication interventions in online spaces need strategies that can speak to and engage all community stakeholders—original posters, commenters, and bystanders—simultaneously.
Best Practice Guidance from the World Health Organization explicitly suggests addressing vocal anti-vaccine personalities in public by focusing on bystanders rather than those with committed beliefs (WHO, 2019). While intuitively appealing (since they are the most likely to be receptive to a behavior-change intervention), delivering an intervention in heterogeneous online forums tailored solely to address bystanders is challenging and may have unintended consequences. Interventionist utterances that correct, refute or challenge misinformation may be effective in shaping the attitudes, beliefs, and behaviors of less psychologically committed bystanders (Chan et al., 2017; Walter et al., 2021; Walter & Murphy, 2018). Unfortunately, such utterances may also precipitate psychological reactance from those more committed to their position (Byrne & Hart, 2009). This may motivate them to amplify arguments that favor their position – potentially eliciting the repetition of posts containing misinformation rather than diminishing its presence and influence. A field experiment from at least one popular social media platform illustrates this concern as posters who were corrected subsequently exhibited more extreme behavior (Mosleh, Pennycook, & Rand, 2021).
1.4 Identity process theory and the expansion of motivational interviewing to community contexts
The question of how individuals interact with a collective—how group membership or participation influences individual behavior—has been discussed extensively within theories of identity development. Prominent among these is Identity Process Theory (IPT) which has a demonstrated track record of applications to health behavior. It provides a framework for understanding the implications of group membership on the valuation of information. IPT suggests that identity emerges from two processes: how people absorb and adopt new information into their identity (called assimilation-accommodation) and how they attach meaning and value to that information (evaluation). Identity principles like self-esteem, self-efficacy, distinctiveness, continuity and coherence guide these two processes. Theorists describe an identity as “threatened” when an identity process is not commensurate with identity principles and suggest that people engage in coping strategies to mitigate the subsequent discomfort. Some coping strategies can be understood as maladaptive (e.g., denial or concealment) in that they reduce identity threat by avoiding the processing of information that threatens one's identity. In contrast, adaptive coping strategies limit identity threat either through creating new collective norms (via group mobilization) or assimilating the new information (and consequently modifying one's identity to reduce conflict) (Jaspal & Breakwell, 2014).
Identity process theory has been applied to understand COVID-19 prevention behaviors (Jaspal & Nerlich, 2020). It has also been used to conceptualize how health risks are processed with reference to whether they affirm or conflict with one's identity (Breakwell & Jaspal et al., 2022). While it may initially seem irrational to voluntarily incur greater risk of severe outcomes from COVID-19, identity process theory would suggest that motivation to do so might arise from social representations of vaccination that have taken on political and identity-related connotations. In short, for some individuals the act of vaccinating would represent a violation of the behavioral norms that embody or exemplify membership in a social group that is central to their identity. In this circumstance, the individual may evaluate the social costs associated with vaccination as outweighing its potential health benefits. Tension between a personal health behavior and a salient social identity would also be expected to increase receptivity to misinformation that affirms the social identity or discounting of accurate information that promotes behavior incongruent with social identity. Empirical evidence supports the idea that individuals selectively incorporate or discount risks in ways that support their cultural identities (Kahan et al., 2007).
IPT would suggest that any framework for community-oriented MI (COMI) to address COVID-19 vaccination needs to incorporate the potential for perceived identity threats to activate cognitive dissonance and ambivalence. The theory suggests personal and social identities are juxtaposed, integrated, and context-dependent (Breakwell, 2014). So, the role of the interventionist can be understood, in part, as facilitating acquisition/accommodation and evaluation to promote more community-oriented adaptive responses. Put another way, to mitigate conflict, an interventionist needs to actively soften the implications of health behavior for group identity. This may be done by identifying ways in which the health behavior can be viewed as congruent with, or incorporated into, in-group membership, and activate group norms and values that might increase positive evaluation of the health behavior.
1.5 Identity salience and behavioral ambivalence
There is a small but substantive body of existing evidence consistent with the general premise that reframing behavior in terms of group-based values has an impact on motivation. For example, conservatives become more supportive of environmental legislation when framed in terms of traditional conservative priorities of purity and sanctity (Feinberg & Willer, 2013). Similarly, framing mask wearing (to reduce COVID-19 transmission) in terms of loyalty and appealing to protecting America as a community increased uptake of masking among American conservatives (Kaplan et al., 2021). Despite this promising evidence, interventions that capitalize on group-based values to enhance personal health motivation are underutilized (Feinberg & Willer, 2019).
Activating personal values is a common technique in MI (Bean et al., 2015). The interviewer's goal is to develop discrepancies between an individual's broader goals values and a behavior targeted for change. The implication of IPT is that group-based values might be leveraged in comparable ways. The integration of such strategies into COMI might be particularly effective given that they have the potential to appeal to aspects of identity that are relevant for highly-committed people who may comment actively on social media and they are also unlikely to elicit backfire effects – or activate sustain talk – from bystanders in these settings (Feinberg & Willer, 2019).
Research on identity-related information processing also implies that stakeholder perceptions of whether or not the infodemiologist delivering COMI is an in-group or out-group member will influence receptivity to the intervention. According to social identity theory (Tajfel & Turner, 2004) and the self-categorization sub-theory (Abrams et al., 1990; Turner, 2010), people are more likely to discount information delivered by out-group messengers because the messenger themselves or their perceived membership in other out-groups sends a signal about whether the information they deliver is likely to affirm or deviate from group norms. Therefore, the identity implications of the information received and the message receiver's perception of the messenger delivering it are both likely important factors at play in online interactions.
1.6 Purpose of the current study
While in principle IPT has the potential to inform the application of MI in online social media spaces, no attempt has previously been made. The goal of this proof-of-concept study was to evaluate the viability and utility of a COMI framework that integrates concepts from IPT to understand stakeholder responses and guide infodemiology interventions designed to address medical misinformation online, using COVID-19 vaccine hesitancy as a case study. We hypothesized that qualitative examination of discussion thread transcripts would yield exemplars of processes unique to the delivery of COMI. These would then serve as a starting point for the identification of specific, relevant intervention skills and strategies that might be effective in these settings.
2 Methods
Discussion thread transcripts provided below are taken from interactions on Facebook conducted by infodemiologists between December 2020 and April 2021 with the goal of evaluating the feasibility and acceptability of a prototype intervention protocol developed by [author 1] and [author 2]. The protocol for intervention included the following steps:1. We posted on communications job boards to recruit potential infodemiologists, asking about their connection to their local community and their willingness to intervene in an online intervention focused on that geographic area. This ensured the infodemiologists self-identified as part of the communities in which they intervened.
2. After identifying appropriate comment threads as described below, the infodemiologist would begin an “intervention” with a question attempting to elicit further explanation from the poster about their point of view. Initial questions were intended to follow MI-based principles of empathy and non-judgmental curiosity.
3. Immediately afterwards, the infodemiologist posted a transparency statement identifying themselves as a member of the research team and links to a webpage with more details of the research and procedures for withdrawal.
4. The infodemiologist then attempted to continue the conversation with the primary commenter, balancing as they saw fit the use of evidence-based approaches (Scales et al., 2021) melded with techniques derived from motivational interviewing. The infodemiologists were expected to be respectful and to model appropriate online commenting behavior.
5. Infodemiologists were counseled to consider both the primary commenter and active and passive bystanders observing these online conversations as they crafted their responses.
6. The infodemiologist could introduce corrective information to blunt an “illusory truth effect” while maintaining a respectful and non-judgmental stance.
7. As part of data recording, infodemiologists reflected in writing on the exchange in our data collection platform. Infodemiologists and researchers then also discussed these reflections and challenges at weekly virtual meetings throughout the course of the study. These group supervision sessions involved discussion of intervention work and review of session transcripts to ensure fidelity to the overall protocol. Challenges to MI skill implementation were reviewed and ongoing skills training was conducted.
Four infodemiologists selected for their interest in communication underwent a skills-based training consisting of independent reading about infodemiology and addressing misinformation in online contexts (e.g. see citations (Gorman & Gorman, 2021; Scales et al., 2021)), practice interventions, and weekly supervision sessions with either [author 1] or [author 2], totaling approximately 20–25 h, until competency was established. Competency was maintained through the weekly supervision sessions as noted above.
We built a surveillance system leveraging Facebook's native features and followed news sites and monitored news feeds allowing us to identify posts containing media reports originating from three geographic regions, Newark, NJ; Chicago, IL; and central Texas. Infodemiologists selected posts with comments containing either misinformation about vaccines or encouraging an anti-vaccine stance. We defined misinformation about COVID-19 vaccines as any post that contained incorrect material about vaccines in general or COVID-19 vaccines specifically, regardless of the motive of the person posting the misinformation. This included factually-incorrect statements (e.g. “the vaccines are killing people”) and true statements expressing uncertainty about the vaccines (e.g. “we don't know the long-term side effects”). To avoid online harassment, infodemiologists avoided highly contentious or overtly partisan posts. Infodemiologists aimed to respond as soon as possible after the original posting, at least within several hours, to maximize engagement. This research was judged as exempt from review by the Ethical and Independent Services review board and was approved by the IRB of the [Academic Medical Center IRB name redacted for anonymized peer review].
De-identified comments were collected by the infodemiologist at the time of the intervention along with URLs, infodemiologist reflections, and native engagement metrics (e.g. likes, shares) and recorded in a password-protected database. A conversation would be considered stale after a maximum of five days, with final engagement metrics updated at that point if necessary.
Note that all transcriptions reported here have been paraphrased to protect the identity of commentators from subsequent identification through search engine queries (Townsend & Wallace, 2016). To emphasize the community orientation of interventions and for conceptual clarity, we refer to commenters and bystanders as defined above but use “stakeholder” to identify contributors to the online discussion in the transcripts. Some transcripts were trimmed for brevity.
2.1 Analytic approach
Infodemiologists transcribed exchanges at the time of the intervention. Our initial coding scheme included deductive codes comprised of 12 elements from our intervention protocol (derived from [citations redacted for anonymous peer review]) plus several codes derived inductively. To avoid bias, the creation of the coding scheme and the first round of coding was conducted by a member of the analysis team who had had minimal contact with the infodemiologist team and did not engage in any of the creation of or training on the protocol ([author 3]). Once completed, [author 1] reviewed the coding scheme, also coded, and then both coders discussed their shared impressions to finalize the code book, discursively resolving any coding discrepancies. Through the course of the analysis, [authors 1 and 3] met frequently to discursively and iteratively engage in analyzing emerging patterns from the transcripts until thematic saturation was reached and a codebook developed using NVivo software. Through the qualitative coding process, big-picture themes emerged inductively from examination of the infodemiologist-commenter-bystander interactions as a whole. Below we use case examples from discussion transcripts to illustrate these themes.
3 Results
Across the 146 transcripts examined, a total of 93 precipitated some type of engagement from commenters or activated bystanders, consisting of reactions (likes or other emotional reactions), comments or both. As transcripts were de-identified, we cannot determine the number of unique users interacting with our posts. Geographically, the origin or focus could be ascertained in 133 posts; 45 posts had a media focus on Texas, 55 on Chicago, and 8 oriented toward Newark. The remaining 25 posts for which geographic focus could be determined were nationally oriented or spread across other states.
We have selected representative examples of more successful interventions that portray our experience with counteracting misinformation online. We found conversations that more closely adhered to motivational interviewing techniques were generally more successful than interventions employing fact-based rebuttals early in the discussion. However, further detailed analysis of these interventions will be provided in forthcoming publications.
Our theoretically guided review of transcripts identified three processes uniquely relevant to the application of COMI addressing misinformation in these digital environments. First, there was an ongoing need to balance attention between focusing on commenters versus bystanders. Second, infodemiologists activated bystanders (eliciting comments from those who were initially passive observers) and then facilitated the integration of those contributions to the online discussion. Third, in efforts to meet community-oriented goals, infodemiologists reframed behavioral uncertainty or seemingly disconcerting information according to implied collective values.
3.1 Tension between focusing on committed believers versus bystanders
Across sessions, infodemiologists were presented with the challenge of deciding whether to formulate a response aimed primarily at commenters with committed beliefs versus considering the impact of rebutting misinformation on bystanders. This first example reveals an infodemiologist's strategy to ensure misinformation does not persist in the forum unrebutted. Here the infodemiologist replies to comments on a Facebook post from a prominent midwestern medical center encouraging people to get the first COVID-19 vaccine available (associated reactions: Like:159, Haha:55, Love:22, Angry:5, Hugs:2, Wow:1, Tears:1; Comments:95, Shares:33).
Stakeholder 1: Won't be surprised to see an ad in many years saying “if you got the covid vax in 2021, you are entitled to compensation.” The FDA hasn't approved them. Can't shame people, whether they get the vax or not, it's NOBODY’S business but ours. Do you shame people into getting other vaccines? Be kind and don't impose your views on others.
Infodemiologist: @1 It's certainly your choice to get the vaccine or not and I agree that folks must be respectful. Can you explain more about your vaccine concerns? They were researched in large trials which proved they effectively reduced covid symptoms. This link talks more about FDA's emergency use. [FDA link] [research disclaimer].
Stakeholder 2: @1- Injuries from vaccines with emergency auth aren't compensated.
Infodemiologist: @2- The vaccines have been studied in trials involving thousands of people. The chances of vaccine-related injury are minimal based on the results. If there are injuries, they can be reported to Vaccine Adverse Event Reporting Systems (VAERS). Some folks can get compensated for injuries [HRSA link] These vaccines remain our best hope of ending the pandemic.
Stakeholder 3: NO vaccines have been FDA approved the article is a lie.
Infodemiologist: @3- In emergency situations, the FDA grants emergency authorization but only something's been studied in big clinical trials. Their usage is authorized if the benefits largely outweigh the risks. There's no compromise on vaccine safety. This link might help explain some of the details of EUA vs approval [FDA link].
Stakeholder 3: @Infodemiologist Thanks. There are many contradicting studies so I'm not going to keep debating. Natural therapies that can heal Covid are better, instead of lockdowns, masks, and injecting poisons. Moderna clearly affects DNA and you can't undo that. Sometimes I wish folks like you and me could just sit down face to face and talk about all this. I must say that you have been respectful with your comments and information, and I appreciate that. Have a great holiday!Image 1
Consistent with MI principles, the infodemiologist's initial post opens with an affirmation of autonomy and a question that elicits the commenter's perspective. The infodemiologist then pivots to present accurate information about COVID-19 vaccination. Their goal was to prevent or diminish an illusory truth effect by rebutting the factual substance of Stakeholder 1's posting. Unfortunately, this introduction of information appears to threaten a group norm. This elicits a reactance response from Stakeholder 2. An additional rebuttal continues to threaten the group norm and a sympathetic expression of reactance is triggered from Stakeholder 3. In this passage, the infodemiologist opts to disregard the reactance responses from commenters and maintains a primary focus on bystanders. Their information-focus posts are best understood as directed at observers whose attitudes may not be represented by active commenters in the thread and thus less likely to feel their identity threatened by the new information.
In our initial example, the infodemiologist pivoted rapidly to a strategy aimed at bystanders. In this second example, the infodemiologist instead sustains a focus on the commenter. In this thread, a meme was posted on a public, pro-science Facebook group favorably comparing vaccines to homeopathy. Many comments were pro-vaccine; however, one commenter raised a concern that mRNA vaccines were a new and unknown technology (associated reactions: Like:2.1k, Love:228, Haha:51, Hugs:6, Tears:1, Comments 166, Shares 339).
Stakeholder 1: A word of caution: these nucleic acid vaccines are a new technology never used before. So we should all agree that the long-term effects are unknown, especially of follow up shots. Plus, I'd like to see head-to-head comparisons between the vaccines and other Covid-19 treatments like hydroxychloroquine, zinc, or Vitamin D. Without answers how can I truly consent to being vaccinated? After all, Thalidomide was once thought to be safe.
Stakeholder 2: @1 Nope, we can't agree. Please check out the Infodemiologist's response. It's comprehensive.
Stakeholder 3: @1 I have an idea – people should report your response and block you.
Stakeholder 1: Despite what the infodemiologist says, there are plenty of experts who agree that these vaccines are unsafe. I'm an engineer and believe we should be testing all hypotheses. I'm not convinced that these vaccines are safe. Here's just one warning from an expert out of many [YouTube weblink].
Infodemiologist: @1 Thanks for the video. [Expert name] is not a doctor or virologist and doesn't have the most reliable and accurate information about the covid vaccines and he's made a number of claims that turned out to be false. [Link to independent factchecking site].
Stakeholder 1: @Infodemiologist Thank you. Let's see what happens over the next year. What do you think about how [EU country] had a high death toll even though it has the highest percent of vaccinations in the EU?
[Euro News web link] I'm skeptical of [FactChecking website] fact checkers, since they are govt controlled. Also, I must reiterate that [Expert] worked in high positions in lots of organizations even the United Nations.
Infodemiologist: @1 [FactChecking website] is pretty highly rated for credible reporting. Also, while [Expert] held those positions, he wasn't working in any capacity that would make him an expert on vaccines or Covid.
Stakeholder 1: @Infodemiologist I hope you're right, but I worry about the damage to freedoms, livelihoods, covid passports, etc. Where I live, millions have been thrown out of work. Why?? Don't you see the danger here? To save a few elderly folks like me, and a few with compromised immune systems? I don't want to live in an authoritarian society. Still, I appreciate your thoughtful comments.
Stakeholder 4: @1 You keep changing the question every time you've been debunked. The science doesn't support what you say.
Infodemiologist: @1 I appreciate our chat and do understand your concerns. Please stay safe and well.
Stakeholder 1: @Infodemiologist Last question if you don't mind: are there scientific studies about mask effectiveness out there? Not official statements but real studies. I haven't seen convincing evidence but you may have better info. TIA.
Infodemiologist: @1 Sure, here are a few that might interest you. [medical journal links].
The infodemiologist is actively balancing the need to express empathy and a desire to understand Stakeholder 1's perspective with the simultaneous need to prevent illusory truth effects among bystanders as Stakeholder 1 posts a range of misinformation about COVID-19 vaccines. Several aspects of the infodemiologist's approach are successful here. First, they explicitly assume a non-judgmental stance towards Stakeholder 1 as a person. They actively affirm Stakeholder 1's personal autonomy and self-efficacy for health-related decision making. As a result, the information presented by the infodemiologist is experienced as a rebuttal of Stakeholder 1's information, but not as a personal criticism or judgement leading to identity threat. Instead, in this context, the identity of the group is pro-science, so as Stakeholder 1 elucidates their views, other Stakeholders push back to inform them that their views are not consistent with the group's identity. Stakeholder 1 attempts to frame their concerns as identity-congruent: as legitimate scientific exploration of all hypotheses, or, separately, based on the belief that governments may not be trustworthy sources of information.
Notably, the infodemiologist retains a consistent focus on Stakeholder 1. In contrast, they might have aligned with Stakeholder 2 or 3 (who offer comments which themselves reject Stakeholder 1's initial stance against vaccination). Doing so would run the risk of alienating Stakeholder 1 and implicitly creating the perception that the infodemiologist was allied with Stakeholder 2 and 3 against Stakeholder 1. That expression of implicit judgement and alliance may have altered Stakeholder 1's reaction to information presented by the infodemiologist and might at least partly explain their reactance response. The combination of both the norms of the pro-science group plus the infodemiologist's willingness to take Stakeholder 1's concerns seriously and address them respectfully appear to achieve some assimilation as Stakeholder 1 frames their final question about masks in an identity-congruent way.
3.2 Activating pro-vaccine bystanders and responding to their contributions
Regardless of whether they focused on commenters or bystanders, infodemiologists in the previous transcripts largely adopted a strategy in which they served as the source of accurate information used to rebut the presentation of misinformation and, as may be expected from IPT, stakeholders resist the infodemiologist in the first transcript as the information provided is identity-threatening. This makes the infodemiologist an outsider and a threat, and therefore suggests a rebuttal-oriented strategy is risky. A key feature of the distributed, networked information environment on social media is that information consumers are now also information producers (Kümpel, 2021). The potential for bystanders to serve as the source of effective, corrective, and accurate information is hinted at in the previous examples, particularly the second one. IPT would suggest this strategy would be less likely to activate a cohesive group-level reactance response.
The following passage came from a Texas local radio news post on Facebook explaining how readers could obtain their second dose of the COVID-19 vaccine. Here, the infodemiologist provided information dispassionately and linked it with sources likely to be trusted by all stakeholders. When the original commenter ultimately responds with a link from Children's Health Defense, an organization often found to be one of the worst spreaders of anti-vaccine misinformation (Yang et al., 2021), the infodemiologist provides a fact-based rebuttal with a reminder that source integrity is of high importance.
Stakeholder 1: Don't do it [get the COVID-19 vaccine].
Infodemiologist: @1 Lots of people are worried about new technology, is there anything specific you're worried about?
Stakeholder 1: @infodemiologist the vaccines don't stop the virus from spreading. They're not even FDA approved and who knows what the long term side effects are. The media aren't telling the truth about deaths from the vaccine and all the problems it's causing. Tell the truth – it'll come out sooner or later once those trying to tell the truth stop getting censored.
Stakeholder 2: @1 right on.
Stakeholder 3: @1 where's your classified source with all the “truth” you claim? [bespectacled, smiling face emoji].
Infodemiologist: @1 The vaccines reduce symptoms, severity of disease and the chances of getting sick, and they're shown to cut the number of deaths. The emergency authorization process is very thorough with thousands of participants.
A new vaccine can seem nerve-wracking, but there's no reason to assume there will be long-term side effects – Covid causes worse long-term effects anyway.
Stakeholder 1: @3 What sources do you have to prove the vaccines protect you? If you do your research you'll see IT IS NOT APPROVED BY THE FDA AND YOU CANNOT SUE IF YOU GET HURT. That's got to raise red flags.
Stakeholder 1: @Infodemiologist no it wasn't according to the news.
Stakeholder 3: @1 the liability clause is literally the same for every vaccine. Are you antivax? Do you doubt all vaccines? Why does this one bother you so much?
Stakeholder 1: @3 nope.
Infodemiologist: @1 This info was really helpful for me to understand why the Covid vaccines are effective [Link to medical center info website].
The original comment in this thread lacks detail. It expresses what can be interpreted as an anti-vaccine message. The infodemiologist's intervention draws out more information from Stakeholder 1, which activates two bystanders (Stakeholders 2 and 3). Stakeholder 3 continues to participate with posts that favor COVID-19 vaccination. Stakeholder 3 might be understood as a bystander whose participation was activated by the infodemiologist's intervention.
Unfortunately, while bystanders may be in possession of accurate information, their comments in online spaces may be counterproductive when they are framed in ways that are perceived as identity threat. Many pro-vaccine bystanders created highly confrontational posts when they chose to comment, such as by belittling the primary commenter or vaccine-hesitant bystanders for violating implied group values. The infodemiologist capitalizes on Stakeholder 3's posting in two ways. First, they use it as an opportunity to offer accurate information by reframing the pro-vaccine arguments or offering a web link to a source likely to be trusted by the commenter and thus less identity threatening. Second, they explicitly empathize with those who may not yet be vaccinated and express support for autonomy. Such empathy implies that Stakeholder 1's views are identity congruent, thus serving not only to reassure them but also reduce reactance based on any perceived identity threat. Broadly speaking, the infodemiologist's tone and comments seek to enhance receptivity to the information presented and diminish the risk this information, or Stakeholder 3's posts generally, elicits reactance from commenters committed to an anti-vaccine position.
3.3 Reframing disconcerting information or uncertainty according to collective values
In the example below, the infodemiologist responds to an article posted by a commenter on Facebook. The posted article is from a local news source and describes a recently published scientific study that found Covid-19 vaccines highly effective. The infodemiologist's initial post is consistent with a rebuttal strategy and presents alternative sources of accurate information. The infodemiologist's second post represents a strategy that appeals to collective values and group norms. Notice that the post is framed in the plural “Many of us …” and implies a collective (rather than a strictly personal) experience or attitude.
Stakeholder 1: Same government source who won't acknowledge all these vaccine side effects, like miscarriage or dying.
Stakeholder 2: @1 I know, right ?!?!? Can you imagine … ….
Stakeholder 3: @1 what, you worried about having a miscarriage?
Stakeholder 1: @3 enjoy being a guinea pig.
Stakeholder 4: [GIF of man in tinfoil hat with caption “Seems a little crazy!”]
Infodemiologist: There have been no deaths or miscarriages officially linked to the vaccine. But how many deaths are due to COVID-19? Over 550,000 deaths in the states alone. We also know pregnant women are high risk for serious illness from COVID. I trust my doctor and look to sources like [COVID experts] to learn more: [web link].
It's easy for sensational posts on social media to frighten us, but it's clear the risks of COVID far outweigh the risks of the vaccine.
Stakeholder 1: @Infodemiologist you really believe that covid directly has caused 550k deaths or you just quoting official stats. Lol. Open your eyes.
Infodemiologist: @1: When I open my eyes, I see so many people suffering during this pandemic. Many of us, myself included, have had loved ones pass away. People who have survived COVID still experience painful symptoms months later. I see a devastating virus that has taken so much from our communities. And I see a vaccine that can protect people and get us back to normal lives.
Stakeholder 5: @1 Aren't all vaccines like that though? Like the ones we give our kids for school?
Stakeholder 6: @5 those vaccines have years of research behind them and are FDA approved, these only have emergency use … the folks getting the vaccine are the experiment.
Stakeholder 5: @6 I hear ya. Still, pointing out the govt. won't take responsibility for any side effects is a scare tactic. There are tons of vaccines but the gvt has never taken responsibility for any of them.
Perhaps the most notable impact of the infodemiologist's appeal to collective values is the activation of Stakeholder 5. The infodemiologist sent the message that people who see vaccination as a way to meaningfully alleviate individual suffering may not be alone. That message is then embodied in the participation of Stakeholder 5, who appears to take a pro-vaccine stance. Together, these facets of the exchange may send a message to other (passive) bystanders that there is a community of people whose values, beliefs, and attitudes align with vaccine uptake. This is an example of catalyzing what Identity Process Theory would understand as incorporating a particular health behavior into group norms.
In this particular example, the infodemiologist's appeal to collective values also represented a shift to focus on bystanders rather than the individual Stakeholder 1. While effective in this particular context, Identity Process Theory would suggest that appeals to collective values and incorporating the health behavior into group norms may engage individual commenters as well as bystanders. Stakeholder 1 is concerned about the health of others. This concern may very well be shared by others present in this online space. Consider the following hypothetical alternative response.
Stakeholder 1: @Infodemiologist you are certain that covid directly has caused 550k deaths or you quoting cdc statistics. Lol. Open your eyes.
Infodemiologist: @Stakeholder 1: I suspect that lots of us here care a great deal about staying healthy – regardless of the exact number of people who have died from COVID-19. If we discount information from sources like Dear Pandemic (that are reporting information from CDC and FDA) then who should we listen to?
The infodemiologist's post in this hypothetical example appeals to collective values while also inviting Stakeholder 1 to share more about their perspective. The post simultaneously allows Stakeholder 1 to reflect on whether they can identify viable alternative information sources and also may catalyze everyone present (bystanders and commenters) to weigh the merits of any alternative information sources against those offered by the infodemiologist.
4 Discussion
The framework presented here provides four key insights into how infodemiologists can address misinformation in online forums. First, in a shift from individual-, dyadic-, or group-focused MI interventions, COMI re-positions the community as a whole as the client. Second, consistent with Identity Process Theory, community-level resources such as collective efficacy or incorporating health behaviors within group norms may be leveraged as sources of behavioral motivation. Third, novel but essential provider strategies for accommodation/assimilation and evaluation serve to manage conflict among community members by reframing comments elicited from active bystanders in ways that reduce perceived identity threat and thereby the likelihood of reactance. Fourth, activating bystanders presents an opportunity to leverage the structure of online social media networks to propagate high-quality information delivered by in-group members that identity process theory suggests may increase receptivity. Each of these insights will be discussed in more detail below.
COMI permits a re-imagining the of community – the group of individuals that comprises those present in an online forum – as the object of intervention. This has three significant implications. First, it expands the universe of strategies available to infodemiologists. They can then move flexibly along a continuum of focus – interspersing utterances that address committed believers with utterances that address the “moveable middle.” Second, this approach also yields the novel possibility of utterances that speak to both groups – the committed and undecided – simultaneously. It reorients the concept of “the client” from an individual to community stakeholders. Third, it also changes the goal of interventions from persuading any single individual to modify their behavior to ensuring a healthy digital information environment with in-group members delivering high-quality information to better inform their community and motivate health-related behaviors. In the process, COMI can help a community recapitulate group norms by understanding how a particular health behavior fits within them.
Second, envisioning the “community as client” in an MI intervention implies that community level resources can and should be leveraged to promote individual behavior change. Individual MI leverages the exploring of discrepancies between that individual's behavior and their broader goals and values to generate motivation for change. Culturally-adapted MI has brought aspects of community values and goals to bear on facilitating individual behavior change (Self et al., 2022). Likewise, according to IPT, it may be possible to enhance motivation for change by reframing new or threatening information in ways that align it with group identity. By identifying ways in which information or the health behavior is congruent with in-group norms and values, a practitioner can facilitate the processes of acquisition/accommodation and evaluation to promote positive community-oriented adaptive responses.
Additionally, practitioners will likely need skills reinforcing and promoting identity motives identified by IPT, like self-esteem, distinctiveness, continuity, belonging and self-efficacy. IPT and MI align along a number of these principles and can likely be leveraged to precipitate cognitive dissonance and, ultimately, behavior change. For example, individual MI has viewed supporting self-efficacy – cultivating an individual's belief in their own capacity to enact change – as a mechanism that increases motivation. This aligns with IPT because self-efficacy is seen as a key motive central to a number of identities, and, in theory, identity threat can be mitigated through reinforcing self-efficacy.
Leveraging community-level resources like group norms and collective self-efficacy brings novel challenges for the COMI provider. Affirmations and reflections that reinforce identity motives like expressing community-level strengths (e.g. self-esteem) and finding common ground (i.e. continuity) become potentially relevant to mitigating perceived identity threats. These utterances provide a mechanism to actively convey a community perspective in the same way that individual level affirmations and reflections have long served as active listening skills for engaging with individuals in MI. Research exploring utterances directed at the social space of a digital community and the information environment in which that community is situated is urgently needed. For example, the concept of collective self-efficacy – an individual's belief in their community's potential to respond effectively to a health threat – has been identified as a predictor of individual health behavior – including COVID-19 vaccination (Gupta & Stewart, 2021). However, both IPT and MI conceptualize self-efficacy as embedded within an individual, so research will be needed on how to effectively incorporate utterances that leverage collective self-efficacy into COMI.
In addition, defining and bounding communities in online spaces is not straightforward (Longoria et al., 2021; Stanford Internet Observatory, 2022). One implication is that there may be advantages to peer-based models of infodemiologist delivered interventions as Identity Process Theory suggests messages delivered by in-group messengers will be perceived as less threatening. Infodemiologists address online groups of which they perceive themselves to be a member, situating them to best identify relevant collective values and group norms, reference them with authenticity, and capitalize on content elicited by their mention. As such, infodemiologists can provide information when necessary according to any number of evidence-based strategies, like framing messages (Jordan et al., 2021), strategically leveraging emotion or humor (Yeo & McKasy, 2021), or employing therapeutic communication (Ritter et al., 2021) with additional strategies described by (Scales et al., 2021). However, they have a rhetorical advantage in being able to authentically leverage in-group vernacular and linguistic register to maximize the effect of these strategies.
Third, extending MI to online community stakeholders requires infodemiologists to be equipped with an array of strategies to manage conflict in these settings. One potential source of conflict is reactance or backfire, where rebutting misinformation may unintentionally motivate some commenters who hold views opposing a health behavior to amplify their argument. Exacerbating conflict in online forums is likely an impediment to thoughtful consideration of beliefs and behavior change. Work from MI adapted for couples and group settings offers some insights into how infodemiologists can approach conflict (Starks et al., 2020; Wagner et al., 2012). These include strategies such as slowing the discussion down, active listening, and affirmations. Infodemiologists demonstrated several conflict-mitigation techniques including reframing, avoiding emotional escalation, and using language that demonstrated active listening. IPT would also suggest a strategy of reframing information initially perceived as identity threatening as identity congruent as a way to minimize reactance (Jaspal & Breakwell, 2014). However, future research will provide a more detailed assessment of infodemiologists' strategies to mitigate conflict.
A second source of conflict is disagreement among stakeholders present in the online forum. Literature on cyberbullying has demonstrated that activated bystanders can mitigate negative effects on victims, terminate a bullying episode, and motivate others to also challenge the bully (Anderson et al., 2014; Salmivalli, 2010). Similarly, our work here suggests bystanders can be activated and similarly leveraged to challenge misinformation. The danger is that bystanders may frame comments in ways that disrupt or disturb the perception of group cohesion or the uniform acceptance of perceived group norms thus exacerbating discord with other stakeholders and eliciting reactance from them. Providers need a set of skills that prepare them to reframe comments from pro-vaccine bystanders in ways that de-emphasizes threats to identity motivations while facilitating acquisition/accommodation and evaluation to promote more community-oriented adaptive responses that minimize conflict or reactance. Again, the existing literature on couples and group applications of MI noted above provide some starting points on how to adapt MI strategies like minimizing conflict to new contexts (Starks, 2022; Starks et al., 2022; Wagner et al., 2012).
Fourth, activating bystanders offers a unique opportunity to leverage the structure of social media to propagate high-quality information beyond the individual thread and infodemiologist. Misinformation is well known to propagate faster than truth (Vosoughi et al., 2018) and does so often because it is more emotionally engaging (Ali et al., 2022). High-quality information on social media can easily be drowned out by other attention-grabbing items like those produced by other users in the online network (Kümpel, 2021; Young & Miller, 2021). However, due to lack of data access, researchers have little insight into how stakeholder behavior changes after online field experiments (Mosleh, Pennycook, & Rand, 2021), with one field experiment demonstrating backfire effects after corrections (Mosleh, Martel, et al., 2021). Since this work suggests that infodemiologists can activate bystanders to productively participate in online forums it raises the possibility of testing IPT-consistent ways of activating bystanders, i.e. by helping solidify their perception that a health behavior aligns with their identity such that they subsequently amplify high-quality information across the network to maximize reach while minimizing psychological reactance.
This study has several limitations. First, we limited our initial, pilot work to three geographical areas (Chicago, Newark, and central Texas), one health-related area (COVID-19 vaccines), and three months of data collection. Additionally, we limited this study to public posts on one social media platform, Facebook, which has clear idiosyncrasies and data collection limitations that markedly limit quantitative analysis of our conversation threads. We also did not objectively assess infodemiologist competency or fidelity to our protocol but relied on weekly supervisions. As this is a pilot, formative study seeking to establish a broad theoretical framework, we are not assessing the degree to which our interventions had impact or were effective in this report. We will address these issues in a future communication.
In summary, our work addressing COVID-19 vaccine hesitancy demonstrates an opportunity to extend MI to community stakeholders. The principles we have uncovered in this work are not limited to COVID-19 vaccines or even vaccines in general but may apply more broadly to other online communities in which medical misinformation proliferates. This work is not attempting to improve MI, which has decades of research and honing described elsewhere (Miller & Rollnick, 2013). Instead, we found the theoretical framework of IPT aligns well with MI and implies strategies to guide practitioners' interventions that speak toward collective identity motivations. These intervention strategies revealed that infodemiologists can successfully engage misinformation in a diverse online platform by reformulating the audience not as any particular individual but as the community as a whole. As a result, the infodemiologist may be affecting change in the information environment a community is immersed in, though more data from digital platforms will be required to fully evaluate this potential impact.
Credit author statement
The first two authors conceived of the study and secured funding, together writing the first draft of the manuscript. Authors three through seven were infodemiologists who advanced the theoretical concepts of the paper through weekly reflection sessions over the course of the project and contributed to revisions of the draft manuscript. The penultimate author provided expert guidance on program evaluation and input on manuscript drafting. The last author helped shape the paper's structure and was deeply involved in manuscript draft revisions, particularly the incorporation of a more robust theoretical framework.
Data availability
The data that has been used is confidential.
Acknowledgements
This work was supported by the 10.13039/100000867 Robert Wood Johnson Foundation (grant numbers 76935 and 78084), 10.13039/100007273 Weill Cornell Medicine's JumpStart program and the Cornell Center for Social Science. The authors acknowledge the helpful guidance and insights of Kathleen Hall Jamieson, Oktawia Wojcik, and Nancy Barrand. The opinions expressed in this piece do not necessarily reflect those of either the Robert Wood Johnson Foundation or Weill Cornell Medicine.
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| 0 | PMC9745298 | NO-CC CODE | 2022-12-16 23:20:03 | no | Comput Human Behav. 2022 Dec 13;:107609 | utf-8 | Comput Human Behav | 2,022 | 10.1016/j.chb.2022.107609 | oa_other |
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Med Clin (Barc)
Medicina Clinica
0025-7753
1578-8989
Elsevier España, S.L.U.
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10.1016/j.medcli.2022.10.001
Artículo Especial
Puesta en marcha de una unidad COVID de alto riesgo. La experiencia de un hospital general
Start-up of a high-risk COVID unit: The experience from a general hospitalBoixeda Ramon ab⁎
Palau Alba a
Garcia Montserrat cd
Plensa Esther c
en nombre del grupo multidisciplinar Unidad COVID AR del Hospital de Mataró
a Servicio de Medicina Interna, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró (Barcelona), España
b Grup de Recerca GEMP@C, Universitat de Barcelona, Barcelona, España
c Servicio de Hematología, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró (Barcelona), España
d ICO-Hospital Germans Trias i Pujol, Badalona (Barcelona), España
⁎ Autor para correspondencia.
13 12 2022
13 12 2022
27 7 2022
3 10 2022
© 2022 Elsevier España, S.L.U. All rights reserved.
2022
Elsevier España, S.L.U.
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pmcIntroducción
La COVID-19, enfermedad causada por el SARS-CoV-2, se identificó en diciembre de 2019 y rápidamente progresó a una pandemia global. La edad y algunas comorbilidades, como la obesidad, las enfermedades cardiovasculares y la diabetes mellitus, se describieron en nuestro entorno como factores pronósticos de mala evolución y aumentaron el riesgo de hospitalización y muerte en las 2 primeras oleadas de la pandemia, antes de la vacunación1. Además, los pacientes afectos de enfermedad oncohematológica, cáncer de pulmón o neoplasias en fases diseminadas demostraron un peor pronóstico2, 3. También se describió que los pacientes con neoplasias hematológicas en tratamiento con quimioterapia reciente eran los que tenían un mayor riesgo de mortalidad asociada a un ingreso por COVID-19 (OR 2,09; IC95%: 1,09-4,08; p = 0,028)4. Por último, la linfopenia, hallazgo muy frecuente en pacientes en tratamiento con quimioterapia o con fármacos biológicos, también se definió como un factor de mal pronóstico en la enfermedad por SARS-CoV-25.
A lo largo de la pandemia, los tratamientos se fueron modificando en función del conocimiento obtenido. Inicialmente la indicación de tratamiento específico se restringía a la infección grave que precisaba ingreso hospitalario. Debido a la aparición de las diferentes variantes del SARS-CoV-2 y a la implementación de la vacunación, superior al 80% de la población en Cataluña6, a principios de 2022 se aprobó la indicación de tratamientos específicos para la enfermedad leve-moderada en pacientes con riesgo de progresión; entre ellos, los pacientes inmunodeprimidos.
En este momento se plantea el reto para los clínicos de adaptarse a este nuevo escenario: indicación de un tratamiento en la fase precoz de la enfermedad, en general en los 5 primeros días desde el inicio de los síntomas de la infección y una administración ambulatoria intravenosa de una sola dosis (sotromivab), 3 dosis (remdesivir) o, incluso, antivirales orales (nirmatrelvir/ritonavir). En este contexto, la existencia de protocolos y circuitos consensuados dirigidos a la prevención, detección precoz de la infección y tratamiento en los casos indicados con el mejor fármaco disponible puede contribuir a mejorar el manejo de estos pacientes. Para ello, parece imprescindible la creación de un grupo multidisciplinar que permita integrar el conocimiento de las enfermedades o tratamientos que puedan causar una inmunosupresión, la actualización de la indicación de tratamientos en estos pacientes de alto riesgo, las peculiaridades de la infección por SARS-CoV-2 y el conocimiento de la respuesta a la vacunación en estos pacientes.
Un nuevo escenario en la pandemia por COVID
El desarrollo y administración generalizada de las vacunas contra la COVID-19 a finales del 2021 ha contribuido a proteger a los pacientes vulnerables. Al mismo tiempo, la aparición de la variante ómicron del SARS-CoV-2, con mayor transmisibilidad pero menor gravedad, ha disminuido de manera progresiva los casos de hospitalización por infección grave y prácticamente han desaparecido los ingresos en las unidades de cuidados intensivos (UCI). El porcentaje de ingresos en las UCI respecto a las hospitalizaciones se ha situado por debajo del 5% por primera vez en esta pandemia en abril de 2022 (semana 14)7, como se muestra en la figura 1 .Figura 1 Ingresos hospitalarios e ingresos en las unidades de cuidados intensivos de Cataluña durante la pandemia por COVID.
Se muestran los ingresos hospitalarios y los ingresos en las UCI durante la pandemia por COVID evidenciando las 6 olas de la pandemia. Se muestra el porcentaje de ingresos en UCI respecto a los ingresos hospitalarios, que se sitúa por debajo del 5% a partir del mes de abril de 2022 (semana 14).
UCI: Unidad de Cuidados Intensivos.
Así, a partir de la sexta ola de la pandemia, ha habido un cambio en las estrategias de control a nivel europeo, en que se ha pasado de una reducción de la circulación comunitaria del virus (uso de mascarilla, lavado de manos, distancia social, restricciones o confinamientos) a una libre circulación en la comunidad con estrategias de protección en los pacientes vulnerables, o con riesgo de progresión (dosis de refuerzo vacunal, diagnóstico y tratamiento precoz en los pacientes vulnerables e, incluso, tratamiento preexposición).
Sin embargo, aunque existe una alta cobertura vacunal de la población general, hay datos limitados sobre la respuesta a las vacunas en los pacientes vulnerables. Una revisión sistemática de 57 estudios analizó la seroconversión en pacientes con neoplasias hematológicas y se evidenció una respuesta a la vacuna entre el 38,1% y el 99%, con una respuesta más alta en las enfermedades mieloproliferativas y una menor respuesta en los pacientes con leucemia linfática crónica (LLC) B. También se evaluó la respuesta a la administración de la vacuna en función de los tratamientos recibidos, observándose una menor seroconversión en los tratamientos con depleción de células B en comparación con los otros tratamientos, especialmente si este tratamiento se administró en los últimos 12 meses8. Otros datos preliminares señalan también una baja respuesta en pacientes de edad avanzada con mieloma9. También se ha descrito una menor respuesta vacunal en los pacientes con neoplasia de órgano sólido, aunque en menor grado que en las enfermedades hematológicas. En esta misma revisión algunos de los factores que se relacionan con una menor respuesta a la administración de vacunas son: edad > 65 años, neoplasias hematológicas, quimioterapia citotóxica, anticuerpos monoclonales (anti-CD20, anti-CD38), fármacos inmunomoduladores, terapias dirigidas (inhibidores de la BCL2, BTK, JAK1/JAK2), enfermedad neoplásica activa o diseminada y linfopenia10.
En nuestro entorno el grupo más prevalente es el de los pacientes en tratamiento con fármacos anti-CD20, especialmente el rituximab. El rituximab es un anticuerpo monoclonal quimérico diseñado por ingeniería genética que reduce las células B CD20+, provocando su destrucción a través de la citotoxicidad celular, la activación del complemento y la inducción de la apoptosis de células B directamente por la unión al fármaco11. En la actualidad, está aprobado por la Asociación Europea del Medicamento para el tratamiento del linfoma no hodgkiniano, la leucemia linfocítica crónica, la artritis reumatoide, la esclerosis múltiple, la granulomatosis con poliangeítis y la poliangeítica12.
Tras el tratamiento con rituximab, las células B suelen recuperarse a los 6 meses, alcanzando los valores normales en sangre a los 12 meses. Menos del 20% de los pacientes tratados con anticuerpos monoclonales presentan un descenso de la concentración sérica de las inmunoglobulinas (IgG o IgM) por debajo de los valores de referencia a los 5-11 meses de la administración de rituximab. Esta hipogammaglobulinemia, junto a la linfopenia, podría explicar la menor respuesta a la administración de vacunas por SARS-CoV-2, sobre todo si este tratamiento se ha realizado en los últimos 12 meses13.
Así, aunque la vacunación en la población general ha protegido de la infección grave a las personas inmunocompetentes, para los pacientes con factores que condicionen una menor seroconversión se deberían adoptar estrategias que minimizaran el riesgo de progresión a enfermedad grave: aumentar la cobertura vacunal (vacunación heteróloga, vacunación de refuerzo), plantear el uso de tratamientos farmacológicos (anticuerpos monoclonales, plasma convaleciente) o no farmacológicos (distancia social, uso de la mascarilla). Y, al mismo tiempo, garantizar la difusión de la información y los consejos de prevención a los pacientes vulnerables para evitar la infección por SARS-CoV-2 y valorar la determinación de anticuerpos después de la vacunación para evaluar el estado serológico, lo que determinará la selección del tratamiento en caso de infección. Otras estrategias serían suspender el tratamiento inmunosupresor en el momento de la inmunización en función del perfil del paciente, la enfermedad asociada y los tratamientos administrados14.
Nuevos tratamientos específicos para el SARS-CoV-2
En el ámbito del sistema catalán de salud existen las recomendaciones de tratamiento dentro del programa de harmonización farmacoterapéutica, según el protocolo de tratamiento farmacológico de la infección por SARS-CoV-2 del Servicio Catalán de la Salud15, y que se sustentan con las indicaciones de la Agencia Española de Medicamentos y Productos Sanitarios16. Durante la evolución de la pandemia de la COVID estos tratamientos han ido cambiando en función de la evidencia obtenida. En la versión del protocolo de 26 de enero de 2022 se indicaba el tratamiento específico de infección leve-moderada, pero con factores de riesgo de progresión, y posteriormente se añadía la indicación de tratamiento con anticuerpos monoclonales en fase preexposición.
El tratamiento preexposición con anticuerpos monoclonales en pacientes de riesgo de progresión sin evidencia de seroconversión (título de anticuerpos inferior a 260 BAU/ml después de una pauta completa de vacunación o con contraindicación de la vacunación por anafilaxia) se aconseja con la combinación de tixagevimab/cilgavimab, que se administra por vía intramuscular de forma consecutiva (2 dosis de 150 mg, una en cada glúteo). Desde el 22 de abril de 2022 se dispone de una prepublicación del ensayo clínico que incluía a 1.417 pacientes hospitalizados con infección confirmada por SARS-CoV-2, en los que se demostraron diferencias en la mortalidad a los 90 días17.
Los tratamientos que se proponen en fase de infección leve-moderada en los pacientes con factores de riesgo de progresión son, por orden de prioridad y según disponibilidad: la combinación de nirmatrelvir/ritonavir de administración oral, el remdesivir (indicado en pacientes con respuesta vacunal) y los anticuerpos monoclonales casirivimab/imdevimab (sin respuesta vacunal y con infección causada por una variante distinta a ómicron) y sotromivab (sin respuesta vacunal y con infección por la variante ómicron).
Actualmente, por la eficacia, facilidad de acceso y de uso, se considera que la primera opción terapéutica recomendada es nirmatrelvir/ritonavir en pauta de 5 días. La combinación de nirmatrelvir/ritonavir se administra de forma oral, con 2 comprimidos de 150 mg de nirmatrelvir y un comprimido de 100 mg de ritonavir cada 12 h. El nirmatrelvir inhibe la proteasa principal del SARS-CoV-2 y reduce la capacidad de replicación del virus, mientras que el ritonavir actúa como potenciador, ya que inhibe el metabolismo de nirmatrelvir y aumenta las concentraciones plasmáticas. En Cataluña el acceso al fármaco es el circuito habitual de la receta electrónica. Hay que ajustar la dosis según la función renal y deben evaluarse las interacciones con otros fármacos. El tratamiento debe iniciarse en los primeros 5 días de los síntomas. Los datos de eficacia provienen del ensayo clínico EPIC-HR18, que incluyó a pacientes ambulatorios no vacunados que tenían una enfermedad leve o moderada causada mayoritariamente por la variante delta y, como mínimo, un factor de riesgo de progresión. De un total de 2.085 pacientes se redujo el riesgo de una variable combinada que incluía hospitalización por COVID-19 o muerte por cualquier causa en un periodo de 28 días en comparación con placebo (0,77% frente a 6,31%; p < 0,001; NNT = 18 [14-25]).
El remdesivir es un análogo de nucleótido que presenta actividad in vitro contra el SARS-CoV-2 mediante la inhibición de la replicación del ARN. En un ensayo en fase 3 (ensayo SIMPLE), demostró que el tratamiento con este fármaco durante 5 o 10 días disminuía el tiempo de recuperación en los pacientes que precisaban un ingreso hospitalario por COVID-1919. En diciembre de 2020, tras revisar todos los datos de eficacia y seguridad disponibles, se limitó su autorización de uso a los pacientes con requerimientos de oxígeno de flujo bajo, flujo alto o ventilación no invasiva, y se excluyó a los pacientes con ventilación invasiva o ECMO. Recientemente, se ha demostrado la reducción de la hospitalización o muerte en el 87% en el tratamiento ambulatorio en la fase precoz, con una pauta corta de 3 días en pacientes con infección leve por SARS-CoV-2 y con factores de riesgo de progresión20.
Casirivimab/imdevimab es una combinación de 2 anticuerpos monoclonales contra la proteína spike del SARS-CoV-2 que ha demostrado una reducción en la carga viral, una disminución de la duración de los síntomas y de la necesidad de atención sanitaria en pacientes con sintomatología leve en una fase precoz de la enfermedad (<7 días de síntomas) y con serologías negativas frente al SARS-CoV-221. Además, también se ha demostrado su eficacia con la administración subcutánea22.
Finalmente, el sotromivab es un anticuerpo monoclonal frente al SARS-CoV-2 que ha demostrado una reducción de la hospitalización y muerte en el 85% de los pacientes con infección por SARS-CoV-2 precoz (<5 días) y alto riesgo de progresión según la edad (>55 años) y comorbilidades, como diabetes, obesidad, enfermedad renal crónica, insuficiencia cardíaca, enfermedad pulmonar obstructiva crónica y asma severa-moderada23.
Para el uso de los anticuerpos monoclonales se precisa una valoración del estado serológico del paciente (respuesta a la vacunación por SARS-CoV-2) y analizar las variantes actuales del SARS-CoV-2, ya que los distintos anticuerpos monoclonales tienen sensibilidades distintas según las variantes. Casirivimab/imdevimab presenta una baja actividad ante las distintas variantes ómicron y sotrovimab es activo ante las variantes omicron BA.1, pero presenta una actividad más reducida ante las variantes BA.2 y BA.4/524, estas últimas actualmente predominantes en nuestro entorno.
Pacientes de alto riesgo con COVID
Uno de los principales problemas en la atención sanitaria a los 2 años del inicio de la pandemia por COVID es el riesgo de infección en los pacientes vulnerables, sobre todo aquellos con inmunodeficiencias y falta de respuesta a la vacunación.
En los pacientes con tratamiento activo por una neoplasia, sobre todo las hematológicas, se ha observado una mayor gravedad en los casos de infección por SARS-CoV-2, probablemente por la linfopenia y la hipogammaglobulinemia, secundarias a la enfermedad subyacente o los tratamientos administrados. Un caso particular son los pacientes que precisan tratamientos anti-CD20, con linfopenia e hipogammaglobulinemia secundarias, en la que se ha descrito una falta de respuesta a la vacuna.
En los momentos en los que hay una disponibilidad limitada de las nuevas alternativas terapéuticas frente a la infección por SARS-CoV-2 se hace necesario establecer unos criterios de priorización en el acceso precoz a ellas.
Del mismo modo que ocurrió durante el programa nacional de vacunación, se han ido definiendo grupos de riesgo de progresión. A finales de enero, se contemplaban los pacientes con inmunodepresión por tratamientos principalmente hematológicos. Después se añadió a los pacientes con quimioterapia citotóxica o con determinación de linfopenia o neutropenia y, de forma paulatina, se han ido incorporando grupos de riesgo en función de la inmunosupresión causada por los fármacos. Este grupo de pacientes conforma el grupo 1. Recientemente se han incorporado los grupos 2-4, en función de la edad, el estado vacunal y la comorbilidad. En la tabla 1 se describen los grupos de población de riesgo de progresión en caso de infección por SARS-CoV-2 leve-moderada.Tabla 1 Situaciones de alto riesgo priorizadas para el tratamiento de la infección por SARS-CoV-2 leve-moderada
Tabla 1Grupo 1. Personas inmunocomprometidas y con otras situaciones alto riesgo, independientemente del estado de vacunación:
• Receptores de trasplante de progenitores hematopoyéticos o CAR-T, en los 2 años tras el trasplante/tratamiento, en tratamiento inmunosupresor o que tengan enfermedad injerto contra huésped independientemente del tiempo desde el trasplante de precursores hematopoyéticos
• Receptores de trasplante de órgano sólido (menos de 2 años o con tratamiento inmunosupresor para eventos de rechazo)
• Tratamiento sustitutivo renal (hemodiálisis y diálisis peritoneal)
• Inmunodeficiencias primarias: combinadas y de células B en las que se haya demostrado ausencia de respuesta vacunal
• Tratamiento activo con quimioterapia mielotóxica para enfermedades oncológicas o hematológicas. Se excluye el uso de hormonoterapia, inhibidores de checkpoint inmunes u otros tratamientos que no condicionan aumento en el riesgo de infección (por ejemplo, anticuerpos monoclonales antidiana no mielotóxicos)
• Pacientes con tratamientos onco-hematológicos no citotóxicos con neutropenia (<500 neutrófilos/mcL) o linfopenia (<1.000 linfocitos/mcL) en el momento de la infección
• Infección por VIH con ≤200 cel/ml (analítica en los últimos 6 meses)
• Fibrosis quística
• Síndrome de Down con 40 o más años de edad (nacidos en 1981 o antes)
Tratamiento inmunosupresor con glucocorticoides orales a altas dosis o durante tiempo prolongado y ciertos inmunomoduladores no biológicos:
• Tratamiento con glucocorticoides orales a altas dosis de manera continuada (equivalente a ≥20 mg/día de prednisolona durante 10 o más días consecutivos en los 30 días previos)
• Tratamiento prolongado con glucocorticoides orales a dosis moderadas (equivalente a ≥10 mg/día de prednisolona durante más de 4 semanas consecutivas en los 30 días previos)
• Altas dosis de glucocorticoides orales (equivalente a >40 mg/día de prednisolona durante más de una semana) por cualquier motivo en los 30 días previos
• Tratamiento en los 3 meses anteriores con alguno de los siguientes fármacos inmunomoduladores no biológicos: metotrexato (>20 mg/sem o >15 mg/m2/sem, oral o subcutáneo), leflunomida, 6 mercaptopurina (>1,5 mg/kg al día) o azatioprina (>3 mg/kg al día), ciclosporina, micofenolato, tacrolimus (formas orales), sirolimus y everolimus en los 3 meses previos.
• Tratamiento inmunosupresor con inmunomoduladores biológicos: personas que han recibido en los 3 meses anteriores (6 meses en caso de anti-CD20) terapia específica con alguno de los fármacos de los siguientes grupos:
• Anticuerpos monoclonales anti CD20: rituximab, ocrelizumab, obinutuzumab, ibritumomab tiuxetan
• Inhibidores de la proliferación de células B: ibrutinib, acalabrutinib
• Proteínas de fusión supresoras de linfocitos T: abatacept
• Inhibidores de la interleucina 1 (IL-1): anakinra, canakinumab
• Anticuerpos monoclonales anti-CD52: alemtuzumab
• Moduladores del receptor de la esfingosina-1-fosfato: fingolimod, siponimod.
• Inhibidores de la proteincinasa: afatinib, axintinb, crizotinib, dabrafenib, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, ruxolitinib, sorafenib, sunitinib, temsirolimus, vandetinib, etc.
• Inhibidores de la familia janus cinasa (JAK): tofacitinib, baricitinib, upadacitinib, filgotinib
Grupo 2. Personas no vacunadasa con >80 años
Grupo 3. Personas no vacunadasa con >65 años y con al menos un factor de riesgo para progresiónb
Grupo 4. Personas vacunadas (> 6 meses) con > 80 años y con al menos un factor de riesgo para progresiónb
a Se consideran personas no vacunadas las personas que no han recibido la pauta de vacunación completa (incluidas las dosis de recuerdo) y no han padecido la enfermedad en los 3 últimos meses.
b Se consideran factores de riesgo de progresión:
• Enfermedad renal crónica: estadios de enfermedad renal crónica 3b, 4 o 5 (tasa de filtración glomerular inferior a 45 ml/min).
• Enfermedad hepática crónica: clasificación en la escala de Child-Pugh de clase B o C (enfermedad hepática descompensada).
• Enfermedad neurológica crónica (esclerosis múltiple, esclerosis lateral amiotrófica, miastenia gravis o enfermedad de Huntington).
• Enfermedades cardiovasculares, definidas como antecedentes de cualquiera de los siguientes: infarto de miocardio, accidente cerebrovascular, accidente isquémico transitorio, insuficiencia cardíaca, angina de pecho con nitroglicerina prescrita, injertos de revascularización coronaria, intervención coronaria percutánea, endarterectomía carotídea y derivación aórtica.
• Enfermedad pulmonar crónica: enfermedad pulmonar obstructiva crónica de alto riesgo (FEV1 posbroncodilatación < 50% o disnea [mMRC] de 2-4 o 2 o más exacerbaciones en el último año o un ingreso) o asma con requerimiento de tratamiento diario.
• Diabetes con afectación de órgano diana.
• Obesidad (IMC?≥?35).
Estructura y funcionamiento de la unidad COVID de alto riesgo
El de Mataró es un hospital general, de referencia del Maresme Central, en la provincia de Barcelona, con una población de 275.000 habitantes. Como recursos asistenciales contamos con un hospital de día con una enfermera de infecciones a jornada completa y de un hospital a domicilio (HAD) que cubre toda la zona de influencia. El centro de tercer nivel y de referencia del nuestro es el Hospital Universitari Germans Trias i Pujol (HUGTiP) de Badalona, a 20 km de distancia. En este centro son servicios de referencia el Institut Català d’Oncologia (ICO) de Hematología, en el que se realiza trasplante hematopoyético, y el Servicio de Nefrología, centro con trasplante renal (en el hospital de Mataró no existe servicio de nefrología).
Unidad COVID de alto riesgo
Ante la creación de una Unidad COVID de alto riesgo (Unidad COVID AR), en nuestro entorno asistencial, asumimos que el perfil del paciente candidato a tratamiento precoz específico para una infección leve-moderada por SARS-CoV-2 es el que está bajo tratamiento con fármacos anti-CD20 (sobre todo rituximab y ocrelizumab) y el que está en tratamiento con quimioterapia. De manera conjunta con el Servicio de Farmacia y los servicios prescriptores se analizaron los tratamientos realizados en nuestro centro en los últimos 6 meses con fármacos anti-CD20 (unos 80 tratamientos). Decidimos convocar a todos los servicios prescriptores (Hematología, Neumología, Medicina Interna, Neurología y Reumatología), junto al servicio de Oncología, a la primera reunión para la creación de la Unidad COVID AR a principios de marzo de 2022.
Uno de los retos en la atención a estos pacientes era la existencia de una determinación de anticuerpos anti-spike para valorar la respuesta vacunal (al ser este dato necesario para decidir la indicación del tratamiento específico) y la detección precoz de la infección por SARS-CoV-2 (indicación del tratamiento en los 5 días de inicio de los síntomas). Se decidió rellenar una hoja con información de los pacientes de alto riesgo (tratamiento con fármacos anti-CD20 y tratamiento con quimioterapia), en la que se indicaba la necesidad de una extracción sanguínea para evaluar la respuesta humoral a las vacunas administradas. En ella se adjuntaban 2 teléfonos del Servicio de Medicina Interna para contactar en caso de infección por SARS-CoV-2 (uno en horario laboral y otro en cualquier momento).
Se acordó entregar la hoja informativa y realizar una serología para anticuerpos anti-spike frente a SARS-CoV-2 a todos los pacientes en tratamiento activo por fármacos anti-CD20 y quimioterapia. En el subgrupo de los pacientes con fármacos anti-CD20 identificamos a los que habían recibido tratamiento en los últimos 6 meses.
Para facilitar la solicitud de las serologías se creó un perfil analítico propio (COVID AR) y también se incluyó la serología de SARS-CoV-2 en el perfil utilizado para el cribado al inicio de quimioterapia en el paciente oncológico.
Protocolo de tratamiento específico para la infección por SARS-CoV-2 leve-moderada en pacientes con riesgo de progresión
Uno de los objetivos de los grupos multidisciplinares de trabajo es promover la práctica cínica protocolizada en las diferentes especialidades y reducir la variabilidad en el manejo de los pacientes. Los protocolos consensuados son un soporte práctico disponible en la intranet del hospital.
Una vez los pacientes con alto riesgo de progresión estuvieron identificados, el proceso de solicitud de las serologías iniciado y los canales de detección precoz abiertos, la Comisión de Infecciones del hospital aprobó el protocolo de tratamiento específico de la infección leve-moderada en pacientes vulnerables. En este protocolo se especificaban los criterios de tratamiento y la indicación de los distintos fármacos. Se establecieron los circuitos de aviso ante la aparición de casos y los recursos asistenciales disponibles en función del tratamiento indicado, así como el seguimiento posterior de la evolución por la Unidad COVID AR.
En resumen, ante un aviso de infección por SARS-CoV-2, el médico referente de la Unidad revisa la historia clínica del paciente y contacta telefónicamente con él para corroborar la información del diagnóstico (el día de la prueba diagnóstica), así como los días de síntomas. Evalúa el estado serológico y, en función de estos datos, decide la indicación del tratamiento y el fármaco priorizado según los protocolos vigentes.
Si el paciente da su consentimiento, se procede a solicitar el fármaco a la Farmacia hospitalaria (en caso de tratamiento oral, para la validación de la receta). Si se precisa administración intravenosa se informa al dispositivo asistencial correspondiente: HAD para tratamiento con remdesivir (3 días) u Hospital de Día para la administración de sotromivab (una sola dosis). Si el paciente es identificado en el Servicio de Urgencias, se inicia el tratamiento indicado y, en caso de precisar más dosis, se ingresa posteriormente en HAD. También se valora el inicio de tratamiento en pacientes con ingreso hospitalario.
Una vez administrado el tratamiento, el médico referente de la unidad realiza un seguimiento telefónico semanal durante 4 semanas y, al mes, fija una visita presencial con control analítico y radiológico.
En caso de no estar indicado el tratamiento por detectar la infección en un periodo >5 días de síntomas (en el caso de nirmatrelvir/ritonavir o sotromivab) o >7 días (en el caso de remdesivir), se informa al paciente e igualmente se realiza un seguimiento telefónico semanal para descartar un empeoramiento clínico hasta el mes de seguimiento.
Si el paciente precisa de ingreso en régimen de HAD, deberá dar su consentimiento y aceptar los criterios de ingreso (tener un teléfono de contacto y asegurar un cuidador en el domicilio 24 h durante el transcurso del ingreso).
Atención al paciente de riesgo en el área de referencia territorial del centro
Con la incorporación del tratamiento oral con nirmatrelvir/ritonavir se consensuó un protocolo entre atención primaria y especializada. De forma resumida, en los grupos de riesgo 1 se indicaba el tratamiento a través de la Unidad COVID AR, mientras que en los grupos 2-4 la indicación venía de los médicos de atención primaria o bien desde las urgencias del hospital. Igualmente, se ofrecía el contacto telefónico de la Unidad para posibles consultas ante la identificación de los pacientes de cualquier grupo de riesgo en cualquier nivel asistencial (atención ambulatoria, hospitalización o urgencias).
En la figura 2 se muestra el circuito asistencial de la atención al paciente con infección por SARS-CoV-2 leve-moderada de alto riesgo.Figura 2 Circuito asistencial de los pacientes con infección por SARS-CoV-2 leve-moderada con factores de riesgo de progresión.
Unidad COVID AR (alto riesgo).
Difusión de las acciones de la Unidad COVID AR y formación continuada
Las propuestas, programas, acciones y recomendaciones de la Unidad COVID AR tendrían escasa proyección si no se acompañaran de un programa de difusión y formación médica continuada dirigida a los diferentes niveles asistenciales. Hay diversas estrategias que incluyen la difusión de los protocolos a través de la intranet del hospital, la elaboración de hojas de recomendaciones, la organización de jornadas formativas, la difusión de contenidos de ámbito hospitalario y ambulatorio y la difusión de los resultados en las distintas reuniones y congresos de las sociedades científicas.
Uno de los principales objetivos es la implicación de la enfermería especializada que atiende pacientes de riesgo de progresión. La educación sanitaria que ejercen en el paciente al inicio y durante los tratamientos y el acceso directo de los pacientes para comunicar cualquier evento adverso los sitúa como un especialista más de referencia.
Promover la investigación en el campo de la infección por SARS-CoV-2 en los pacientes de alto riesgo
Finalmente, el registro de la actividad de la Unidad AR y sus resultados tiene que proporcionar proyectos de investigación que lideren los integrantes de la Unidad y que ayuden a mejorar la atención a los pacientes vulnerables con relación a factores pronósticos de respuesta a los tratamientos y a la calendarización de los programas de vacunación, entre otros.
Impacto de la infección por SARS-CoV-2 leve-moderada en los pacientes de alto riesgo en la práctica real
Desde la aprobación del tratamiento de la infección leve o moderada se ha atendido en el Hospital de Mataró a un total de 31 pacientes, los 6 primeros sin la estructura de la Unidad COVID AR. Desde la implementación de la Unidad COVID AR se ha conseguido un alto porcentaje de determinación de serologías, que permitieron una indicación precoz del tratamiento. En 8 pacientes no se indicó tratamiento específico al estar fuera de periodo (>5 o 7 días).
En la tabla 2 se muestran los pacientes atendidos, la enfermedad de base y el tratamiento inmunosupresor, así como la indicación de tratamiento específico y la ubicación de la administración.Tabla 2 Pacientes atendidos en el Hospital de Mataró desde la indicación de tratamiento por infección por SARS-CoV-2 leve-moderada con factores de riesgo de progresión
Tabla 2Paciente Enfermedad Tratamiento Serología Medicamento Ubicación
1 LNH Rituximab ? Remdesivir HaD
2 LNH Rituximab Desconocida Remdesivir HaD
3 LNH Rituximab ? - >7 días
4 Linfoma Rituximab ? Remdesivir HaD
5 Linfoma Rituximab ? - >7 días
6 EM Rituximab ? Remdesivir Hospitalización
7 Linfoma Rituximab negativas - >7 días
8 LLC Obinutuzumab ? Remdesivir Hospital de día
9 Neoplasia de colon Folfox Desconocida Remdesivir HaD
10 Neoplasia de pulmón Osimertinib Desconocida Remdesivir HaD
11 LES Rituximab Desconocida Remdesivir HaD
12 Linfoma Rituximab Negativas Sotromivab Hospital de Día
13 Trasplante renal Tacrolimus ? Remdesivir HaD
14 MM TAPH Desconocida N/R CCEE
15 Linfoma Rituximab Negativas Sotromivab Urgencias
16 Linfoma Rituximab Negativas - >5 días
17 Neoplasia de colon Capox Desconocida Remdesivir HaD
16 Linfoma Rituximab Negativas Sotromivab Hospital de Día
17 Leucemia Azacitidina + Venetoclax Desconocida Remdesivir Hospitalización
18 Colangiocarcinoma Gemcitabina Desconocida - FG<30
19 Trasplante cardíaco Tacrólimus ? Remdesivir HaD
20 Neoplasia mama Paclitaxel Desconocida - >7 días
21 Linfoma Rituximab Negativas - >7 días
22 Neoplasia de ovario Niraparib Desconocida Remdesivir Urgencias/HaD
23 LNH Rituximab Desconocida Sotromivab Hospital de Día
24 Sarcoma indiferenciado VAC Desconocida Remdesivir Urgencias
25 Anemia hemolítica Rituximab Desconocida N/R CCEE
26 EM Ocrelizumab Negativas Sotromivab Hospital de Día
27 Mesotelioma maligno Carboplatino Positivas N/R CCEE
28 Colangiocarcinoma Gemcitabina Desconocida - >7 días
29 Neoplasia esofagogástrica Radioterapia Negativas Sotromivab Hospitalización
30 Carcinoma de origen desconocido Folfox Negativas Sotromivab Hospitalización
31 Neoplasia mama Eribulina Desconocida - >7 días
Capox: capecitabina/oxaliplatino; CCEE: consultas externas; EM: esclerosis múltiple; FG: filtrado glomerular; Folfox: leucovorina cálcica/fluorouracilo/oxaliplatino; HaD: hospital a domicilio; LES: lupus eritematoso sistémico; LLC: leucemia linfática crónica; LNH: linfoma no hodgkiniano; MM: mieloma múltiple; N/R: nirmatrelvir/ritonavir; TAPH: trasplante autógeno de progenitores hematopoyéticos; VAC: vincristina/dactinomicina/ciclofosfamida.?: serología desconocida en el momento de la indicación de tratamiento; posteriormente, serologías negativas.
Como indicador de la actividad ambulatoria de la Unidad COVID AR, durante los meses de mayo y junio de 2022, 2 meses con un aumento de ingresos hospitalarios por infección por SARS-CoV-2 (séptima ola), ingresaron en el Hospital de Mataró 183 pacientes con COVID-19, 24 de los cuales precisaron tratamiento específico con antivirales. En el mismo periodo de tiempo, se administraron 14 tratamientos con antivirales ambulatorios en la Unidad COVID AR.
Conclusiones
La creación de un grupo multidisciplinar, la Unidad COVID AR, con todos los profesionales implicados en la atención a los pacientes en riesgo de progresión en caso de infección por SARS-CoV-2 leve-moderada, ha significado un cambio cualitativo en el manejo y la atención a estos pacientes. A partir de una primera fase de difusión de la información de los nuevos protocolos de tratamiento y la necesidad de serologías para SARS-CoV-2 y de la identificación precoz de los casos de infección, se ha derivado la aprobación de los protocolos, tanto a nivel hospitalario como territorial, lo que ha permitido una respuesta eficaz y rápida en este nuevo abordaje de la pandemia. El afianzamiento del grupo de trabajo, desde una perspectiva personal y profesional, ha aportado, además, la creación de una red colaborativa ágil y la puesta en marcha de proyectos clínicos y de investigación.
Financiación
Ninguna.
Conflicto de intereses
Los autores declaran no tener relación financiera que pudiera dar lugar a un conflicto de intereses en relación con este trabajo.
Ramon Boixeda ha recibido ayudas por ponencias, colaboraciones científicas o asistencia a congresos de Astra-Zeneca, Bayer, Boheringer-Ingelheim, Chiesi, Esteve, Ferrer, Gilead, GSK, Menarini, Novartis, Pfizer y Rovi.
Alba Palau ha recibido ayudas para asistencia a congresos de Gilead y GSK.
Montserrat García ha recibido ayudas por ponencias, colaboraciones científicas o asistencia a congresos de Boheringer-Ingelheim, Janssen, Novartis, Rovi y Pfizer.
Esther Plensa ha recibido ayudas por ponencias, colaboraciones científicas o asistencia a congresos de Boheringer-Ingelheim, Janssen, Novartis, Leo Pharma, Bristol Myers Squibb y Pfizer.
Anexo Miembros de la Unidad COVID de alto riesgo del Hospital de Mataró
Ramon Boixeda (Servicio de Medicina Interna. Hospital de Mataró, Consorci Sanitari del Maresme. Mataró), Alba Palau (Servicio de Medicina Interna. Hospital de Mataró, Consorci Sanitari del Maresme. Mataró), Montserrat García (Servicio de Hematología. Hospital de Mataró, Consorci Sanitari del Maresme. Mataró; ICO-Hospital Germans Trias i Pujol. Badalona), Gabriela Casinos (Servicio de Medicina Interna. Hospital de Mataró, Consorci Sanitari del Maresme. Mataró), Javier Fernández (Servicio de Medicina Interna. Hospital de Mataró, Consorci Sanitari del Maresme. Mataró), Laia Albiach (Servicio de Medicina Interna. Unidad de Infecciones. Hospital de Mataró, Consorci Sanitari del Maresme. Mataró), Esther Plensa (Servicio de Hematología. Hospital de Mataró, Consorci Sanitari del Maresme. Mataró), Lluís Campins (Servicio de Farmacia. Hospital de Mataró, Consorci Sanitari del Maresme. Mataró), Sandra Bacca (Hospitalización a Domicilio. Hospital de Mataró, Consorci Sanitari del Maresme. Mataró), Vanessa Vicente (Hospital de Día. Hospital de Mataró, Consorci Sanitari del Maresme. Mataró), Virginia Casado (Servicio de Neurología. Hospital de Mataró, Consorci Sanitari del Maresme. Mataró), Candela Álvarez (Servicio de Oncología. Hospital de Mataró, Consorci Sanitari del Maresme. Mataró), Paula Fernández (Servicio de Medicina Interna. Unidad de Hospitalización de Oncología. Hospital de Mataró, Consorci Sanitari del Maresme. Mataró), Alejandro Robles (Servicio de Neumología. Hospital de Mataró, Consorci Sanitari del Maresme. Mataró), Mari del Carmen de la Torre (Unidad de Cuidados Intensivos. Hospital de Mataró, Consorci Sanitari del Maresme. Mataró), César Socolich (Servicio de Urgencias. Hospital de Mataró, Consorci Sanitari del Maresme. Mataró).
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| 36522194 | PMC9745547 | NO-CC CODE | 2022-12-15 00:02:33 | no | Med Clin (Barc). 2022 Dec 13; doi: 10.1016/j.medcli.2022.10.001 | utf-8 | Med Clin (Barc) | 2,022 | 10.1016/j.medcli.2022.10.001 | oa_other |
==== Front
Eur J Clin Pharmacol
Eur J Clin Pharmacol
European Journal of Clinical Pharmacology
0031-6970
1432-1041
Springer Berlin Heidelberg Berlin/Heidelberg
3432
10.1007/s00228-022-03432-w
Research
Patients with bariatric surgery: Urgent need for accurate registration of the contraindication to enable safe pharmacotherapy in hospital and primary care
http://orcid.org/0000-0001-5062-9331
Lau Cedric [email protected]
134
Sbaa Ouarda 1
Smeenk Robert 2
http://orcid.org/0000-0001-9071-6421
van Kesteren Charlotte 1
1 grid.413972.a 0000 0004 0396 792X Department of Clinical Pharmacy, Albert Schweitzer Hospital, Dordrecht, the Netherlands
2 grid.413972.a 0000 0004 0396 792X Department of Surgery, Albert Schweitzer Hospital, Dordrecht, the Netherlands
3 grid.430814.a 0000 0001 0674 1393 Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands
4 grid.7692.a 0000000090126352 Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
13 12 2022
16
10 7 2022
21 11 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Purpose
To enable the use of automatic clinical decision support for pharmacotherapy in patients with bariatric surgery, it is necessary to register the contraindication “bariatric surgery” in the hospital, general practitioner (GP), and community pharmacy electronic health record systems. The aim of this research was to quantify the correct registration of this contraindication in hospital, GP, and community pharmacy records. Furthermore, we investigated whether the registration status in primary care was dependent on the registration status in the hospital.
Methods
From patients who underwent bariatric procedures performed in the Albert Schweitzer Hospital (Dordrecht, the Netherlands) between 2018 and 2021, the percentage of registered contraindications in hospital medical records was assessed. Due to feasibility reasons, a subset of the patients’ data was created for assessing the percentage of registered contraindications in GP and community pharmacy records.
Results
Out of 664 patients who underwent bariatric surgery, the contraindication bariatric surgery was registered in 69.1% of the cases. Out of 552 patients, 28.3% and 25.1% were correctly registered in GP and community pharmacy records, respectively. There was no correlation between registration status in the hospital EHR and registration status in GP practices or community pharmacies.
Conclusions
The percentage of correct registration of bariatric surgery in hospital, GP, and community pharmacies is low. To avoid doctors prescribing and pharmacists dispensing drugs to post-bariatric patients without knowing that they have undergone this procedure, better registration of the contraindication is required to enable optimal use of clinical decision support systems for the pharmacotherapy of patients after bariatric surgery.
Keywords
Medication error
Bariatric surgery
Electronic health records
Clinical decision support systems
Care transition
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pmcBackground
The number of bariatric surgical procedures performed has increased globally in the last decade. Of these procedures, Roux-en-Y gastric bypass and gastric sleeve are most frequently performed [1, 2]. In recent years, there has been increased awareness of the correct use of medication after bariatric surgery. Several reviews illustrate that the pharmacokinetics of drugs can change as a consequence of bariatric surgery [3–6], leading to adjusted drug dosing advice. A recent report also described pharmacovigilance signals showing changes in drug efficacy and adverse drug reactions after bariatric surgery [7].
A contraindication is defined as a patient’s feature based on which a drug should be avoided or the dose of the drug adjusted accordingly. It is coded in an unambiguous and comprehensive way as structured data into the electronic health record systems (EHRs) used by physicians and pharmacists. After correct registration of this contraindication, e.g., bariatric surgery, healthcare professionals can exchange the contraindication. In case a drug is prescribed or dispensed to a patient with bariatric surgery, relevant drug-specific recommendations will appear automatically, if available. However, when the contraindication is not entered as structured data, e.g., only described as nonstructured text in the medical history, recommendations will not be automatically triggered when a relevant drug is prescribed or dispensed. Unstructured data are difficult to extract. To date, it is challenging to analyze free-text clinical notes in EHRs [8].
In the Netherlands, recommendations are available for the dose and choice of drugs with respect to the contraindication “bariatric surgery,” proposed by guidelines of the Working Group of the Royal Dutch Association for the Advancement of Pharmacy (KNMP). The recommendations are incorporated into the Dutch computerized medication surveillance systems for all prescribers, including general practitioners (GPs), bariatric surgeons, and pharmacists. These recommendations are frequently updated, forming a major step forward in the implementation of medication safety and optimizing dosing advice in daily clinical practice. However, to use these recommendations via a clinical decision support system, it is essential that bariatric surgery be registered as a contraindication in EHRs.
The Albert Schweitzer Hospital in Dordrecht is one of 19 hospitals in the Netherlands in which bariatric surgery is performed. In this hospital, approximately 200 procedures are conducted annually. Normally, bariatric surgeons inform GPs about the treatment in the hospital. Relevant patient-specific structured information can be shared via a national network (“Landelijk Schakelpunt”) to which the majority of community and outpatient pharmacies, GP practices, and hospitals in the Netherlands are connected.
Clinical decision support for patients with bariatric surgical procedures can be enabled, provided that bariatric surgery is entered as a contraindication in a structured way. Given the potential lifetime benefits of a correctly documented contraindication in all prescribing and pharmacy systems, it is important to ensure that contraindications are properly registered and exchanged with other healthcare providers. Clinical decision support systems have been implemented in multiple countries, such as the USA, Canada, the UK, Denmark, and Australia [9].
The primary aim of this research was to study the percentage of bariatric surgical procedures currently registered by healthcare professionals treating these patients, including hospitals, GPs, and community pharmacists. As a secondary aim, we assessed whether the registrations in GP and pharmacy systems were dependent on the registration status in the hospital.
Methods
Study design, population, and data collection
This cross-sectional study was conducted in the Albert Schweitzer Hospital, a teaching hospital situated in Dordrecht (the Netherlands). The patients who underwent bariatric surgical procedures between 2018 and 2021 and all registrations of the contraindication “bariatric surgery” were extracted from the EHR system HiX 6.1 (Chipsoft, Amsterdam, the Netherlands). In the Netherlands, patients are eligible for bariatric surgery if they are 18 years old or older. The starting date of 2018 was chosen because therapeutic recommendations about dose adjustments after bariatric surgery were implemented in Dutch healthcare systems since then. Moreover, bariatric surgeons in our clinic have implemented the registration of contraindications since 2018.
This study was an evaluation of the process of registering bariatric surgery as a contraindication among patients who underwent bariatric surgery. Due to the nature of this study being an evaluation of healthcare procedures, the local review committee approved this study and declared that it was waived for informed consent from patients.
The percentage of bariatric surgery registered as a contraindication was assessed in both the hospital and primary care settings. For the evaluation in primary care, the researchers contacted the GPs and community pharmacists of patients to check whether the contraindication had been already registered correctly. If no registration was present, the researchers advised them to register the contraindication to enable future benefit. In some cases, GPs and community pharmacies share information about contraindications via a linked electronic patient system. Therefore, the contraindication could have been registered during the research period, which could potentially lead to an overestimation of the registration. Hence, the date of registration was included to prevent incorrect interpretation of the data.
The GPs and community pharmacists were contacted in order from most to least number of patients registered per GP practice or pharmacy. For feasibility reasons, we intended to retrieve data from a subset that consisted of at least 80% of the patients to evaluate registration of the contraindication in a primary care setting.
Statistical analyses
Data were entered into an Access (Microsoft Access; IBM Corp.; version 2016) spreadsheet on a password-protected network. Descriptive statistical analyses were conducted with Access. Medians (ranges) were reported when continuous data were not normally distributed, tested by means of a Q-Q plot. Since a subset was used for the evaluation in primary care, the patient characteristics of the subset and complete dataset were compared with either a two-sample T-test or Chi-square test (two-sided, α = 0.05).
Results
Characteristics of the study sample
From the hospital EHRs, 686 bariatric surgical procedures were extracted between 2018 and 2021. Twenty-two patients underwent multiple bariatric surgical procedures. The first records of these duplicates were excluded, leaving 664 unique patients for assessment of registration in hospital EHRs. Of these, a subset of 552 (83%) was created to retrieve pharmacy and GP data. The subset was based on the pharmacies and GPs that had the most patients per GP practice or pharmacy, as described in the “Methods” section. Figure 1 shows the flowchart for patient eligibility and inclusion. There were no statistically significant differences in the patients’ characteristics between the subset and complete dataset (Table 1).Fig. 1 Flowchart of patient eligibility and study inclusion
Table 1 Overview of patient characteristics
Characteristic Dataset registration in hospital (n = 664) Dataset registration in GP and community pharmacies (n = 549)
Sex: female, n (%) 524 (78.9%) 432 (78.7%)
Age when undergoing bariatric surgery (sd) 44.0 (12.1) 44.0 (12.0)
Year of bariatric surgery, n (%)
2018 220 (33.1%) 174 (31.7%)
2019 196 (29.5%) 161 (29.3%)
2020 105 (15.8%) 89 (16.2%)
2021 143 (21.5%) 125 (22.8%)
Type of bariatric surgery, n (%)
Roux-en-Y gastric bypass 440 (66.3%) 359 (65.4%)
Gastric sleeve 221 (33.3%) 188 (34.2%)
Other 3 (0.5%) 2 (0.4%)
In our dataset, 78.9% of the patients who underwent bariatric surgery were female. The numbers of surgical procedures performed in 2020 and 2021 were lower due to the coronavirus disease 2019 (COVID-19) pandemic. The most commonly performed type of surgery in our clinic was Roux-en-Y gastric bypass.
Registration within the hospital electronic patient record
Out of 664 bariatric patients, bariatric surgery was registered in the primary hospital for a total of 459 cases overall (69.1%). Although the registration percentage tended to increase between 2018 and 2020, this was not the case in 2021 (Fig. 2).Fig. 2 Overview of correctly registered contraindications in the hospital medical record over time
Registration in the primary care setting
In the GP and pharmacy systems, 153 (27.9%) and 133 (24.2%) were registered correctly, respectively. The registrations in the order of hospital, GP, and pharmacy system are visualized in a Sankey diagram in Fig. 3. Green bars indicate correct registration, while red bars indicate incorrect registration. Complete registrations with the contraindication registered in both the GP and pharmacy systems occurred 49 out of 549 times (8.9%), as indicated in the bottom right corner of Fig. 3. In 312/549 (56.8%) cases, neither the GP nor the pharmacy had a registration of the contraindication.Fig. 3 Sankey diagram of bariatric surgery registered as contraindication in hospital and primary care. Red: not registered, green: registered. GP: general practitioner, pharmacy: community pharmacy, surgeries: bariatric surgical procedures performed in Albert Schweitzer Hospital between 2018 and 2021
Based on discussions with GPs and pharmacists, we identified several barriers to having the contraindication registered. First, pharmacies were rarely informed about the contraindication bariatric surgery by either the hospital or GP. Second, pharmacists remarked that patients do not inform them either, possibly due to a lack of awareness of the importance of adequate medication surveillance by pharmacists. Furthermore, although most GPs registered bariatric surgery in the patient records as nonstructured data, some of them were not aware of the need to separately enter the contraindication as structured data.
Furthermore, we did not find a correlation between registration status in the hospital EHR and registration status in GP practices or community pharmacies (Table 2). The number of registered contraindications in the primary care system was slightly higher when the contraindication was registered in the hospital EHR. However, the differences between the groups of registered and unregistered contraindications in the hospital EHR were not statistically significant. Therefore, registration in the hospital did not lead to an improved registration in primary care.Table 2 Registration status in the hospital vs. registration status at GP clinics and community pharmacies. Values were tested with chi-square tests (α = 0.05). GP: general practitioner
Registered in the hospital (n = 395) Not registered in the hospital (n = 154) Difference
Registration status GP
Registered 118 (29.9%) 35 (22.7%) n.s
Unregistered 277 (70.1%) 119 (77.3%)
Registration status community pharmacies
Registered 98 (24.8%) 35 (22.7%) n.s
Unregistered 297 (75.2%) 119 (77.3%)
Discussion
To enable optimal clinical decision support in both hospital and outpatient settings, it is essential to register the contraindication “bariatric surgery” in a structured way in all EHRs. To our knowledge, this is the first study that investigated the extent to which the contraindication bariatric surgery was registered. The contraindication was registered in the hospital EHR for less than 70% of the patients, but the percentages were strikingly lower for GPs and community pharmacies.
The results of our study indicated that a substantial portion of patients who have undergone a bariatric surgical procedure are at risk of being prescribed and dispensed new drugs, which should be better avoided or dosed alternatively. This could be overcome by a better registration in both hospital and primary care settings.
In this research, we did not find an association between registration status in the hospital and in primary care. Thus, registration in hospitals does not guarantee registration in other healthcare institutes. This is probably due to the lack of an automatic integrated medication record system between the inpatient EHR, GP EHR, and community pharmacy system. Therefore, it would be preferred if all healthcare professionals had access to a nationally accessible system of shared contraindications and allergies (nationwide medication record system) [10], without the need for manual registrations. Health information exchange is an evolving concept in multiple countries, including the USA, UK, Australia, Scandinavian countries, Germany, and the Netherlands [11]. In the future, we strongly recommend the registration of contraindications in hospitals to be automatically shared in such a nationwide medication record system.
Patients who underwent bariatric surgery in our hospital before 2018 or who underwent surgery elsewhere were not included in this study. A possibility to identify these patients is by medication reconciliation by a pharmacy technician. Even when the registration did not take place correctly at the time of the surgery, we believe that registration afterward can still be beneficial to patients for future use of medication.
As a limitation of our study setup, we retrieved 83% of the data in the primary care setting. The patient characteristics of the subset were not different from those of the complete dataset. Therefore, there are no reasons to believe that the results of this present research would be different if all data had been retrieved. Although the data were collected from a single bariatric center in the Netherlands, we believe that the results can to some extent be extrapolated to other centers in the Netherlands and perhaps to other countries with similar healthcare systems with clinical decision support systems. Similar barriers for registration will be encountered in other regions, as long as manual registrations are needed in a nationwide system of shared contraindications.
Registration of bariatric surgery as a contraindication can be improved through additional education of healthcare providers and patients. It is essential that hospitals, GPs, and pharmacies cooperate to facilitate proper transfer of relevant patient-specific medical information, including the contraindication bariatric surgery. Moreover, we encourage advising patients to actively share their medical history of bariatric surgery to ensure correct registration in pharmacy and prescribing systems.
Our study focused on the registration itself and not on the number of medication errors that could have been prevented. Further research could be conducted on the medication-related harm that was caused by incorrect registration to further increase awareness among healthcare professionals.
Conclusions
We demonstrate that registration and exchange of the contraindication bariatric surgery in prescribing and community pharmacy systems needs improvement. Better registration of the contraindication enables automatic clinical decision support and thus improves pharmacotherapy for bariatric patients.
Author contribution
All authors contributed to the study conception and design. Data collection and analyses were performed by Ouarda Sbaa and Cedric Lau. The first draft of the manuscript was written by Cedric Lau, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Availability of data and materials
The datasets generated and analyzed during the current study are not publicly available due to individual privacy concerns, but are available from the corresponding author upon reasonable request.
Declarations
Ethical approval
This study was an evaluation of the process of registering bariatric surgery as a contraindication for patients who underwent bariatric surgery. The local committee of the Albert Schweitzer Hospital approved the protocol and declared that no informed consent from patients was required.
Competing interests
The authors declare no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Article
XAI-FR: Explainable AI-Based Face Recognition Using Deep Neural Networks
Rajpal Ankit [email protected]
1Ankit Rajpal
is currently working as an Assistant Professor at Department of Computer Science, University of Delhi. His research interests include image and video watermarking, machine learning, and Data Mining. He has published several papers in reputed international journals and conferences.
http://orcid.org/0000-0002-1385-5572
Sehra Khushwant [email protected]
2Khushwant Sehra
is currently working as a Research Scholar with the Department of Electronic Science, University of Delhi. His research interests include modeling, simulation and fabrication of GaN based HEMT devices. He has worked on image processing, including digital image watermarking and development of facial recognition systems for uncontrolled environments.
Bagri Rashika [email protected]
1Rashika Bagri
received her Master’s Degree in Computer Science from University of Delhi in July, 2021 and Bachelors in Computer Science from University of Delhi. She is currently working as a research scholar in the Department of Computer Science, University of Delhi. Her areas of Interests include Machine Learning, Deep learning and Computer Vision.
Sikka Pooja [email protected]
1Pooja Sikka
received her Bachelor’s in Computer Science from SGGSCC, University of Delhi followed by Masters in Computer Science from Department of Computer Science, University of Delhi. She is currently working in EXL services as a business analyst.
1 grid.8195.5 0000 0001 2109 4999 Department of Computer Science, University of Delhi, New Delhi, 110007 India
2 grid.8195.5 0000 0001 2109 4999 Department of Electronic Science, University of Delhi, South Campus, New Delhi, 110021 India
13 12 2022
118
30 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Face Recognition aims at identifying or confirming an individual’s identity in a still image or video. Towards this end, machine learning and deep learning techniques have been successfully employed for face recognition. However, the response of the face recognition system often remains mysterious to the end-user. This paper aims to fill this gap by letting an end user know which features of the face has the model relied upon in recognizing a subject’s face. In this context, we evaluate the interpretability of several face recognizers employing deep neural networks namely, LeNet-5, AlexNet, Inception-V3, and VGG16. For this purpose, a recently proposed explainable AI tool–Local Interpretable Model-Agnostic Explanations (LIME) is used. Benchmark datasets such as Yale, AT &T dataset, and Labeled Faces in the Wild (LFW) are utilized for this purpose. We are able to demonstrate that LIME indeed marks the features that are visually significant features for face recognition.
Keywords
Explainable AI
Face Recognition
Deep Neural Network
LeNet-5
AlexNet
Inception-V3
VGG16
==== Body
pmcIntroduction
A face recognition system provides a means for the automatic recognition of the various subjects against the already stored datasets. The applications of face recognition include unlocking smartphones, searching missing persons, etc. With advancement in digital technology, face recognition is also being used in various cyber investigations [1, 2]. This complements well with the aftermath of the COVID-19 outbreak, which has forced the world to adopt face recognition technology with a primary focus on the contact-less operation [3, 4]. The most prominent issue that affects the outcome of face recognition systems is related to the illumination variation, which may be due to varying lighting conditions [5]. Aside from this, concerns with posture variation or camera angles can cause significant changes in facial appearance and/or form, as well as intra-subject face variations [2, 4–6]. Also, the occlusion of a face by other objects or varying levels of emotions may impede the performance of face recognition systems [7].
To deal with uncontrolled environments which may lead to false positives and negatives during classification, and to improve the overall performance of the face recognition systems, various techniques have been proposed by research groups all over the world. Tang et al. [8] employed a novel Distance Weighted Linear Regression Classifier (DWLRC) to overcome the problem of faces being misclassified in the systems using linear regression. The distance between each sample point and the original linear space is utilized as an adjustment parameter to optimize the regression line in order to produce a better result under varied scenarios. The proposed methodology outperforms the traditional Linear Regression Classifier (LRC), Nearest-Farthest Subspace (NFS), Kernel Linear Regression Classifier (KLRC), and Center-based Weighted Kernel Linear Regression Classifier (CWKLR). The method reported recognition rates of 96% on the AT &T dataset.
In addition to the above, other Machine Learning (ML) algorithms have also been utilized for the robust classification of face samples. Damale et al. [9] have presented three different methods based on ML paradigms, based on Support Vector Machine (SVM), Perceptron Multilayer (MLP), and Convolutional Neural Network (CNN). SVM and MLP approaches rely on features extracted through Principal Component Analysis (PCA) and Linear Discriminant Analysis (LDA), whereas in CNN the images are directly used as a feature vector. The proposed systems, as reported, demonstrated test accuracies of nearly 87%, 86.5%, and 98% for SVM, MLP, and CNN respectively on self-generated databases. Abuzneid et al. [10] proposed an improved face recognition system using Back-Propagation Neural Network (BPNN) supported by a pre-processing through a Haar-Cascade detection, Histogram Equalization (HE), and local feature extraction through Local Binary Patterns (LBP) descriptor. The system, as reported achieves an accuracy of ∼ 98% on both Yale and ORL datasets with a significant reduction in computational time. In addition to this, an Ensemble-aided face recognition approach proposed by Venkateswar et al. [11], demonstrated good performance in rough environments by relying on Image Frontalization and pre-processing through different enhancement methods. The feature extraction is based on several descriptors including histograms of gradients (HOG), improved center-symmetric local binary patterns (ICSLBP), SIFT descriptors, and dominant color structure descriptors for final classification through SVM. This approach combines the utility of robust pre-processing with a good classification accuracy of 99% and 94% for the data samples from FERET and LFW databases respectively.
Qu et al. [12] demonstrated another face recognition system based on CNN and FPGA. This is important primarily because the FPGA is able to implement parallel computing and can be used to design exotic logic circuits, which help in achieving higher processing speed in comparison to standard CPU, GPUT, and TPU processors. The network is reported to work at the clock frequency of 50MHz achieving the recognition speeds of up to 400FPS and a recognition rate of 99.25%. A modified Deep Neural Network (DNN) system was reported by Aiman et al. [13], which consists of CNNs, RELUs, and fully connected layers to improve recognition rates when the training dataset is limited. This is done by using the data augmentation technique which helps in increasing the number of training face samples. Further, as reported, this also improves the generalization capabilities of the employed CNN systems. The group reports, the accuracy of 95.21% the AT &T face database for 4 training samples whereas 99.92% for 5 training samples. A new eight-layered CNN architecture was proposed by Coskun et al. [14], which relies on the batch Normalization process to improve the accuracy of the proposed system and a Softmax classifier to classify the face samples. Görgel et al. [15] proposed another face recognition system that uses deep-stacked denoising sparse autoencoders (DSDSA) for the identification of face areas and/or distinctive landmark features. The classification methodology relies on multi-class support vector machines (SVM) and SoftMax classifiers. A novel deep neural network presented by Zhao et al. [16], makes use of CNN to realize a feature vector for human face representation. This is followed by PCA for dimension reduction to remove the redundant and contaminated visual features. The authors report a recognition rate of 98.52% on the CAS-PEAL dataset, and the system as reported is robust under face recognition attacks. FaceNet [17], introduced by Google researchers, proposed a face recognizer based on machine learning. The group makes use of two pre-trained models from CASIA-WebFace and VGGFace2 for testing the system performance. The proposed system is robust and can achieve recognition rates of 100%. This is because FaceNet relies on comparing each face sample, one after the other with the pre-trained Tensorflow model. The pre-trained data model has a considerable influence on the accuracy of the FaceNet approach, with VGGFace2 producing better average recognition accuracy.
Face recognition has also found its way towards robust and intelligent video surveillance. In this regard, Wang et al. [18] have put forward a brute force detection method for violence detection based on CNN and trajectory features. The authors have proposed two methods to deal with face images extracted at lower resolutions from a surveillance video by using multi-foot input and SPP-based CNN models. The accuracy as reported on Crow and Hockey datasets is 92% and 97.6%, respectively. To improve the performance of face recognition systems in adverse conditions (such as blurred low - resolution samples, improper illumination, etc), Li et al. [19] have proposed a new technique called as Learning the Covariance Matrix Of Gabor Wavelet (GW) (LCMoG). The Covariance Matrix, however, is disjoint from the Euclidean space, and therefore, Euclidean-based measures cannot be adopted directly. To address this, the authors propose two methods, one based on shallow CNN (called LCMoG-CNN) to project covariance matrix of GW into a feature vector of euclidean space, and the other based on matrix-logarithm (called LCMoG-LWPZ) which uses Whitening PCA to learn face features from the embedded covariance matrix. The recognition accuracies for LCMoG-CNN and LCMoG-LWPZ methods on Feret and Extended Yale-B datasets as reported is above 95% even under noisy environments. Further, the proposed models demonstrated a higher recognition accuracy of 96% through hybrid LCMoG-(LWPZ + CNN) on CMU MoBo and YouTube datasets. Fredj et al. [20] have developed a CNN framework based on aggressive data augmentation for face recognition in unconstrained environments. The authors have reported the robust performance of the proposed system in classifying noisy (face samples captured with higher noise content) and occluded face samples by using a deep face representation. The proposed model as reported demonstrates accuracies of 99.2% and 96.63% for LFW and YTF datasets, respectively. Xie et al. [21] have reported a novel face recognition model that targets images having narrow spectral bands, often called hyperspectral face recognition. The authors put forward a modified version of the light CNN framework that is supported by transfer learning methodology. With this, the hyperspectral face samples could be projected into another subspace that has the capability to improve the classification accuracy of the proposed system. The proposed system as reported, sports classification accuracies of 92.83% (for PolyU), 95.12% (for CMU), and 99.73% (for UWA).
A CNN-based model for 3D face recognition was put forward by Dutta et al. [22]. The model works on 40 component faces generated by a combination of a mathematical model (4 components) and a data-level fusion technique (36 components) to project samples into a new space called ’complement component face space’. The model relies on extracting relevant features through a combination of SVD and fused through a crossover operation of a genetic algorithm based on hamming distance. Particle Swarm Optimization (PSO) is then used for discarding redundant features so that only the relevant features are selected, thereby improving the system performance. The proposed system, as reported demonstrates classification accuracy of 97.86%, 98.25%, and 99.89% for Frav3D, Bosphorus, and Texas3D datasets, respectively. Variability in the captured face samples degrades the performance of a face recognition system. In this regard, Meng et al. [23] have proposed a system called ’MagFace’ that works on an adaptive mechanism by sifting through easy and hard samples to avoid overfitting on noisy low-resolution samples. This consequently improves the face recognition in wild environments, and the proposed system sports verification accuracies of 92–99% on easy benchmarks, and 90–96% on difficult benchmarks. Qui et al. [24] on the other hand, focus on the generalization of face recognition systems in presence of real-world occluded face images. In this regard, the authors have proposed a single end-to-end DNN called Face Recognition with Occlusion Masks (FROM) which learns to discover corrupted features from Deep CNNs and clean them from dynamically learned masks. The proposed system, as reported exhibits classification accuracies of 96.22% for RMF2 and 98.32% for LFW-SM (Simulated Masks). A detailed review on the low - resolution face recognition systems [25, 26] gives insights into the different aspects of the face recognition system. These, however miss out on the most crucial aspect, that is the model explainability. Although there has been some investigation into the Explainable Face Recognition (XFR) [27–29], the model explainabiltiy for face recognition system has not gained much traction. In this regard, the work done in this manuscript is one such attempt towards XFR using LIME.
A close observation towards all the methods proposed for improving the face recognition systems as discussed above, reveals that the major focus of all the research groups has been towards improving the statistics of the proposed system. All the face recognition systems listed above were traditionally deployed like black boxes and did not indicate to the end-user the rationale behind these decisions. Answering "why" and "how" predictions are made, assists in understanding the behavior of the model. To elucidate this, an AI tool–LIME has been utilized to investigate the superpixels that have contributed to the black box for the classification of subjects. To the best of our knowledge, it has not been explained yet as to what features drive the black box in classifying a particular subject.
This paper is structured as follows. Section 2 presents the dataset description followed by a preliminary description of different Deep Neural Networks (DNN) used in this paper. Experimental setup and results are discussed in Sect. 3 and the explainability of models is discussed in Sect. 4 Finally, the paper is concluded in Sect. 5
Materials and Methods
This section presents the datasets used during the experiments and the deep neural networks used in XAI-FR framework. A brief description of the working of different DNN models employed and the working of LIME has been explained with a specific focus towards the explainability of black boxes in classifying a face sample.
Datasets Used
This section briefly summarizes the datasets used for experimentation.
The Yale Dataset
Yale face database comprises 165 grayscale images of 15 distinct subjects [30]. Each subject has 11 face samples, one for each face expression (happy, normal, sad, sleepy, surprised, and wink) and configuration (center-light, with glasses, left-light, without glasses, right-light). An example of different face samples available in the Yale face database is shown in Fig. 1(a).
The AT & T Dataset
The AT &T database originally known as ’The ORL Database of Faces’ comprising 400 grayscale images of 40 distinct subjects [31]. For each subject, there are 10 images that capture every possible combination of features. The face samples for each subject are available in PGM format. An example of different face samples available in the AT &T Face Database is shown in Fig. 1(b).
The LFW Dataset
LFW (Labeled Faces in the Wild) is a database of face images created to investigate the problem of unrestricted face recognition [32]. More than 13,000 photos of faces were gathered from the internet for the data collection. The collection contains 1680 subjects, each of which has two or more distinct photographs. In the present work, we considered only those subjects that have at least 70 face samples. An example of different face samples available in the LFW Face Database is shown in Fig. 1(c).Fig. 1 Sample face images from a YALE, b AT &T, and c LFW Datasets
Methods
A Deep Neural Network [33, 34] is an artificial neural network [35] with several layers between the input and output layers. The subsections that follow briefly describe the variants of deep neural networks and explainable AI method – LIME used for the interpretability of the trained models..
LeNet-5 Model
The LeNet-5 model was proposed by LeCun et al. [36] for handwritten and machine-printed character recognition. This architecture is a simple multi-layer convolution neural network for the classification of images. A schematic of LeNet-5 model adapted from [36] is depicted in Fig. 2. Two convolutional and average pooling layers make up the LeNet-5 architecture. This is followed by two fully connected layers. Finally, a Softmax classifier is used which classifies images into respective classes.Fig. 2 Depiction of LeNet-5 Architecture as adapted from [36]
AlexNet Model
The AlexNet model was proposed by Krizhevsky et al. [37] achieved a top-5 error rate of 15.3 % on the ImageNet LSVRC-2010 dataset comprising 1.2 million high-resolution images. The AlexNet is comparatively deeper as compared to its LeNet-5 counterpart. The schematic architecture of AlexNet is shown in Fig. 3. The AlexNet has 11 layers comprising five layers of convolutions layers and the subsequent three layers of max pooling. After convolution and max-pooling blocks, the architecture consists of 3 fully connected layers having RELU activation function, except in the last layer.Fig. 3 Depiction of AlexNet Architecture as adapted from [38]
Inception-V3 Model
Inception-V3 is the third variant of GoogLeNet used for image analysis and object detection. Inception-V3 scores over other CNN classifiers in terms of speed and accuracy. The previous models were just improving the performance and accuracy of their model but compromising the computational cost. To improve the system performance, the Inception-V3 relies on various tricks for optimizing its network. Szegedy et al. [39], had proposed several upgrades for the Inception-V3 model which increased the accuracy and reduced the computational complexity. These include optimizing the network, in order to loosen the constraints for easier remodeling by including factorized convolutions, regularization, dimension reduction, and parallelized computations. The architecture of an Inception-V3 network, as depicted in Fig. 4.
As can be observed from Fig. 4, the Inception-V3 architecture consists of a stem, comprising traditional pooling and convolutional layers. Subsequently, it comprises a pooling layer followed by fully connected and softmax layers. The Inception-V3 architecture also involves reduction modules that are designed for reducing the dimensions of the input. The architecture has about 24 million parameters and takes a default input of size 299×299×3.Fig. 4 Schematic representation of a Inception -V3 Architecture as adapted from [40]
VGG16 Model
Simonyan et al. [41] introduced VGG16, a CNN model that achieved 92.7 percent top-5 test accuracy in the ImageNet Dataset. The ImageNet comprises 14 million images belonging to 1000 different classes. It improves on AlexNet by successively replacing large kernel-sized filters of sizes 11 and 5 in the first and second convolutional layers with multiple kernel-sized filters of size 3.Fig. 5 Schematic of a VGG16 Architecture as adapted from [41]
In Fig. 5, the convolution layers using a non-linear activation function, known as rectified linear unit (ReLU), are represented by all the blue color rectangles. VGG16 comprises 13 convolution layers and 5 max-pooling layers. In addition to these, three green rectangles represent fully connected layers. Finally, there is an output layer which is a fully connected softmax output layer y^ with possible values corresponding to the number of classes.
LIME
Local Interpretable Model-agnostic Explanations, better known as LIME is an explainable AI method developed by Ribeiro et al. [42]. LIME can be used for a classifier model that classifies tabular data, pictures, or texts to better understand the behavior of the applied black-box classifier model. It is ’Local’, meaning that LIME attempts to explain the proposed black-box model by approximating the model’s local linear behavior, and it is ’Interpretable’, meaning that it provides a solution to understand why the model acts the way it does. The four steps involved in LIME: Input data permutation: In this step, LIME generates several perturbed images similar to the input image by turning on and off some of the super-pixels of the image.
Class prediction of each artificial image: In this step, a class prediction for perturbed each artificially generated image is carried out using the trained model.
Weight computation for each artificial image: In this step, a weight is computed for each artificial image to measure its degree of importance. The distance is computed between every artificially generated image point and the corresponding points of the original input image. Using a kernel function, the distance metric value is mapped into a weight value between 0 to 1. The closer proximity of the perturbed instance to the instance being explained contributes to the higher associated weightage signifying its importance.
Explaining important features by fitting a linear classifier: This step involves fitting a linear regression model with the help of the weighted artificial data points. In this way, the fitted coefficient is obtained for each feature. On sorting based on coefficient values, the superpixels corresponding to higher coefficient values are the ones contributing significantly to the prediction of the black-box machine learning model.
Experimental Setup and Results
All experiments have been performed in Python 3.7 in the Google Colaboratory using runtime environment for NVIDIA Tesla K80 GPU. In order to test the applicability of deep neural networks (DNN) summarized in Sect. 2.2, the datasets mentioned in Section Sect. 2.1 were split in a ratio of 80:10:10 for realizing disjoint sets for training, validation, and test sets, respectively. The choice of hyperparameters for each DNN is based on the exploration of search space. The batch size is set to 32, the learning rate equals 0.001, and the optimizer employed is Adam optimizer [43, 44].
Results and Discussions
In this section, we present the results of employing LeNet, AlexNet, Inception-V3, and VGG16 on the three face datasets mentioned above. The plots depicted in Fig. 6 shows the variation of validation accuracy of the face recognizers based on different deep neural networks with respect to the number of epochs for each of the three datasets. The LeNet based face recognizer (Fig. 6(a)) shows fluctuations till epoch=30 after which it almost stabilizes. The AlexNet based face recognizer (Fig. 6(b)) shows poor generalization performance on the unseen face samples. Likewise, Inception-V3 based face recognizer (Fig. 6(c)) is unable to stabilize with an increase of number of epochs. The VGG16 based face recognizer stabilizes after 15 epochs and (Fig. 6(d)) shows the best generalization capability. The classification performance of the above-mentioned four deep neural networks on different datasets is given in Table 1. We note that VGG16 yields consistently the best performance across the chosen datasets in terms of classification accuracy, recall, precision, and F1-Score.Fig. 6 Plots depicting variation in validation accuracy w.r.t. number of epochs for three datasets namely, AT &T, Yale, and LFW for the face recognizers based on a LeNet, b AlexNet, c Inception-V3, and d VGG16
Table 1 Comparison of Performance Metrics of DNN Models on Different Datasets
Metrics
Models LeNet-5 AlexNet Inception-V3 VGG-16
Yale AT &T LFW Yale AT &T LFW Yale AT &T LFW Yale AT &T LFW
Accuracy (%) 94.11 95.00 90.00 94.11 97.50 94.00 88.23 97.50 93.70 94.11 100.00 97.00
Recall (%) 95.00 90.00 89.00 95.00 92.00 92.00 82.00 99.00 92.00 95.00 100.00 94.00
Precision (%) 97.00 92.00 89.00 95.00 92.00 92.00 88.00 99.00 92.00 95.00 100.00 97.00
F1-Score (%) 95.00 91.00 89.00 93.00 92.00 89.00 83.00 99.00 92.00 93.00 100.00 95.00
Model Explainability
In this section, we evaluate the explainability of each of the four DNN-based face recognition models. Towards this end, LIME has been used to mark the superpixels that have contributed towards the classification label generated for a particular subject. The regions shown in green color have contributed positively for the predicted label and the regions shown in red color have contributed negatively to the predicted label. Out of 40 test samples from the AT &T database, we randomly picked an image (true label 5) for which each of the four models predicted the correct label. Figure 7 shows the prediction scores of top six matches for each of the LeNet-5, Alex-Net, Inception-V3, and VGG16 models. As expected, for each model, the prediction score of the correctly predicted subject (99.81%, 99.92%, 92.78%, and 95.86% for the LeNet-5, AlexNet, Inception-V3, and VGG16 model respectively) that appears leftmost in a row is significantly higher than the other images that appear in the same row. Each sub-figure shows explanations generated for the best six matches. It may be noted that even though each of the models predicts the correct label, it focuses on somewhat different features for generating its prediction. As we could not find an image for which each of the models predicted a wrong label, Fig. 8 depicts different instances predicted wrongly corresponding to the models LeNet-5, ALexNet, Inception-V3, and VGG16 respectively. As the models output a wrong label, we note that in Fig. 8, the prediction score of the true label is lower than the best match that resulted in a wrong prediction.Fig. 7 LIME-generated explanations for a correctly predicted face (True label: 5) using a LeNet-5, b AlexNet, c Inception-V3, and d VGG16. Each sub-figure shows explanations generated for the best six matches along with prediction score
Fig. 8 LIME-generated explanations for the subjects with true labels 9, 23, 23, and 7 predicted wrongly by the models a LeNet-5, b AlexNet, c Inception-V3, and d VGG16 respectively
Subjective Assessment of LIME generated Explanations
For subjective assessment of the LIME-generated explanations, we randomly selected 20 samples from the test dataset. Each image was passed to the LeNet, AlexNet, Inception-V3, and VGG16 models for recognizing the person in the image. For each image, the explanation generated by LIME for each of the four deep learning models was shown to a group of twenty volunteers. Each volunteer was asked to score the models on a scale of 4, Thus, given an image, a volunteer would assign a score of 4 to the model for which LIME generated the most comprehensible explanation as per his/her judgement and a score of 1 to the model for which the generated explanation was least comprehensible. The responses were collected using a Google Form. Based on the responses of 20 volunteers, LIME explanations using the VGG16 model ranked highest with an average score of 3.35, followed by Alex-Net, Inception-V3, and LeNet, having average scores 3.02, 2.87, and 1.75 respectively.
Conclusions and Future Scope
In this paper, we have examined the interpretability of four deep neural networks (DNN) models, namely, LeNet-5, AlexNet, Inception-V3, and VGG16 on the AT &T dataset. For this purpose, we used Local Intepretable Model-Agnostic Explanations (LIME) as the explanation model to mark the visually significant features in terms of the superpixels. Based on an experimental study involving twenty volunteers, we found that that the explanations generated for the classification performed by VGG16 were significantly more explainable than those produced for the other models. Furthermore, the LIME-generated superpixels on face images correspond to the region of non-interest (RONI) comprising background features. RONI can be segmented in future work so that these insignificant features do not influence the interpretability XAI methods.
Acknowledgements
The authors would like to thank University of Delhi for providing the tools for the completion of this work.
Funding
This research received no specific grant from any funding agency.
Data Availability
The authors confirm that the data and material supporting the finding of this study are available within the article.
Code Availability
The codes that support the finding of this study are available from the corresponding author upon reasonable request.
Declarations
Conflict of interest
The authors declare that there is no conflict of interest.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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| 0 | PMC9745692 | NO-CC CODE | 2022-12-15 00:02:40 | no | Wirel Pers Commun. 2022 Dec 13;:1-18 | utf-8 | Wirel Pers Commun | 2,022 | 10.1007/s11277-022-10127-z | oa_other |
==== Front
Med Microbiol Immunol
Med Microbiol Immunol
Medical Microbiology and Immunology
0300-8584
1432-1831
Springer Berlin Heidelberg Berlin/Heidelberg
758
10.1007/s00430-022-00758-1
Original Investigation
A high CMV-specific T cell response associates with SARS-CoV-2-specific IL-17 T cell production
http://orcid.org/0000-0001-9718-7243
Frozza Fernanda Tereza Bovi [email protected]
1
Fazolo Tiago 1
de Souza Priscila Oliveira 1
Lima Karina 1
da Fontoura Julia Crispim 1
Borba Théo Souza 1
Polese-Bonatto Márcia 2
Kern Luciane Beatriz 2
Stein Renato T. 23
Pawelec Graham 45
Bonorino Cristina 16
1 grid.412344.4 0000 0004 0444 6202 Basic Health Sciences Department, Federal University of Health Sciences of Porto Alegre (UFCSPA), Immunotherapy Laboratory–UFCSPA, R. Sarmento Leite, 245-Centro Histórico, Porto Alegre, 90050-170 Brazil
2 grid.414856.a 0000 0004 0398 2134 Social Responsibility–PROADI-SUS, Hospital Moinhos de Vento, Porto Alegre, Rio Grande Do Sul Brazil
3 grid.412519.a 0000 0001 2166 9094 Escola de Medicina, Pontifícia Universidade Católica Do Rio Grande Do Sul - PUCRS, Porto Alegre, Rio Grande Do Sul Brazil
4 grid.10392.39 0000 0001 2190 1447 Department of Immunology, University of Tübingen, Tübingen, Germany
5 grid.420638.b 0000 0000 9741 4533 Health Sciences North Research Institute, Sudbury, ON Canada
6 grid.266100.3 0000 0001 2107 4242 Department of Surgery, University of California at San Diego - UCSD, La Jolla, CA USA
Edited by Matthias J. Reddehase.
13 12 2022
117
8 8 2022
24 11 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Human cytomegalovirus (CMV) is a widespread persistent herpes virus requiring lifelong immune surveillance to maintain latency. Such long-term interactions with the immune system may be associated with deleterious effects including immune exhaustion and senescence. Regarding the COVID-19 pandemic, we asked whether CMV-specific cellular and humoral activity could influence immune responses toward SARS-CoV-2 and/or disease severity. All adults with mild (n = 15) and severe (n = 14) COVID-19 were seropositive for anti-CMV IgG, but negative for IgM antibodies. Antibody titers did not correlate with COVID-19 severity. Six patients presented elevated frequencies of CMV-specific CD4 + and CD8 + T cells producing IFNγ, IL-17, and TNFα, designated as CMV high responders (hiT CMV). In comparison to low CMV responders, hiT CMV individuals exhibited higher frequencies of SARS-CoV-2-specific CD4 + IL-17 + and CD8 + IFNγ + , IL-17 + or TNFα + T cells. These results indicate that high frequencies of CMV-specific T cells may be associated with a SARS-CoV-2-reactive profile skewed toward Th17-dominated immunity.
Graphical abstract
Supplementary Information
The online version contains supplementary material available at 10.1007/s00430-022-00758-1.
Keywords
Cytomegalovirus
SARS-CoV-2
Cellular immunity
Lymphocytes
Cytokines
Th17
Moinhos de Vento HospitalPrograma de Apoio ao Desenvolvimento Institucional do Sistema Único de Saúde (PROADI)Ministry of Health (BR)http://dx.doi.org/10.13039/501100002322 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
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pmcIntroduction
Human cytomegalovirus (CMV) belongs to the Herpesviridae family causing persistent latent infection in immunocompetent individuals. After primary infection, the host may experience several episodes of reinfection or reactivation, as the virus persists in a latent phase in hematopoietic progenitors and cells within the myeloid lineage [1]. Cytomegalovirus represents one of the most common infections globally, with a prevalence ranging from 50 to 95% depending on age and socioeconomic status [2]. Studies from Southern Brazil [3–5] show an 88–98% IgG prevalence in adults below 55 years old, and 100% in older individuals, with anti-CMV IgM present in 2.4% of the adult population, most of them under 35 years old and probably representing new infections [5].
The chronic interaction of CMV with the immune system, necessary for maintaining latency and preventing pathology, may eventually be associated with deleterious effects reflecting immune exhaustion and senescence, especially in the elderly [6–8], while in CMV-positive young people and adults, the presence of highly differentiated and sensitized T cells is potentially an immunological advantage for responses against other pathogens [9–12]. We asked whether the severity of SARS-CoV-2 disease, which has pathological mechanisms associated with severe acute respiratory syndrome that include dysfunctional and exacerbated immune responses [13], was associated with the immune response to CMV infection. We found that, although anti-CMV IgG titers did not correlate with COVID-19 severity, high frequencies of CMV-specific CD4 + and CD8 + T cells were associated with elevated levels of SARS-CoV-2-specific IL-17-producing CD4 + and CD8 + T cells. This suggests that CMV may skew the anti-SARS-CoV-2 activity toward an immune phenotype polarized to a Th17 type of response which could influence inflammation and the course of disease.
Methods
Patients
This is a case–control study focused on the analysis of CMV humoral and cellular immune responses in mild and severe COVID-19 patients. A convenience sample of COVID-19 patients was obtained from Moinhos de Vento and Restinga Extremo Sul hospitals, located in Porto Alegre, Brazil. Adults with confirmed SARS-CoV-2 positivity that arrived at either hospital were invited to participate in the study. Participants included were recruited from June to December 2020, all > 18 years of age who presented with cough and/or axillary temperature above 37.8 °C and/or sore throat, and who were hospitalized, in emergency rooms or outside health units. Nasopharyngeal and oropharyngeal swabs were collected to confirm the COVID-19 diagnosis. Clinical and demographic data were collected at inclusion. Disease severity was obtained according to the World Health Organization classification following a standardized protocol [14]: severe COVID-19 patients were classified based on oxygen saturation < 90% in room air, with signs of severe respiratory distress and pneumonia. Mild disease was defined by the absence of any of the criteria above for severe COVID-19. The study was conducted according to the Declaration of Helsinki. This study was approved by the Institutional Review Board (IRB 30,749,720.4.1001.5330) at Hospital Moinhos de Vento and Ethics Committee from Fundação Faculdade Federal de Ciências Médicas de Porto Alegre (CEP-UFCSPA) (CAAE 30,749,720.4.3001.5345). Informed consent was obtained from all participants or legal guardians.
SARS-CoV-2 RT-qPCR
A qualitative RT-PCR assay to SARS-CoV-2 was performed for all participants as detailed in our previous work [15]: bilateral nasopharyngeal and oropharyngeal swabs were collected and transported in medium with saline solution and RNAlater®, RNA Stabilization Solution (Catalog number AM7021, Invitrogen™). For RNA extraction, MagMax™ Viral/Pathogenic Nucleic Acid Isolation Kit (Applied Biosystems) was used in the KingFisher Duo Prime System (ThermoFisher, USA) automated platform. The RT-PCR assay was performed in a 10 µL total reaction, using Path™ 1-Step RT-qPCR Master Mix, CG (catalog number A15299, AppliedBiosystems), and TaqMan™ 2019-nCoV Assay Kit v1 (catalog number A47532, AppliedBiosystems). As control, 5 µL (200 copies/µL) of the TaqMan™ 2019-nCoV Control Kit v1 (catalog number A47533, AppliedBiosystems) was used. QuantStudio 5 (ThermoFisher Scientific, USA) was applied to perform the PCR.
ELISA
IgG and IgM antibodies for CMV and IgG and IgA for SARS-CoV-2 S-RBD (Spike-Receptor Binding Domain) and N (Nucleocapsid) peptides were analyzed. Heat-Inactivated (56 ºC for 60 min) plasma samples from the study participants were used in the assay.
Anti-CMV antibodies were tested using commercial kits provided by BioClin (Brazil). Qualitative IgM determination was performed by enzyme immunoassay (Biolisa CMV IgM, K123—BioClin). Positive results were defined by absorbance greater than the cut-off calibrator. For IgG, we performed a quantitative determination (Biolisa CMV IgG, K122—BioClin). To quantify the sample absorbances as IU/mL (International Units per mL), five reference standard solutions containing IgG anti-CMV antibodies in different concentrations were used in the assay, and a concentration curve was obtained from each absorbance and known IgG (in IU/mL). Samples’ absorbances were converted to IU/mL based on the assay concentration curve. Negative and positive controls from the kits were used in the assays to confirm test accuracy.
For anti-S-RBD and anti-N IgG and IgA, we followed our previous study protocol [15]. Briefly, ELISA plates (Kasvi, Brazil) were coated overnight with 1 μg/mL of SARS-CoV-2 Spike Protein (S-RBD; Catalog nr. RP-87678, Invitrogen) or N peptide (Fiocruz, Brazil). Next, blocking buffer was added for 1 h at room temperature. Samples were serially diluted in 0.05% PBS-Tween 20 (milk 1%) starting at 1:25 and incubated for 2 h at 37 °C. Secondary antibodies diluted in 0.05% PBS-Tween were then added and plates were incubated for 1 h at room temperature. Anti-human peroxidase produced in rabbits (Catalog nr. IC-1H01—Rhea Biotec, Brazil) was used for IgG, and anti-human peroxidase produced in goat (Catalog nr. A18781—Invitrogen, USA) was used for IgA, both at a 1:10,000 dilution. The assay was developed with TMB Elisa Substrate—High Sensitivity (Abcam, United Kingdom) for 30 min, and 1 M chloric acid was added to stop the reaction. An ELISA reader (Biochrom EZ 400) was used to measure anti-CMV and anti-SARS-CoV-2 antibodies with a 450 nm O.D. To calculate the area under the curve (AUC), a baseline of 0.07 was applied [16].
PBMC Isolation
Blood samples were collected in EDTA tubes and stored at room temperature. PBMCs were isolated by density gradient centrifugation, using Ficoll™ PLUS (GE Healthcare®). Cells were resuspended in Fetal Bovine Serum (FBS) with 5% DMSO and stored in liquid nitrogen until analysis.
T cell In vitro simulation
After thawing, PBMCs were counted and viability was evaluated, with subsequent plating in 96-well plates at 3 × 105 PBMCs per well in 100 μL of RPMI-1640 medium (Sigma-Aldrich—R8758) supplemented with fetal bovine serum (10%) and antibiotics (100 IU penicillin/mL, 100 μg streptomycin/mL and 2 mM L-glutamine (Lonza, Belgium)). Cells were stimulated with a CMV mega pool (2 µg/mL, composed of 42 peptides from cytomegalovirus, including pp50, pp65, IE1, IE2, and envelope glycoprotein B—Mabtech, Sweden) or 1 µg/mL of peptide PepTivator SARS-CoV-2 Prot S (130–126-700—Miltenyi Biotec, Germany), PepTivator SARS-CoV-2 Prot N (130–126-698—Miltenyi Biotec, Germany) or PepTivator SARS-CoV-2 Prot M (130–126-702—Miltenyi Biotec, Germany). PMA (50 ng/mL, Sigma, USA) plus ionomycin (1 μg/mL, Cayman chemical company, USA) and DMSO were used as positive and negative controls, respectively. Plates were incubated at 37 °C/5% CO2 for 18 h. Three hours before harvesting the cells, 1 μg/ml of Golgi Plug (BD Biosciences, USA) was added to each well. Cells were labeled and analyzed by flow cytometry to establish their phenotypes as follows.
CD4 + and CD8 + immunophenotyping
Cells were labeled with BD Horizon™ Fixable Viability Stain 510 for viability, and then with surface marker antibodies: anti-CD3-PE-Cy7 (clone SK7), anti-CD4-PerCP-Cy5.5 (clone RPA-T4), and anti-CD8-APC-H7 (clone SK1). For intracellular cytokine labeling, cells were first stained with surface markers, and then fixed, and permeabilized with Cytofix/Cytoperm kit (BD Biosciences-Pharmingen, USA). They were then stained with anti-IFNγ-FITC (clone 4S.B3), anti-TNFα-APC (clone MAb11), and anti-IL-17-PE (clone SCPL1362) antibodies. For surface antibody staining, incubation was for 30 min at room temperature in the dark. For intracellular antibodies, the interval was 40 min at 2–8 °C. Samples were analyzed using BD Biosciences—FACSCanto II and FlowJo 10.7.1 software. CMV- and SARS-CoV-2-specific CD4 + and CD8 + cells are represented as frequencies of viable PBMCs.
Serum cytokine measurements
IFN-γ, TNF, IL-4, IL-6, IL-10, and IL-17A concentrations in inactivated serum were analyzed with a commercial BD CBA Human Th1/Th2/Th17 cytokines kit (cat 560,484, BD Inc., USA), as described in our previous work [15]. Briefly, a mixture of capture beads coated with capture antibodies specific for each cytokine and a phycoerythrin (PE) detection reagent were used according to the manufacturer’s instruction. Then, samples were measured on the BD FACS Canto II flow cytometer and analyzed by FCAP Array software 3.0. Individual cytokine concentrations were indicated by their fluorescent intensities and represented in pg/mL.
Statistical analysis
The Shapiro Wilk test was used to determine normal distribution of results. For age, mean ± standard deviation was considered, and an unpaired T-test with Welch’s correction was applied. Fisher’s exact test was used to calculate proportions between groups. For anti-CMV IgG, days of symptoms until blood collection and CD4 + and CD8 + specific T cell frequencies, median ± interquartile range was considered. A nonparametric two-tailed Mann Whitney test was used for comparison between two groups and the Kruskal–Wallis test for comparisons between more than two groups. Spearman r was used for correlations between variables (corrplot package in R). Statistical analysis was conducted in GraphPad Prism 9.0 and R 4.1.
Results
As shown in Table 1, severe COVID-19 patients were significantly older than mild patients (53.6 ± 17.9 vs 38.8 ± 12.6, p < 0.05), in addition to having a higher proportion of comorbidities (9 (64.3%) vs 2 (13.3%), p < 0.001) such as hypertension, congenital heart disease, chronic obstructive pulmonary disease (COPD), Diabetes Mellitus 1 or 2, prior stroke, heart failure, and obesity. These results align with previous studies that attribute comorbidities as a risk factor for the severity of COVID-19 [17, 18].Table 1 Patient’s baseline and COVID-19 related data
Mild Severe p-value
N 15 14
Age, mean ± SD 38.8 ± 12.6 53.6 ± 17.9 0.02 (*)
Female, n (%) 9 (60) 8 (57.1) > 0.99
Racial/ Ethnic group
Caucasian, n (%) 12 (80) 9 (64.3) 0.43
Black, n (%) 2 (13.3) 1 (7.1) > 0.99
Other/ Not Reported, n (%) 1 (6.7) 4 (28.6) 0.17
Symptoms
Days of symptoms until blood collection, median (IQR) 17 (15–22) 10.5 (7–14.7) 0.05 (*)
Fever, n (%) 11 (73.3) 11 (78.6) > 0.99
Dyspnea, n (%) 7 (46.7) 9 (64.3) 0.46
Comorbidities, n (%) 2 (13.3) 9 (64.3) 0.008 (**)
Asthma, n (%) 1 (6.7) 2 (14.3) 0.6
Hypertension, n (%) 1 (6.7) 5 (35.7) 0.08
Congenital heart disease, n (%) 0 (0) 1 (7.1) 0.5
COPD, n (%) 0 (0) 3 (21.4) 0.1
DM 1, 2, n (%) 1 (6.7) 3 (21.4) 0.33
Prior Stroke, n (%) 0 (0) 1 (7.1) 0.48
Heart Failure, n (%) 0 (0) 1 (7.1) 0.48
Obesity, n (%) 0 (0) 1 (7.1) 0.48
Demographic and COVID-19-related data from the study sample. Age was analyzed by unpaired T-test with Welch’s correction and anti-CMV IgG and days of symptoms were analyzed by unpaired Mann–Whitney test. Fisher’s exact test was used to compare proportions of racial groups, comorbidities, and symptoms between groups, with p values < 0.05 (*), < 0.01 (**) and < 0.001 (***). Abbreviations: COPD: Chronic Obstructive Pulmonary Disease; DM 1, 2: Type 1, 2 Diabetes Mellitus; NR Not Reported
To investigate cytomegalovirus prevalence in mild and severe COVID-19 patients, we evaluated anti-CMV IgG and IgM positivity to determine the presence of primary infection (IgM +), latency (IgG +), or reactivation cases (IgM + , IgG +) in our sample. While none of the patients with confirmed COVID-19 was CMV IgM-seropositive (Fig. 1A), all were IgG-seropositive. No significant difference in IgG titers was found according to the severity of the disease (Fig. 1B).Fig. 1 Qualitative anti-CMV IgM (A) and quantitative anti-CMV IgG (B) assays in mild (n = 15) and severe (n = 14) COVID-19 patients. Samples of serum were diluted according to the kit instructions. Cut-offs of 0.194 (absorbance) for IgM and 1.2 (IU/mL) for IgG were calculated based on the calibrator of the commercial kits used for the analysis. (C) Comparison of anti-CMV IgG quartiles by age in severe COVID-19 patients (n = 14). Statistical analysis using nonparametric Mann–Whitney test for A–B and Kruskal–Wallis test for C, with p values < 0.05 (*), < 0.01 (**) and < 0.001 (***)
The wide range of anti-CMV IgG titers in severe COVID-19 patients (18.4 IU/mL (2.8–39.5)) might be attributable to age variation in this group (53.6 ± 17.9 years). Based on studies that showed associations between anti-CMV IgG titers and age [19], we separated severe patients by anti-CMV IgG quartiles and found that individuals with higher IgG titers indeed tended to be older (Fig. 1C). We also assessed the proportion of comorbidities in each anti-CMV IgG quartile and observed that six of the nine severe patients with comorbidities (66.7%) were concentrated in the third and fourth quartiles, whereas four of the five individuals with no comorbidities (80%) belonged to the first and second IgG quartiles. In contrast, neither age nor the presence of comorbidities correlated with anti-CMV IgG titers in patients with mild COVID-19.
We then asked if CMV-specific T responses were different in COVID-19 patients according to disease severity. We assessed the frequencies of CD4 + and CD8 + CMV peptide-specific T cells by the production of IFNγ, IL-17, and TNFα by flow cytometry (gating strategy presented in Fig. 2A). Despite the lack of difference in terms of severity of disease, a group of CMV responders [patients’ number 1 to 6 (Fig. 2B–G)], exhibited frequencies of CMV-specific cells above the third quartile for at least five of the six subpopulations analyzed (CD4 + IFNγ + > 1.1%; CD4 + IL17 + > 4.9%; CD4 + TNFα + > 1.83%; CD8 + IFNγ + > 1.75%; CD8 + IL-17 + > 1.57%; CD8 + TNFα + > 3.9%). Figure 3 shows that, overall, CMV-specific T responses had significant correlations with each other, in contrast to the absence of association with anti-CMV IgG titers.Fig. 2 A Gate strategy for T cell responses after stimulation with CMV peptides. The same gates were applied for SARS-CoV-2 peptides and controls. Each panel depicts how peptide-specific CD4 + and CD8 + T cells were selected: viable PBMCs were isolated through size and complexity (FSC-A, SSC-A) together with BD Horizon™ Fixable Viability Stain 510. Anti-CD3 stained cells were then selected to isolate only lymphocytes that were positive for anti-CD4 or anti-CD8 with the respective cytokines (IFNγ, IL-17 or TNFα). B–G Frequencies of CMV-specific CD4+ and CD8+ T cells in mild (n = 15) and severe (n = 14) COVID-19 patients. T responses represented in frequencies of parent: B CD4 + IFNγ + , (C) CD4 + IL-17 + , D CD4 + TNFα + , E CD8 + IFNγ + , F CD8 + IL-17 + , and G CD8 + TNFα + , after stimulation with CMV peptides. Bars represent median with interquartile range, and dots represent each patient. Six individuals from mild (1, 2, 3) and severe (4, 5, 6) groups exhibited frequency of cells above the third quartile for at least 5 of the 6 subpopulations analyzed. Statistical analysis by Mann–Whitney test, with p values < 0.05 (*), < 0.01 (**) and < 0.001 (***)
Fig. 3 Correlation matrix between anti-CMV IgG titer and CMV-specific CD4 + and CD8 + T cell frequencies in COVID-19 patients (n = 29). Anti-CMV IgG titers presented in IU/mL and T responses in frequencies of parent. Circle size and color intensity indicate the strength of correlation by Spearman r (bigger and darker circles denote stronger associations), and colors depict positive (blue) or negative (red) correlations, with p < 0.05 (*), < 0.01 (**) and < 0.001 (***)
By separating this group of CMV high T responders (designated “hiT CMV”) from those with lower levels of response (“loT CMV”), we investigated SARS-CoV-2-specific CD4 + and CD8 + cells in both groups following stimulation of PBMCs with Spike (S), Membrane protein (M) or Nucleocapsid (N) peptides. We matched baseline characteristics between hiT and loT CMV groups for further analysis. Mean age of the hiT CMV group (n = 6) was 46 ± 9.4 years, similar to 48 ± 19.2 years of the loT CMV group (n = 10). Three patients (50%) in the hiT group and 5 (50%) in the loT CMV group presented with one or more comorbidities. The number of symptomatic days prior to blood collection was 13 (10.5–20.2) for the hiT patients and 10.5 (3.5–16.2) for the loT group.
hiT CMV individuals showed an increase in the frequencies of SARS-CoV-2-specific CD4 + IL-17 + , CD8 + IL-17 + , CD8 + TNFα + , and CD8 + IFNγ + cells (Fig. 4B–G), whereas loT CMV showed elevated CD4 + TNFα + frequencies for all three peptides analyzed (Supplementary Table 1). A comparison of the proportions of SARS-CoV-2-specific cytokine production between hiT and loT CMV individuals revealed that S- and N-specific CD4 + and CD8 + profiles were skewed to a Th17 type response in the hiT CMV group, with predominant IL-17-producing cells and an absence of CD4 + TNFα + cells (Fig. 4H). PBMCs stimulated with M peptide showed a less skewed response profile in the hiT CMV group. Thus, unlike the polarized Th17 profile stimulated by S and N peptides in hiT CMV responders, an overall more diversified phenotype of response was observed in the loT CMV individuals.Fig. 4 A Gating representation showing SARS-CoV-2-specific CD4 + and CD8 + frequencies in hiT and loT CMV individuals. B–G SARS-CoV-2-specific responses after stimulation with Spike B–C, Membrane D–E or Nucleocapsid F–G peptides, respectively, in hiT CMV (n = 6) and loT CMV (n = 10) COVID-19 patients. T responses represented in frequencies of parent. Bars represent the median and interquartile range, and dots represent each individual, with white and black circles representing mild and severe COVID-19 patients, respectively. H Stacked histogram of SARS-CoV-2-specific CD4 + and CD8 + T cells in hiT and loT CMV groups after stimulation with Spike, Membrane or Nucleocapsid peptide pools. Each fraction refers to the median frequency of IFNγ, IL-17 or TNFα-producing T cells upon stimulation. Statistical analysis using the nonparametric Mann–Whitney test, with p values < 0.05 (*), < 0.01 (**) and < 0.001 (***)
We then investigated possible associations between responses against the two viruses in CMV high and low T responders. Figure 5A–B shows that anti-CMV IgG correlated positively with anti-RBD IgG and anti-N IgA antibodies in hiT CMV, but not loT CMV individuals. In the hiT CMV group, anti-RBD IgG levels, but not IgA, correlated positively with all other anti-SARS-CoV-2 antibodies assayed. Anti-S-RBD and anti-N IgG were positively correlated with anti-N IgA in the loT CMV group.Fig. 5 Correlation matrices between CMV- and SARS-CoV-2-specific responses. A–B anti-CMV IgG and anti-SARS-CoV-2 (RBD or N-specific) IgG and IgA correlation matrix in (A) hiT CMV (n = 6) and B loT CMV (n = 10) groups. C–D Correlation between CMV- and SARS-CoV-2-specific T responses in C hiT CMV (n = 6), and D loT CMV (n = 10) groups. CD4 + and CD8 + cells represented in frequencies of viable PBMCs. Circle size and color intensity indicate the strength of correlation by Spearman r (bigger and darker circles denote stronger associations), and colors exhibit positive (blue) or negative (red) correlations, with p < 0.05 (*), < 0.01 (**) and < 0.001 (***)
Next, we asked if the frequency of CMV-specific T cells producing IFNγ, IL-17, or TNFα correlated with SARS-CoV-2-specific responses. Figure 5C shows that, in the hiT CMV group, both CD8 + and CD4 + IFNγ + responses to CMV positively correlated with anti-SARS-CoV-2 IFNγ + responses, while only CMV-specific CD4 + IL-17 + consistently correlated positively with IL-17 + anti-SARS-CoV-2 responses; anti-CMV CD8 + IL-17 + , instead, negatively correlated with IL-17 + anti-SARS-CoV-2 responses. Correlations of CMV-specific CD4 + TNFα + cells were also mostly positive between them and anti-SARS-CoV-2 TNFα + , except for CD8 + TNFα + cells and anti-M TNFα + cells (both CD4 + and CD8 + , Fig. 5E). For the loT CMV group, these patterns were not observed (Fig. 5D).
Finally, considering the elevated frequency of IL-17 responses in the hiT CMV individuals, we analyzed Th1 (IFNγ, TNFα), Th2 (IL-4, IL-10) and Th17 (IL-6, IL-17) cytokines in the patients’ serum to investigate if there were systemic implications related to the Th17 skewed profile observed. As shown in Fig. 6A–F, we found no differences in the concentration of these cytokines between hiT and loT CMV groups. However, their profile, or proportion, was unique for each group: hiT CMV individuals exhibited more IL-17 and IL-6 than any other cytokine, whereas the loT CMV group presented an IL-6 and IL-10 enriched state (Fig. 6G). This distinct IL-17 predominance corroborates our findings regarding the peptide-specific T cell responses with a Th17 polarized profile in the hiT CMV group.Fig. 6 Serum Th1, Th2, and Th17 cytokines in hiT (n = 6) and loT CMV (n = 10) groups: A IFNγ, B IL-4, C IL-6, D IL-10, E IL-17A and F TNFα. Values represented in pg/mL. Bars represent the median and interquartile range, and dots represent each individual, with white and black circles representing mild and severe COVID-19 patients, respectively. G Proportion of serum cytokines in hiT and loT CMV groups. Values refer to the median concentration (pg/mL) of each cytokine in hiT and loT CMV groups and are normalized to 100% of all cytokines. Statistical analysis using the nonparametric Mann–Whitney test, with p values < 0.05 (*), < 0.01 (**) and < 0.001 (***). H–I Matrix correlation of serum cytokines in (H) hiT and (I) loT CMV groups. Circle size and color intensity indicate the strength of correlation by Spearman r (bigger and darker circles denote stronger associations), and colors depict positive (blue) or negative (red) correlations, with p values < 0.05 (*), < 0.01 (**) and < 0.001 (***)
The balance of Th1/Th2/Th17 serum cytokines was analyzed through a matrix correlation in each group. Figure 6H–I shows that the loT CMV group exhibited strong positive correlations between Th1, Th2 and Th17 cytokines, suggesting a balance between pro and anti-inflammatory responses during COVID-19. On the other hand, hiT CMV individuals did not show the same equilibrated profile, with negative correlations between Th2 (IL-4) with Th1 (IFNγ and TNFα) cytokines.
Altogether, these data indicate that the predominant CD4 + IL-17 + frequencies toward CMV and SARS-CoV-2 may have systemic implications, including a higher proportion of serum IL-17A compared to other cytokines, and an imbalance of Th1, Th2 and Th17 immune profiles during infection.
Discussion
Since the SARS-CoV-2 outbreak, countless efforts have been made to investigate and understand risk factors related to a worse COVID-19 prognosis. The phenomena of cytomegalovirus reactivation in COVID-19 patients, in addition to longer ICU stay and lower chances of convalescence [20–26], highlight how important it is to study the impact of CMV infection and latency in the immune defense against SARS-CoV-2.
Given the mean age of our sample ranging from 20 to 81 years (45.9 ± 16.8 years), the absolute positivity rate for IgG showed the expected CMV prevalence in Southern Brazil [3–5]. We found that, despite the high prevalence of anti-CMV IgG, which indicates previous infection and latency (IgG + and IgM-), antibody titers did not correlate with severity of COVID-19 or humoral responses to SARS-CoV-2. Additionally, age and comorbidities did not significantly correlate with anti-CMV IgG titers in severe COVID-19 patients. This was perhaps unexpected given published studies showing associations between high titers of IgG to cytomegalovirus with disease progression and mortality in COPD [27, 28], hypertension [29], and cardiovascular diseases [30], which have all been identified as risk factors for COVID-19 severity [31].
We also found that CMV-specific T cell responses were not associated with COVID-19 clinical course. Strikingly, in the individuals with higher CMV-specific T responses, CD4 + and CD8 + immune profiles following Spike and Nucleocapsid stimulation in vitro were polarized toward a Th17-type of response, in contrast to more heterogeneous proportions of Th1 and Th17 cytokines in loT CMV individuals. Immune responses orchestrated by IL-17 are commonly associated with defense against extracellular fungi and bacteria through the recruitment of neutrophils and mononuclear phagocyte activation [32, 33]. Th17-dominated immunity is not the most effective type of response against viruses, which is associated with type 1 immunity and IFNγ production [34]. This agrees with recent studies that show IL-17 as a dysfunctional type of response against SARS-CoV-2, responsible for so-called “immune misfiring” [35], and associated with a worse prognosis of the disease, including mortality [36, 37]. Nevertheless, we could not confirm a relationship between the Th17 phenotype displayed by hiT CMV individuals and disease severity. It is possible that the “immune misfiring” is not as obvious as death or hospitalization—in the sense that infection seems to leave long-lasting symptoms, often neurological—and thus worth following up. In this context, the Th17 immune profile uncovered in this study, in association with CMV infection, might be implicated in the disease’s recovery process and incidence of inflammatory injury.
The mechanism responsible for the Th17 unbalanced response during COVID-19 is unclear. Hasan et al. [38] suggested that in some individuals, SARS-CoV-2 infection initiates a predominant IL-17-enriched chemokine transcriptional response while producing a low to moderate antiviral response by impairing interferon regulatory factors. The elevated frequency of SARS-CoV-2-specific CD4 + IL-17 + cells, in addition to an absence of CD4 + TNFα + response in the hiT CMV group, also points to a polarized T helper cell profile with predominant Th17-mediated activity. In line with this, Mason and colleagues [50] investigated the CMV secretome during latency and found an elevated production of chemokine ligand (CCL)8, responsible for the recruitment of CD4 + T cells, and, more importantly, a downregulation of CMV-specific IFNγ + and TNFα + CD4 + T cells, proposing it as a virus strategy to inhibit antiviral effector functions of recruited T cells and to skew it to a more favorable condition, as observed in our study in the hiT CMV individuals.
Also, because the development of Th17 cells during viral infections correlates with high levels of IL-6 and transforming growth factor-β (TGFβ) [39, 40], the inflammatory environment created by SARS-CoV-2 infection, marked by IL-1β, IL-17A, IL-18, and IL-6 upregulation [41], might be a potential factor involved in the unbalanced immune profile uncovered in the present study. The excess of SARS-CoV-2-specific CD8 + IFNγ, TNFα, and IL-17-producing cells also highlight the exacerbated inflammatory state evidenced in CMV high responders. In fact, a recent study by Naendrup and colleagues [42] found that most COVID-19 patients with cytomegalovirus or EBV reactivations were under systemic corticosteroid treatment due to a hyper inflammation state.
How anti-CMV T response could contribute or be related to this process could not be confirmed in this study. Besides, most existing research in this area focuses only on CMV seropositivity and its impact on T cell senescence and disease severity [43, 44]. Jo et al. [44] found that putatively senescent SARS-CoV-2-reactive CD8 + T cell populations were higher in CMV-seropositive young individuals than in seronegative ones, whereas Shrock et al. [43] observed that CMV seropositivity correlated with the hospitalization rate among COVID-19 patients. Our results suggest that CMV-specific T responses can also be investigated as a marker of immune polarization during SARS-CoV-2 infection.
Could pre-existing CMV-specific T cells be enhancing pro-inflammatory immunity mounted against SARS-CoV-2? Furman et al. [45] found that, upon influenza vaccination, CMV-seropositive young adults presented an upregulated immune function marked by elevated levels of IFNγ and increased CD8 + T cell sensitivity compared to CMV-seronegative individuals. Also, Barton et al. [46] showed in mice that CMV infection can protect animals against lethal infection with certain other pathogens by a mechanism involving prolonged production of cytokines and systemic activation of macrophages, thereby upregulating the basal activation state of innate immunity against subsequent infections. Moreover, some studies suggest that viral latency caused by Epstein-Barr (EBV) and CMV are responsible for a pro-inflammatory polarization that reduces Th2 upregulation and therefore decreases the incidence of allergies [47]. Thus, CMV latency may modulate immune responses to other antigens through a polarized cytokine environment. Another possibility is that CMV-specific T cells could be just contributing to an already dysfunctional immune response against SARS-CoV-2. Limaye and Boeckh [48] imply that, in the context of other respiratory infections, cytomegalovirus can prolong a pre-existing inflammatory environment through the upregulation of cytokines and inflammatory mediators. Finally, CMV-specific T cells could be cross-reacting with SARS-CoV-2 epitopes and leading to the augmentation of pro-inflammatory responses during infection. A preprint of research from Weber et al. [49] detected T cell cross-reactivity to cytomegalovirus and SARS-CoV-2 epitopes, partially explaining why individuals with a high frequency of CMV-specific T cells also had an elevation of CD4 + IL-17 + and CD8 + IFNγ, IL-17 + and TNFα + responses specific to SARS-CoV-2 peptides.
More evidence is needed to understand the mechanistic link between cytomegalovirus and SARS-CoV-2-specific T cell responses. To the best of our knowledge, this is the first study that focuses on anti-CMV humoral and cellular immune activity and its associations with SARS-CoV-2 T cell-specific immune profiles. Because we had no CMV-negative patients, it is not possible to attribute causality to the results obtained. Nonetheless, CMV-specific T cell responses in COVID-19 patients could be implicated in an immune polarization process during SARS-CoV-2 infection.
Limitations
The sample size was relatively small and restricted to a Brazilian cohort in this study, and it is not possible to confirm that high T responses to cytomegalovirus are the cause of SARS-CoV-2 immune dysregulation because all patients were CMV IgG-seropositive. Because all data stem from COVID-19 patients, it cannot be excluded that SARS-CoV-2 caused the different profiles of T cell responses to CMV. Also, additional data with respect to CMV- and SARS-CoV-2-specific Th2 cytokines in hiT CMV and loT CMV responders would give an important and comprehensive insight into the effect of CMV in T cell response to SARS-CoV-2. Due to the lack of differences between groups and an overall low frequency observed, we also did not mention in this study the presence of polyfunctional cells toward CMV and SARS-CoV-2 peptides.
Conclusions
COVID-19 patients with a high frequency of CMV-specific CD4 + and CD8 + cells exhibit a profile skewed toward CD4 + Th17 responses on stimulation with SARS-CoV-2 peptides, as well as broader specific CD8 + T cell activity reflected by IFNγ, IL-17, and TNFα production. Thus, CMV-amplified IL-17-dominated responses to SARS-CoV-2 could be further investigated as a mechanistic player for long-lasting damage as a result of maladjusted immunity from COVID-19 acute phase.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 40 KB)
Acknowledgements
We wish to thank Dr. Alessandra Peres, Dr. Gilson Dorneles, and all the colleagues from the immunotherapy laboratory for the technical support. We also thank all the patients that agreed to participate in this study.
Funding
This study was supported by PROADI, Moinhos de Vento Hospital, and the Ministry of Health. Fellowships for Fernanda Tereza Bovi Frozza, Priscila Oliveira de Souza, and Tiago Fazolo are from CAPES; fellowships for Karina Lima, Julia C. Fontoura, and Cristina Bonorino are from CNPq.
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of interest
None.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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| 36512097 | PMC9745694 | NO-CC CODE | 2022-12-15 00:02:40 | no | Med Microbiol Immunol. 2022 Dec 13;:1-17 | utf-8 | Med Microbiol Immunol | 2,022 | 10.1007/s00430-022-00758-1 | oa_other |
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1305
10.1007/s12664-022-01305-9
Abstracts
63rd Annual Conference of the Indian Society of Gastroenterology, ISGCON 2022—January 5th – 8th, 2023 in Jaipur
13 12 2022
1124
© Indian Society of Gastroenterology 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
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pmc ABSTRACTS
Indian Society of Gastroenterology
Plenary Session
001
Fecal microbiota transplantation with anti-inflammatory diet followed by anti-inflammatory diet alone is effective in inducing and maintaining remission over 1 year in mild to moderate ulcerative colitis- A randomized controlled trial
Saurabh Kedia, Shubi Virmani, Sudheer Kumar Vvyyurru, Peeyush Kumar, Bhaskar Kante, Pabitra Sahu, Kanav Kaushal, Mariyam Farooqui, Mukesh Kumar Singh, Mahak Verma, Aditya Bajaj, Manasvini Markandey, Karan Sachdeva, Prasenjit Das, Govind K Makharia, Vineet Ahuja
Correspondence - Vineet Ahuja - [email protected]
Department of Gastroenterology and Human Nutrition, Room No. 3111, Third Floor, Teaching Block, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029, India
Objective Microbiome and dietary manipulation therapies are being explored for treating ulcerative colitis (UC). We aimed to examine the effect of fecal microbiota transplantation (FMT) and anti-inflammatory diet in inducing remission followed by long-term maintenance with anti-inflammatory diet in patients with mild-moderate UC.
Design This open-labelled randomized controlled trial (RCT), randomized patients with mild-moderate (simple clinical colitis activity index [SCCAI] 3 – 9) endoscopically active UC (ulcerative colitis endoscopic index of severity [UCEIS] >1) on stable baseline medications in 1:1 ratio to FMT and anti-inflammatory diet (FMT-AID) vs. optimized standard medical therapy (SMT). FMT-AID arm received 7 weekly colonoscopic infusions of freshly-prepared FMT from multiple rural donors (week 0–6) with anti-inflammatory diet. Baseline medications were optimized in SMT arm. Clinical responders (decline in SCCAI >3) at 8 weeks in both arms were followed till 48 weeks on baseline medications (with anti-inflammatory diet in FMT-AID arm). Primary outcome measures were clinical response and deep remission (clinical-SCCAI <2 and endoscopic-UCEIS <1) at 8 weeks, and deep remission and steroid free clinical remission at 48 weeks.
Results Of 113 patients screened, 73 were randomized, and 66 were included in (35-FMT-AID; 31-SMT) modified intention-to-treat analysis (age-35.7+11.1 years; males-60.1%; disease duration-48 [IQR:24–84] months; pancolitis-34.8%; SCCAI-6 [IQR:5–7]; UCEIS-4 [IQR:3–5]) (Fig. 1). Baseline characteristics were comparable. FMT-AID was superior to SMT in inducing clinical response (23/35 [65.7%] vs. 11/31 [35.5%], p=0.01, OR-3.5 [95% CI:1.3–9.6]), remission (21/35 [60%] vs. 10/31[32.3%], p=0.02, OR-3.2 [95% CI:1.1 – 8.7]), and deep remission (12/33 [36.4%] vs. 2/23 [8.7%], p=0.03, OR-6.0 [95% CI:1.2 – 30.2]) at 8 weeks. Anti-inflammatory diet was superior to SMT in maintaining deep remission till 48 weeks (6/24 [25%] vs. 0/27, p=0.007) (Figs. 2 and 3).
Conclusion Multi-donor FMT with anti-inflammatory diet effectively induced deep remission in mild-moderate UC which was sustained with anti-inflammatory diet over one year.
Keywords Diet, Fecal microbiota transplantation, Standard medical therapy, Ulcerative colitis
002
Gut microbial dysbiosis, gut barrier integrity, and severity of chronic pancreatitis: exploring a mechanistic link using an experimental model
Ambika Prasanna , Aparna Jakkampudi, Priyanka Sarkar, Ranjit Tokala, Subhaleena Sarkar, Sreelatha Chintaluri, Nageshwar Reddy, Rupjyoti Talukdar
Correspondence – Rupjyoti Talukdar - [email protected]
Department of Medical Gastroenterology; Welcome DBT Indian Alliance Labs., Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500 082, India
Pancreatic diseases such as pancreatitis, contribute to marked morbidity and mortality. Recent studies have suggested a link between gut microbial dysbiosis and chronic pancreatitis (CP), but the potential roles of the microflora and the immune system that play a crucial role in maintaining the homeostasis have not been fully elucidated in CP in a mechanistic manner. In this study, we report the changes that occur in the gut microbiome along with the other metabolic factors in the L-Arginine model of CP in a time dependent progressive manner. Along with that, we also evaluated the role of high fat diet in CP disease progression and the gut microbial alterations associated in aggravating the disease.
One of the key findings of this study was the early development of the fibrogenesis (p=< 0.01) in the CPHFD group caused due to diet modulation that continued to remain same until severe CP developed. These findings showed significant correlation of fibrosis score (% area) with relative abundances of few bacterial species including Prevotella copri.
Keywords Chronic pancreatitis, Gut barrier, Gut microbial dysbiosis
003
Prevalence of celiac disease in patients with liver diseases: A systematic review and meta-analyses
Shakira Yoosuf 1 , Prashant Singh 2 , Ashank Khaitan 1 , Tor Strand 3 , Vineet Ahuja 1 , Govind K Makharia 1
Correspondence – Shakira Yousuf - [email protected]
1Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029, India, 2University of Michigan, USA, and 3Innlandet Hospital Trust
Introduction A subset of patients with celiac disease (CeD) have liver involvement in the form of hypertransaminsemia, liver cirrhosis and autoimmune hepatitis. We conducted a systematic review with meta-analyses to determine pooled prevalence of CeD in patients with cryptogenic cirrhosis, all-cause cirrhosis, cryptogenic hypertransaminsemia, and all-cause hypertransaminsemia.
Methods We searched PubMed and EMBASE up to January 2022. Cross-sectional, case-control and prospective cohort studies performing serological tests and/or intestinal biopsy for CeD on patients with cryptogenic cirrhosis, all-cause cirrhosis, cryptogenic hypertransaminsemia and all-cause hypertransaminsemia were included, to calculate pooled estimates of seroprevalence and prevalence of biopsy-confirmed CeD in these four groups.
Results Of 6871 articles screened, 20 articles were included finally in three meta-analyses for cryptogenic cirrhosis, all-cause cirrhosis and cryptogenic hypertransaminsemia. For the all-cause hypertransaminsemia group, a qualitative review of four studies was done instead of a meta-analysis, due to significant differences in studies. The pooled seroprevalence and prevalence (95% CI) of biopsy confirmed CeD in cryptogenic cirrhosis were 15.3% (4.9-29.5%) and 4.6% (2.2-7.5%), respectively. Pooled seroprevalence and prevalence of biopsy confirmed CeD in all-cause cirrhosis were 14.2% (3.9-28.8%) and 0.8% (0-3.4%), respectively. Pooled seroprevalence and prevalence of biopsy-confirmed CeD in cryptogenic hypertransaminsemia were 7.7% (4.7-11.4%) and 5.7% (3.2-8.8%), respectively.
Conclusion Nearly one in 20 patients each with cryptogenic cirrhosis and cryptogenic hypertransaminsemia have CeD, hence they should both be considered high-risk groups for CeD. While prevalence of CeD in all-cause cirrhosis is similar to that in general population, it may be worth screening them for CeD as liver pathology has potential for reversal in them.
Keywords Celiac disease, Liver
004
Long-term safety and efficacy of azathioprine in the management of inflammatory bowel disease: A real-world experience
Rohan Yewale, Balakrishnan S Ramakrishna, Babu Vinish D, Kayalvizhi Jayaraman
Correspondence – Rohan Yewale - [email protected]
Institute of Gastroenterology, Hepatobiliary Sciences and Transplantation, SRM Institute for Medical Science, Vadapalani, Chennai 600 026, India
Background Azathioprine (AZA) is used to maintain remission in inflammatory bowel disease (IBD). Both patients and caregivers harbor apprehensions regarding long-term efficacy and safety of AZA in IBD. We analyzed AZA use and outcomes in a mixed cohort of IBD patients followed up over a long period of time.
Methods Long-term compliance, tolerance, clinical-outcome at last follow-up, type, and duration to onset of adverse-events, and subsequent amendment to treatment, with regard to AZA, were analyzed retrospectively in a cohort of 472 patients with IBD under treatment at a single center in south India between 2013-2022.
Results 320/472 patients (207 Crohn’s disease [CD], 113 ulcerative colitis [UC]) received AZA with a median follow-up of 41 months (IQR 15.5-77.5). Total duration of AZA exposure was 1,359 patient-years with median duration of AZA usage of 33 months (IQR 11.75-60). 26.9% received AZA for >5 years. Mean initiation and maximum doses of AZA were 0.97 mg/kg/day and 1.72 mg/kg/day, respectively. 20.6% experienced side-effects, myelotoxicity (7.2%) and gastro-intestinal intolerance (5.6%) being most common. 6 patients developed malignancy. 39.4% of side-effects were dose-dependent and abated after dose modification or temporary withdrawal of AZA. 38.1% had clinical relapses while on AZA, requiring pulse corticosteroids. 72.7% attained durable clinical-remission (11.8% on AZA monotherapy, 53.1% on combination therapy with 5-ASA and 7.7% on combination therapy with biologics). 6.9% continued to have active disease and 20.4% had >1 relapse after commencement of AZA.
Conclusion AZA is safe, effective, and well tolerated in long-term management of patients with IBD.
Keywords Azathioprine, Inflammatory bowel disease, Long-term efficacy
005
Transfusion related lung complications are uncommon in non-ventilated liver disease patients undergoing low-volume plasma exchange
Vijay Alexander , Jess Rasalam, Snehil Kumar, Vinoi David, Dolly Daniel, Sukesh Chandran, Kandasamy Subramani, Binila Chacko, Ebor Jacob, Lalji Patel, Santhosh Varughese, Vadivukkarasi Jayalakshmi, Kunwar Ashish, Uday Zachariah, Ashish Goel, Chundamannil Eapen
Correspondence – Chundamannil Eapen - [email protected]
Department of Hepatology, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Background Plasma exchange (PLEX) is increasingly used to treat liver disease. We aimed to study transfusion related lung complications - transfusion related acute lung injury (TRALI) and transfusion related circulatory overload (TACO), in patients undergoing low volume PLEX (PLEX-LV) to treat liver disease.
Methods Prospectively accrued data of patients in our department who underwent PLEX-LV (50% of estimated plasma volume exchanged per PLEX session) for liver disease from 2016-2022 was retrospectively analyzed. Patients on ventilatory or oxygen support prior to PLEX were excluded. Incidence and cause of breathlessness during transfusion and within 6 hours of cessation of last transfusion of blood products used for PLEX were analyzed.
Results Fifty-six (baseline ventilatory or oxygenation support required: 51, corona virus disease–19 [COVID-19] infection: 5) of 298 liver disease patients who underwent PLEX-LV during the study period were excluded. Two hundred and forty-two study patients (158 males; age: 38, 3 – 72 years; median, range, acute-on-chronic liver failure: 117, acute liver failure: 74) received 5197 units of fresh frozen plasma (FFP) during 779 PLEX-LV sessions.
Three patients (1.2%, TACO: 2, pulmonary hemorrhage: 1), developed breathlessness within 6 hours of completion of any PLEX session. No patient had TRALI. Incidence of TACO was 0.3% (2/779) of PLEX-LV sessions and 0.04% (2/5197) of FFP units transfused during PLEX. All 3 patients died despite maximal supportive care.
Conclusion We found transfusion related lung complications to be uncommon in non-ventilated liver disease patients (most had liver failure) undergoing PLEX-LV. Careful attention to cumulative fluid balance may help reduce incidence of TACO further.
Keywords Plasma exchange, TACO, TRALI
006
Updated trends of inflammatory bowel disease from the global burden of disease study
Arshdeep Singh 1 , Khichdee Dharni 2 , Sonika Sharma 2 , Vandana Midha 1 , Ramit Mahajan 1 , Parambir S Dulai 3 , Ajit Sood 1
Correspondence – Ajit Sood - [email protected]
1Department of Gastroenterology, Dayanand Medical College and Hospital, Civil Lines, Tagore Nagar, Ludhiana 141 001, India, 2Punjab Agricultural University, Ferozepur Road, Ludhiana 141 027, India, and 3Feinberg School of Medicine, North-western University Chicago, IL, United States
Background The global burden of inflammatory bowel disease (IBD) has been reported to be increasing. Methodologies and datasets are routinely updated, allowing for more accurate estimates. We report a comprehensive analysis of the disease burden and trends at the global and regional levels from 1990 to 2019, based on data from the updated Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019.
Methods Incidence, prevalence, deaths, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life years (DALYs) were estimated from the GBD-2019 database. The three decadal trends of the disease measures were also calculated.
Results In 2019, there were 4.9 million (4.3-5.5) cases of IBD globally. The age-standardized prevalence and incidence rates (per 100,000 population) decreased from 73.23 (63.8-83.6) and 6.1 (5.3-6.9) in 1990 to 59.2 (52.7-66.4) and 4.9 (4.4-5.6) in 2019, respectively. The highest age-standardized prevalence and incidence rates (per 100,000 population) were recorded in North America, while Oceania recorded the lowest rates (209.5 [195.4-224.4] and 24.5 [22.6-26.7], and 3.87 [3.1-4.7] and 0.5 [0.5-0.7], respectively). High sociodemographic index (SDI) locations had the highest age-standardized prevalence rate, though the rates declined in 2019 compared to 1990. Over the three decades, the age-standardized prevalence and incidence rates increased in the middle, low middle, and low SDI quintiles. The age-standardized rates for deaths, DALYs, YLDs, and YLLs decreased globally, from 1990 to 2019.
Conclusion This updated estimate from the GBD demonstrates an increasing disease burden of IBD in the middle and low SDI locations, while stabilization in the high SDI locations. Continuous monitoring and adjusting estimates may allow for region-specific policies, to address the challenges in tackling IBD.
Keywords Incidence, Inflammatory bowel disease, Prevalence
Young Investigator Award Session
007
The myth of hepatotropism of hepatitis B virus; Placenta a new home for the virus
Ashish Kumar Vyas
Correspondence – Ashish Kumar Vyas - [email protected]
Department of Microbiology, All India Institute of Medical Sciences, AIIMS Campus Road, Saket Nagar, Habib Ganj, Bhopal 462 026, India
Background The transplacental routes of vertical transmission of hepatitis B virus (HBV) has been known for over a decade. Here we present evidence that suggests HBV can replicate in the placenta.
Methods Forty-one HBsAg-positive pregnant women and 10 controls were enrolled in the study after obtaining informed consent. HBV positives were further divided into the high viral load (HVL) Group and low viral load (LVL) group according to Indian National Association for Study of the Liver (INASL) guidelines 2018. The presence of the HBV DNA in the placenta and expression of NTCP in the placenta was analyzed by qPCR/RT-qPCR and/or immunohistochemistry (IHC). The presence of HBeAg and HBcAg in the placenta was assessed by IHC.
Results NTCP expression was significantly upregulated in trophoblasts of HVL compared to control and LVL groups. Immunostaining of NTCP, HBeAg, and HBcAg on trophoblasts along with the presence of HBV DNA indicated, that these cells are not only susceptible to HBV infection but may also support viral replication. This is further supported by the finding that trophoblasts of the several HBeAg seronegative samples harbored the HBeAg.
Conclusions The presence of the HBV receptor, NTCP in the placenta along with the presence of viral DNA, HBeAg in the placenta of patients without circulating HBeAg suggests that placenta act as a replication host.
Keywords Hepatitis B virus, Vertical transmission, Placenta, Sodium taurocholate co-transporting polypeptide
008
A double blind randomized controlled trial on role of nutritional therapy to prevent recurrence of hepatic encephalopathy in cirrhosis
Barjesh Chander Sharma, Hardik Ahuja, Sanjeev Sachdeva, Bhawna Mahajan, Ashok Sharma, Sushma Bara, Siddharth Srivastava, Ajay Kumar, Ashok Dalal, Ujjwal Sonika
Correspondence – Hardik Ahuja - [email protected]
Department of Gastroenterology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, 1, J L N Marg, New Delhi 110 002, India
Background Overt hepatic encephalopathy (OHE) has high cumulative risk of recurrence and is associated with poor survival. The role of nutrition therapy is well documented in cirrhosis but its efficacy in preventing the recurrence of OHE has not been studied.
Methods In this double blind randomized controlled trial (RCT), we randomly assigned 150 cirrhotics with history of OHE in the recent past to receive nutrition therapy (Group I) or no nutrition therapy (Group II) and followed up for 6 months. The primary efficacy end point was the time to first breakthrough episode of HE. The key secondary end points were the time to first hospitalization involving HE, improvement in health-related quality of life, anthropometry parameters, changes in serum cytokines (IL-1,6,10, TNF), endotoxin, myostatin, correlation of baseline arterial ammonia levels, psychometric tests score, critical flicker frequency, child’s score, model for end-stage liver disease (MELD) score with recurrence of OHE.
Results There was significant reduction in the occurrence of breakthrough episode of HE in group I (10 vs. 36, hazard ratio [HR] 0.20 [95%] confidence interval [CI], 0.10 to 0.40; p<0.001), HE related hospitalization (8 vs. 24, HR 0.27 [95%] confidence interval [CI], 0.12 to 0.61; p<0.001), recurrence of HE (15 vs. 53, p<0.001) and mortality (0 vs. 5, p=0.04). Significant improvements in all parameters were seen at the end of 6 months. There was less incidence of MHE, ascites, gastrointestinal bleed and jaundice in Group I.
Conclusions Treatment with nutrition therapy prevented recurrence of OHE, decreased hospitalization and mortality as compared to no nutrition therapy.
CTRI number: CTRI/2020/08/026993
Keywords Ammonia, Health related quality of life, Minimal hepatic encephalopathy, Sarcopenia
009
Crosstalk between the host Gut mycobiome (fungome) and bacteriome with their glycemic status in chronic pancreatitis patients
Sreelekha Chintaluri , Priyanka Sarkar, Subhaleena Sarkar, Misbah Unnisa, Ambika Prasanna, Aparna Jakkampudi, Nageshwar Reddy, V V Ravikanth, Rupjyoti Talukdar
Correspondence – Rupjyoti Talukdar - [email protected]
Department of Medical Gastroenterology; Welcome DBT Indian Alliance Labs., Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500 082, India
Chronic pancreatitis is irreversible fibrotic pancreatic disease. In this study we aimed to determine the crosstalk between the fungome and the bacteriome with the hosts glycemic status. We observed significant clinical differences with the HbA1c levels and RBS levels across the three study groups. On the microbial metagenomic level we observed several bacterial and fungal species to show significant correlation with the glycemic status in both positive and negative manners.
Keywords Bacteriome, Chronic pancreatitis, Cross-talk, Fungome
010
Low serum albumin is the strongest predictor of non-response for anti-TNF therapy in biological naive inflammatory bowel disease patients in resource-constrained regions with inaccessibility to the measurement of drug pharmacokinetics
Peeyush Kumar, Sudheer Kumar Vuyyuru, Prasenjit Das, Bhaskar Kante, Mukesh Ranjan, Sandeep Mundra, Rithvik Gola, Mukesh Singh, Shubi Virmani, Raju Sharma, Govind K Makharia, Saurabh Kedia, Vineet Ahuja
Correspondence – Vineet Ahuja - [email protected]
Department of Gastroenterology, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029, India
Background There is an unmet need for defining factors that can predict both primary non-response (PNR), as well as secondary loss of response (SLR), to anti-tumor necrosis factor-α (anti-TNF-α) agents in inflammatory bowel disease (IBD). The present study evaluated clinical, biochemical, and molecular markers of PNR and SLR in patients with ulcerative colitis (UC) and Crohn’s disease (CD).
Methods This retrospective study included patients with IBD treated with anti-TNF-α agents from January 2005-October 2020. Data concerning clinical and biochemical predictors was retrieved from a prospectively maintained database. Immunohistochemistry (IHC) for expression of oncostatin M (OSM), oncostatin M receptor (OSM-R) and Interleukin-7R (IL-7 R) receptor were done on pre-anti-TNF-α initiation mucosal biopsies obtained from IBD biorepository.
Results One hundred-eighty-six patients (CD-118, UC-68) received anti-TNF-α therapy (mean age and median disease duration at anti-TNF-α initiation-34.1±13.7 years and 60 [IQR:28-100.5]) months. Primary non-response was seen in 17% and 26.5% and SLR in 47% and 28% of patients with CD and UC respectively. In CD, low albumin (HR [CI]: 0.07 [0.02-0.20], p<0.001), po stoperative recurrence (HR [CI]: 5.24 [1.9-14.5], p=0.001) and high IL-7R expression (HR [CI]:1.5 [1.04-2.15], p<0.027); and low albumin (HR [CI]: 0.09 [0.03-0.28], p<0.001) predicted PNR on univariate and multivariate analysis respectively. Low albumin (HR [CI]: 0.306 [0.15-0.62], p=0.001) also predicted SLR on multivariate analysis. In UC, low albumin (HR [CI]: 0.07 [0.03-0.20], p<0.001), high CRP (HR [CI]: 1.18 [1.07-1.29], p<0.001) and high OSM (HR [CI]: 1.44 [1.02-2.08], p value<0.04) and OSM-R (HR [95%CI]: 1.33 [0.97-1.81], p=0.07) stromal expression; and low albumin (HR [CI]: 0.108 [0.03-0.39], p=0.001) predicted PNR on univariate and multivariate analysis respectively.
Conclusion Low serum albumin prior to anti-TNF-α therapy initiation significantly predicted PNR in UC patients and PNR as well as SLR response in CD patients. Mucosal markers of PNR were high stromal OSM and OSM -R in UC and high IL7R in CD patients.
Keywords Inflammatory bowel disease, Non-response, Tumor necrosis factor alpha
011
Patients with non-celiac gluten sensitivity exhibit site-specific gut microbial differences than those with irritable bowel syndrome
Kunal Dixit 1 , Anam Ahmed2, Dhiraj Dhotre3, Alka Singh2, Wajiha Mehtab4, Ashish Chauhan2, Vineet Ahuja2, Yogesh Shouche3, Govind K Makharia2
Correspondence – Govind K Makharia - [email protected]
1Symbiosis School of Biological Sciences, Sus-Pashan Road, Lavale, Pune 412 115, India, 2Department of Gastroenterology, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029, India, 3National Centre for Cell Science, NCCS Complex, University of Pune Campus, Pune University Road, Ganeshkhind, Pune 411 007, India, and 4Department of Home Sciences, University of Delhi, South Moti Bagh, New Delhi 110 021, India
Objective There is an overlap between symptoms of non-celiac gluten sensitivity (NCGS) and irritable bowel syndrome (IBS). We explored the small intestinal, large intestinal and whole gut microbiota in them to understand if any difference exits in them and we further assess effect of gluten-free diet (GFD) on microbiota in NCGS.
Methods Four hundred and ninety-two patients with IBS (based on Rome IV criteria) were screened for anti-gliadin Ab and diagnosis of NCGS in AGA positive individuals was made on the basis of Salerno criteria. Stool and mucosa-associated (small intestinal and colonic) microbiota was assessed in 130 patients with IBS (AGA negative) 14 patients with NCGS both at the baseline and 6 weeks after GFD to observe the effect of intervention on site specific microbiota profile. Microbiota was analyzed using 16S RNA gene amplicon profiling followed by downstream analysis by DADA2 pipeline and R statistics.
Results NCGS patients exhibited differences in gut microbiota associated with small intestinal as compared to IBS. DESeq2 analysis revealed differentially higher abundance of Stenotrophomonas, Deinococcus, Leucobacter, Solibacillus, and Alcaligenes in NCGS. Moreover, there was reduction in abundances of potential gluten-degrading genera and higher ratio of Prevotella to Burkholderia in duodenal mucosa, which can act as a biomarker for NCGS. There was an increase in bacterial networking and decrease in interindividual variability in the whole gut and site specific (small intestine) microbiota, respectively after GFD.
Conclusion Significant difference exits in small intestinal microbiota of NCGS patients. Six weeks GFD not only alleviates symptoms but also restores microbial diversity considerably.
Keywords 16S rRNA sequencing, Gluten-free diet, Human microbiome, Mucosa-associated, Small intestine
012
Systematic estimation of prevalence of microsatellite instability and Lynch syndrome amongst colorectal cancer patients in India
Harsh Sheth 1 , Abhinav Jain2,3, Chandini Patel1, Prachi Soni1, Mithun Shah3, Pankaj Shah3, Suresh Advani4, Liyana Thomas4, Vipul Yagnik5, Avinash Tank6, Chirag Shah7, Bhavesh Thakkar8, Darshan Bhansali8, Manish Gandhi8, Tarang Patel8, Natu Patel8, Ashok Patel8, Ruchir Patel2, Ravindra Gaadhe9, Chintan Shah10, Michael Jackson11, Mauro Santibanezkoref11, John Burn11, Jeynathy Eswaran11, Frenny Sheth1, Jayesh Sheth1, Sunil Trivedi1
Correspondence – Harsh Sheth - [email protected]
1Department of Advanced Genomic Technologies, FRIGE Institute of Human Genetics, FRIGE House, Jodhpur Village Road, Satellite, Ahmedabad 380 015, India, 2Gastro1 Hospital, Center Point, Near Vandematram Cross Road, Gota, Ahmedabad 382 470, India, 3Zydus Cancer Hospital, Zydus Hospital Road, Thaltej, Ahmedabad 380 054, India,4Sushrut Hospital, 365, Sant Vershaw Kakkaya Marg, Swastik Park, Chembur, Mumbai 400 071, India, 5Nishtha Surgical Hospital and Research Centre, 4th Line, Kilachand Shopping Centre, Station Road, Patan 384 265, India, 6Dwarika Clinic, 301 Shilp Arcade, Jodhpur Cross Road, Satellite, Ahmedabad 380 015, India, 7Mission Gastro Hospital, 6th Floor Golden Icon, Above Hundai Showroom Besides Qaraar Banquets, Ahmedabad 380 015, India, 8CIMS Hospital, Off. Science City Road, Science City, Panchamrut Bunglows II, Sola, Ahmedabad 380 060, India, 9GastroPlus Hospital, 4th Floor, Devraj Mall, Near Thakkarbapa Nagar Cross Road, India Colony Road Bapunagar, Ahmedabad 382 350. India, 10HOC Vedanta Hospital, Science City Road, Sola, Ahmedabad 380 060, India, and 11Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
Background Colorectal cancer is the fifth most common cancer in India, however, there is a paucity of systematically collected data related to its molecular epidemiology, specifically related to tumor microsatellite instability (MSI) and Lynch syndrome prevalence.
Methods We prospectively recruited 207 unrelated patients who were diagnosed with colorectal cancer (CRC) from whom primary tumor biopsy along with a matched blood sample was obtained. A systematic genetic testing approach in accordance with the UK’s National Institute of Health and Care Excellence was utilized. Briefly, DNA from tumor biopsies were tested for MSI status followed BRAF V600E testing in samples which showed MSI-high result. Germline testing for the mismatch repair (MMR) genes was carried in patients who had MSI-high and BRAF V600E negative tumors.
Results Mean age at cancer diagnosis across the cohort was 52.1 years with male to female ratio of 2:1 and 55% of the patients had tumors in the descending colon or rectum. MSI-high status was observed in 79 patients (40.7%) and, it was inversely associated with age (OR=0.95, 95% CI=0.92-0.97, p=<0.001) and cancers in distal colon and rectum (OR=0.49, 95% CI=0.24-1.00, p=0.05 for distal colon; OR=0.11, 95% CI=0.03-0.39, p=0.001 for rectum). Of these, 76 patients had BRAF V600E negative mutation status (96%). Of these patients, 48 were diagnosed with Lynch syndrome (63%; MLH1=38, MSH2=4, MSH6=4, PMS2=1, EPCAM=1). The variants c.154del and c.306G>T in the MLH1 gene were most commonly observed across Lynch syndrome patients in our cohort.
Conclusions This is the first systematic evaluation of the molecular epidemiology of CRC in India. We observe a high proportion of patients with young onset CRC coupled with high prevalence of MSI-high status and Lynch syndrome. The study results provide a unique opportunity to explore development of novel Lynch syndrome detection and cancer prevention pathway in Indian healthcare settings.
Keywords Colorectal cancer, India, Lynch syndrome, Microsatellite instability, Prevalence
Presidential Posters
013
Long-term gastrointestinal sequelae following Corona virus disease-19: A prospective follow-up cohort study
Rithvik Golla, Sudheer Kumar Vuyyuru, Bhaskar Kante, Peeyush Kumar, David Thomas Mathew, Saurabh Kedia, Govind K Makharia, Vineet Ahuja
Correspondence – Vineet Ahuja - [email protected]
Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029, India
Background and Aims Corona virus disease-19 (COVID-19) is associated with long-term gastrointestinal sequalae; however prospective longitudinal data is sparse. We prospectively studied the frequency, spectrum, and risk factors of post infection functional gastrointestinal disorders/disorders of gut-brain interaction (PI-FGID/DGBI) following COVID-19.
Methods Out of 416 cases with COVID-19, finally 320 cases with 320 healthy spouses/family controls (Group-A) and 280 healthy covid serology negative controls (Group B) were prospectively followed up at 1,3 and 6 months using validated Rome IV criteria to evaluate the frequency of PI-FGID/DGBI.
Results Of 320 cases that had follow-up, at 1 month, 36 (10.9%) developed FGID symptoms. At 3 months, 27 (8.4%) and at 6 months, 21 (6.4%) persisted to have symptoms. At 3 months, 8 (2.5%) had irritable bowel syndrome, 7 (2.2%) had functional diarrhea, 6 (1.9%) had functional dyspepsia, 3 (0.9%) had functional constipation, 2 (0.6%) had FD-IBS overlap, and 1 (0.3%) had functional abdominal bloating/distension. Among the symptomatic at 3 months, 8 (29.6%) were positive for isolated carbohydrate malabsorption, 1 (3.7%) was positive for post infection malabsorption syndrome (PI-MAS) and 1 (3.7%) was positive for intestinal methanogen overgrowth (IMO). None of the healthy controls developed FGID until 6 months of follow-up (p<0.01). The predictive factors at 3 and 6 months were severity of infection (p<0.01) and presence of GI symptoms at time of infection (p<0.01).
Conclusion COVID-19 led to significantly higher number of new onset PI-FGID/DGBI as compared to healthy controls at 3 and 6 months of follow-up. If further investigated a proportion of them can have underlying malabsorption.
Keywords COVID-19, Functional gastrointestinal disorders, Long COVID, Post infection-irritable bowel syndrome
014
Persistent gonadal dysfunction in male Budd-Chiari syndrome patients after successful therapy: Does oxidative stress has a role?
Kashmira Kawli, Aditya Kale, Sidharth Harindranath, Akash Shukla
Correspondence - Akash Shukla - [email protected]
Department of Gastroenterology, Seth G S Medical College and K E M Hospital, Acharya Donde Marg, Parel East, Parel, Mumbai 400 012, India
Introduction Hypogonadism is known in patients with Budd-Chiari syndrome (BCS) and is reversible after appropriate therapy.
Methods We performed prospective observational study involving 30 male patients with BCS who underwent appropriate intervention and medical therapy and were followed up for period of 18 months. At 18 months patients underwent biochemical, hormonal assay, and semen analysis. Those patients with persistence of hypogonadism (n=17) and 10 healthy controls were analyzed for reactive oxygen species (ROS)- malondialdehyde (MDA), superoxide dismutase, catalase, endotoxin.
Results Mean age- 27.4 years (interquartile range [IQR] = 19-40 years). Fifteen patients were child A and 2 were Child B at 18 months. Hypogonadotropic hypogonadism was seen in 12 and hypergonadotropic hypogonadism in 5. Sperm count was normal in 9 while 2 had severe oligospermia. Levels of reactive oxygen species were elevated in all patients with BCS however levels were significantly elevated (p=<0.05) for endotoxin (1.4 + 0.42 vs. 0.6 + 0.2), Catalase (1226.85 + 401.4 vs. 242.46 + 206.9). Superoxide dismutase levels were significantly depleted in patients with BCS as compared to healthy controls (3409.4 + 1376 vs. 4907 + 1605, p=0.0013). Although MDA is elevated in patients with BCS (541.16+ 150 vs. 489.17+ 100.26), levels did not reach significance.
Conclusion Hypogonadism can persist in male patients with BCS despite appropriate therapy and after a long follow-up period (18 months). There is definite evidence suggesting role of reactive oxygen species in the persistence of hypogonadism in these patients.
Keywords Budd-Chiari syndrome, Hypogonadism, Oxidative stress
015
Mucosal impedance spectroscopy: For objective real time assessment of mucosal health
Priyanka Arora 1 , Jaspreet Singh 2 , Anuraag Jena 1 , Surinder Kumar 1 , Viren Sardana 3 , Siddhartha Sarkar 3 , Lileshwar Kaman 4 , Arunanshu Behera 4 , Divya Dahiya 4 , Ritambhara Nada 5 , Cherring Tandup 4 , H S Jatana 2 , Usha Dutta 1
Correspondence – Usha Dutta - [email protected]
Departments of 1Gastroenterology, 4Surgery, and 5Histopathology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India, 2Semi Conductor Laboratory, Mohali, India, and 3Central Scientific Instrument Organization, Sector 30-C, Sector 30, Chandigarh 160 030, India
Aim To develop, design and validate a low-cost mucosal impedance (MI) device and determine its role in differentiating diseased mucosa from normal mucosa.
Methods Biocompatible catheter was designed and developed after multiple iterations. It was validated with commercially available catheter and histopathological analysis in blinded manner. Patients undergoing resection of gastrointestinal tract were recruited after informed consent and resected specimens were analyzed ex vivo for MI, within 10 minutes of resection. Average of three MI readings of diseased segment and adjacent normal segment (whenever available) were analyzed. MI values of diseased and normal mucosa was compared by Mann-Whitney U test, Wilcoxon sign ranked test was used for analysis of paired mucosal samples. A p value of <0.05 was considered to be significant.
Results In-house catheter was validated with another commercially available impedance measuring device. It was found to show a high degree of positive correlation (rho=0.616; p<0.001). All diseased vs. normal of 232 patients (mean age 46±15 years [180 inflammatory pathology, 52 malignant pathology]) who were undergoing abdominal surgery were enrolled. Median impedance value of diseased segments was significantly lower than adjacent normal segments of gut in 130 paired samples studied (1832 [727] ohm vs. 2604 [1295] ohm; p<0.001). MI value of segments of gut containing malignant tissue (n=50) and inflammed tissue (n=80) was significantly lower than the MI value of adjacent normal segments of gastrointestinal tract (1880 [977] ohm vs. 2583 [1431] ohm; p<0.001) and (1787 [557] ohm vs. 2515 [1244] ohm; p<0.001) respectively. Median reduction in visually diseased segment was by 712 (661) ohm and percentage reduction was by 24% from adjacent normal segment. Biocompatible endoscopic catheter of 3 mm diameter was developed which has been tested in 3 patients and also found to differentiate diseased from normal mucosa
Conclusion Impedance spectroscopy is effective real time simple objective tool to identify diseased gut mucosa from healthy mucosa.
Keywords Endoscopic catheter, Impedance, Inflammation, Malignancy
016
Prevalence of sarcopenia in patients with inflammatory bowel disease and factors associated with it
Vikram Dharap, Philip Abraham, Devendra Desai, Tarun Gupta, Pavan Dhoble, Nirad Mehta, J Modhe
Correspondence - Philip Abraham - [email protected]
Department of Gastroenterology, P D Hinduja Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim, Mumbai 400 016, India
Introduction Sarcopenia is a progressive and generalized skeletal muscle disorder with significant reduction in skeletal muscle mass associated with low muscle strength and physical performance. In inflammatory bowel disease (IBD) it is affected by many factors and can be present in patients even when in clinical remission. It has been implicated in various disease complications, affecting its prognosis.
Aims To study prevalence of sarcopenia in patients with IBD and factors associated with it.
Methods Consecutive consenting patients with IBD between June 2021 and June 2022 were enrolled. Associated diseases that could contribute to sarcopenia were excluded. Anthropometric measurements, body mass index (BMI), and mid-arm muscle circumference were recorded. Muscle strength was measured by hand-grip strength (hand-held dynamometer), physical performance by gait speed (4-meters walk test) and muscle mass by measuring skeletal muscle index with single L3-level CT scan. As per European Working Group on Sarcopenia in Older People, 2018 definition, probable sarcopenia had low muscle strength), sarcopenia (low muscle strength and low muscle mass), and severe sarcopenia (low muscle strength, low muscle mass, and low physical performance). Factors associated with sarcopenia were studied.
Results Of 117 patients (65 men; mean age 42.4 years [standard deviation 15.3]; 73 UC, 42 CD, 2 IBD-U), 40 (34.2%) patients had probable sarcopenia, 47 (40.2%) sarcopenia (29 UC, 18 CD) including 10 with severe sarcopenia. Ten (21.3%) patients with sarcopenia were in remission. On univariate analysis BMI, disease activity, hemoglobin, and biologic use showed significant association with sarcopenia; only BMI was significant on multivariate analysis.
Conclusion Sarcopenia was detected in 40% of patients with IBD; one-fifth of them were in clinical remission. Low BMI significantly correlated with occurrence of sarcopenia.
Keywords IBD, Malnutrition, Sarcopenia
017
Early (within two weeks) versus late percutaneous catheter drainage in patients with acute necrotizing pancreatitis
Pankaj Gupta, Harsimran Shah, Shameema Farook, Chaitanya Bendale, Anupam Singh, Jimil Shah, Jayanta Samanta, Harshal Mandavdhare, Vishal Sharma, Saroj Sinha, Usha Dutta, Manavjit Sandhu
Correspondence - Pankaj Gupta - [email protected]
Department of Radiodiagnosis, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India
Introduction Early drainage has been advocated in the management of the symptomatic pancreatic collection. However, there is a paucity of data on the safety and efficacy of early drainage. To compare the results of early (≤2 weeks) vs. late (>2 weeks) percutaneous catheter drainage (PCD) in patients with acute necrotizing pancreatitis (ANP).
Methods This retrospective study comprised consecutive patients with ANP who underwent PCD in the first two weeks of illness. Matched controls that underwent PCD between the 3rd and 4th week of disease formed the comparison group. The technical success rate, clinical success rate, complications, and clinical outcomes were compared between the two groups.
Results Seventy-four patients (median age, 37.1±12.7 years) comprised the study group (I). An equal number of patients with comparable baseline characteristics comprised the control group (II). The mean pain to PCD interval was 10.1±2.9 days in group I vs. 21.6±4.5 days in group II. The procedures were technically successful in all patients in both groups. The clinical success rate was 79.7% in group I vs. 93.2% in group II (p=0.069). There were 23 catheter-related complications (15 minor and 8 major). The incidence of complications was significantly higher in group I (n=17, 22.9%) than in group II (n=6, 8.1%) (p=0.013). Of the clinical outcomes, the need for surgery was significantly higher in group I than in group II (13 patients vs. five patients, p=0.031). All other clinical outcomes were comparable between the two groups.
Conclusion Early PCD within the first two weeks of illness is feasible, effective, and has an acceptable complication rate.
Keywords Acute necrotizing, Catheters, Drainage, Pancreatitis,
018
Stool multiplex molecular polymerase chain reaction assay in comparison to conventional stool tests in detecting gastrointestinal infections as cause of flares of inflammatory bowel disease
Manek Kutar , Devendra Desai, Philip Abraham, Tarun Gupta, Pavan Dhoble
Correspondence – Manek Kutar- [email protected]
Department of Gastroenterology, P. D. Hinduja Hospital and Medical Research Center, Veer Savarkar Marg, Mahim, Mumbai 400 016, India
Introduction Inflammatory bowel disease (IBD) is characterized by intermittent and unpredictable flares. Other than natural history, flares can be caused by superadded gastrointestinal (GI) tract infections. Diagnosis of infection is conventionally made by microscopy and stool culture specimens. These are limited by lengthy turnaround time, low sensitivity, inability to detect agents other than bacteria and effect of pre-test antibiotic usage. Stool multiplex molecular polymerase chain reaction (PCR) assay (BioFire® FilmArray® GI Panel) allows simultaneous detection of nucleic acids from 23 bacteria, viruses and parasites.
Aims
1. To compare infectious organisms detected by Biofire® FilmArray® test and conventional stool test (microscopy and culture) in IBD flare patients.
2. Determine impact of detection of infective agents in the management of flares, as measured by use of anti-infective agents
Methods Single center, prospective, cohort study. Inclusion criteria: Consenting patients above 18 years with IBD flare. Exclusion criteria: Colorectal cancer, toxic megacolon, intestinal perforation, previous IBD surgery. Sample size: 58.
Results The following tables show organisms detected and change in management Conventional stool test n (%) Biofire® n (%) P value (Chi-square test)
Organism detected 6 (10.3) 32 (55.1) 0.0001
Organism not detected 52 (89.7) 26 (44.9)
Total 58 58
Conventional stool test n (%) Biofire® n (%) P value (Chi-square test)
Change in management 3 (5.1) 11 (18.9) 0.023
No management change 55 (94.9) 47 (81.1)
Positive reports 58 58
Stool Biofire® showed better organism detection rate and more frequent need for change in management as compared to conventional tests. Comparative cost of conventional stool test cost was Indian rupee (₹) 4300 and that of stool Biofire® ₹ 12,000.
Conclusion Stool Biofire®, as compared to conventional stool tests, detected significantly more infective organism in IBD flare and resulted in 4-fold more change in management of the flare.
Keywords Biofire, Flare, IBD
019
2D-Shear wave elastography: A novel non-invasive marker for differentiation between benign and malignant focal lesions of liver
Aditya Verma, Bony George, Srijaya S
Correspondence – Aditya Verma - [email protected]
Department of Medical Gastroenterology, Government Medical College, Ulloor-Akkulam Road, Chalakkuzhi, Thiruvananthapuram 695 011, India
Background Detection and characterization of focal liver lesions (FLLs) poses a frequent challenge in clinical practice. 2D-shear wave elastography (2D-SWE) is a recent technique which uses acoustic radiation force to induce mechanical vibrations and assess tissue elasticity.
Aims To study the elasticity characteristics of focal liver lesions by 2D shear wave elastography and to determine whether it can be used to differentiate benign from malignant lesions.
Methods All patients with FLL underwent 2D-SWE and elasticity quantification. Contrast-enhanced computed tomography (CECT) or magnetic resonance imaging (MRI) findings were used as the reference method for the diagnosis of FLLs.
Results Two hundred and sixteen patients with FLL were evaluated by the 2D-SWE. 130 patients had malignant FLLs of which 90 had hepatocellular carcinoma (HCC), 20 had intrahepatic cholangiocarcinoma (IHCC) and 20 had metastatic lesions. Of the 86 benign FLL, there were 36 hemangiomas, 12 FNH, 24 simple cysts, 4 complex cysts, and 10 abscesses. Mean liver stiffness of various lesions by 2D-SWE was 65.7 (IHCC), 60.5 (HCC), 45.4 (metastases), 7.6 (hemangioma), 16.9 (FNH), 9.14 (abscess), 8.62 (simple cyst) and 2.95 (complex cyst). ROC analysis revealed that a SWE cut off of 40 kPa could distinguish between benign and malignant lesions with sensitivity of 100% and specificity of 80%. (AUROC of 0.871). The lesion to background liver parenchyma stiffness ratio in cirrhotic patients was 4.81 for IHCC, 3.16 for metastasis and 1.93 For HCC. Therefore in cirrhotic patients, a lesion to liver stiffness ratio < 2 along with SWE of lesion more than 40 kpa favors HCC. However, in non-cirrhotic livers, there was no statistically significant difference between stiffness ratio of various malignant focal lesions.
Conclusion 2D-SWE could be used as a novel, non-invasive adjunct for the differentiation of benign and malignant focal lesions of liver.
Keywords 2-D shear wave elastography, Focal lesion liver, Hepatocellular carcinoma
020
Model for end stage liver disease - Sarcopenia score for prediction of mortality in liver cirrhosis
Hitesh Ramesh, Deepak Suvarna
Correspondence – Deepak Suvarna - [email protected]
Department of Medical Gastroenterology, J S S Hospital, Mahatma Gandhi Road, Fort Mohalla, Mysuru 570 004, India
Introduction One of the major limitations of model for end-stage liver disease (MELD) score is its failure to assess nutritional status of patients, thereby underestimating disease severity. So patients with low MELD score, but with sarcopenia may be under prioritized. Our objective was to evaluate if inclusion of sarcopenia within MELD score could improve prediction of mortality in patients with liver cirrhosis.
Methods We evaluated 65 patients with liver cirrhosis for sarcopenia. Sarcopenia evaluation was done bedside using SARC-F questionnaire, Chair rise test and measuring hand grip strength using electronic hand dynamometer. Sarcopenia was defined using previously published hand grip strength cut offs (Asian working group for sarcopenia). Patients with sarcopenia were given additional 10 points to MELD score. Patients with and without sarcopenia were followed up for a period of 6 months.
Results Twenty-nine patients (44.6%) with liver cirrhosis had sarcopenia. Mean hand grip dynamometer strength (kg) was 20.214.57 kg and 31.34 7.93 kg in patients with and without sarcopenia respectively (p-< 0.001). Sarcopenic patients had a higher frequency of ascites (p = 0.618), hepatic encephalopathy (p = 0.53), variceal bleeding (p = 0.47) and SBP (p = 0.43) in comparison to non-sarcopenic patients during 6 months of follow-up. But p value was not statistically significant. The mean MELD Score was 20.62±6.13 and 19.67±6.75 among patients with and without sarcopenia respectively. Mean MELD-Sarcopenia score was 30.61± 6.28 among sarcopenic patients.
Conclusions Sarcopenia was detected in significant patients with cirrhosis of liver. Incidence of liver cirrhosis related complications and mortality was higher among patients with sarcopenia compared to non-sarcopenic patients. Sarcopenia was independently associated with increased risk of mortality. however, modification of MELD score to include sarcopenia (MELD-Sarcopenia score) was not associated with improvement in prediction of mortality at 6 months.
Keywords MELD score, Sarcopenia
021
Evolution of Rosemont`s “indeterminate for chronic pancreatitis” as diagnosed on endoscopic ultrasound in patients presenting with recurrent acute pancreatitis with one year follow-up
Arun Vaidya, Kshaunish Das, Partha Patra
Correspondence – Arun Vaidya - [email protected]
Department of Gastroenterology, Seth Sukhlal Karnani Memorial Hospital, and Institute of Post-Graduate Medical Education and Research, SSKM Hospital Road, Bhowanipore, Kolkata 700 020, India
Background and Aim Some patients presenting with recurrent acute pancreatitis (RAP), when undergo endoscopic ultrasound (EUS), are classified as indeterminate for chronic pancreatitis (CP) according to Rosemont criteria. Our aim was to study the clinical and radiological outcome of such patients over a period of one year.
Methods We conducted prospective observational cohort study and included Rosemont “Indeterminate” for CP patients above 12 years of age. All the patients were closely followed up at 3 monthly intervals in pancreatic clinic and subjected to ultrasound abdomen and blood sugar profile 6 monthly. EUS was done after 12 months of baseline EUS. Fecal elastase was performed after 1 year of enrolment.
Results Total 21 RAP patients after excluding chronic pancreatitis on CT abdomen and magnetic resonance cholangiopancreatography (MRCP) undergone EUS. Fourteen were found to be Indeterminate for CP and included in study. Males were 93%. Median age was 26 years. Median duration between first attack of acute pancreatitis (AP) and EUS was 34 months with median of 4 attacks of AP prior to EUS. Most common etiology of RAP was idiopathic followed by ethanol and hypertriglyceridemia. History of smoking present in 36% patients. On 1 year follow-up, 35.7% remained pain free and 28.6% had AP attack. Endocrine and exocrine insufficiency was seen in 1 and 2 patients respectively. Gallstones and sludge were detected in 3 patients on follow-up ultrasound abdomen. Follow-up EUS done in 8 patients revealed Rosemont ‘normal’ in 1, ‘Indeterminate’ in 2, suggestive of CP in 3 and consistent with CP in 2 patients.
Conclusions EUS has high diagnostic yield. Indeterminate for CP is common in younger adults with idiopathic being most common etiology. Rosemont ‘’Indeterminate” progress to definitive CP in majority of patients.
Keywords Chronic pancreatitis, Idiopathic, Indeterminate, Rosemont`s criteria
022
Efficacy and safety of digital single-operator cholangioscopy guided laser lithotripsy for impacted cystic duct stones- A single tertiary care centre experience
Radhika Chavan , Vatsal Bachkaniwala, Chati Gandhi, Sanjay Rajput
Correspondence – Radhika Chavan - [email protected]
Department of Medical Gastroenterology, Ansh Clinic, A-1, Jaisinghbhai Park Hirabhai Tower, Nirant Cross Road, Uttam Nagar, Maninagar, Ahmedabad 380 008, India
Background and Aim Cholangioscopy have expanded the horizons of pancreaticobiliary evaluation. Cholangioscopy guided laser lithotripsy have been reported to be safe and effective for difficult bile duct stones. Cystic duct stones (CDS) pose special challenge for endoscopic treatment because of tortuous nature of the cystic duct, so traditionally it is managed with surgery. We aimed to see efficacy and safety of cholangioscopy guided laser lithotripsy for cystic duct stones.
Methods All consecutive patients who underwent laser lithotripsy for cystic duct stones from July 2018 till February 2022 were recruited after obtaining institutional board review approval. Details regarding previous Endoscopic retrograde cholangiopancreatography (ERCP) and cholecystectomy were maintained prospectively. ERCP was performed in all patients and digital single-operator cholangioscopy (DSOC) with laser lithotripsy (Holmium) was performed. Primary endpoint was complete cystic duct clearance determined by cholangioscopy.
Results Total 167 patients underwent laser lithotripsy for various indication during the study period. Out of 167 patients, 30 patients (median age 45.5 [range 26-73] years, male-20) underwent laser lithotripsy for CDS. Out of 30 patients, 21 patients had retained impacted CDS after cholecystectomy. Median size of CDS was 15 mm (range 11-20mm). Mechanical lithotripsy had failed in 12 patients. DSOC guided laser lithotripsy was utilised in all patients with technical success of 93.3%. CDS clearance was achieved in 29 (96.6%) patients. In one patient procedure was aborted because of respiratory distress. Post ERCP CBD stenting was done in all patients which were removed subsequently (at median 4 weeks). Median duration of procedure was 65 (40-90) minutes. There were few adverse events (mid abdominal pain-5, post-ERCP pancreatitis-2, and death-1). The median follow-up duration was 6 (range 3-43) months.
Conclusions DSOC guided laser lithotripsy is safe and effective for cystic duct stones. It is minimally invasive and can be considered for the management of retained impacted CDS after cholecystectomy.
Keywords Cholangiography, Gallstone, Laproscopic, Lithotripsy, Mirizzi syndrome
023
SoCr score – A novel predictor to assess steroid response in acute severe ulcerative colitis
Antony George, Jijo Varghese, Krishnadas Devadas
Correspondence – Antony George - [email protected]
Department of Medical Gastroenterology, Government Medical College, Ulloor - Akkulam Road, Chalakkuzhi, Thiruvananthapuram 695 011, India
Introduction Acute severe ulcerative colitis (ASUC) is a dreaded complication of ulcerative colitis (UC), with high mortality. 15% to 57% of patients fail to respond to systemic corticosteroids, the cornerstone of ASUC management, and might require colectomy or rescue medical therapies like infliximab or cyclosporine. The available predictive models of steroid response are based on western population studies, some utilizing expensive tests like fecal calprotectin. Our study aims to develop a simple predictor model for steroid response in ASUC.
Methodology A prospective observational study was conducted over 7 years (2015-2022). ASUC was defined based on Truelove and Witts criteria. Various clinical and laboratory parameters were assessed on the day of admission.
Results Eighty-seven patients were taken up for the study. Sixteen patients failed to respond to steroids. Among the variables analyzed, albumin, CRP, sodium, and hemoglobin were significant in predicting response to steroids. On regression analysis, CRP and sodium were independent predictors of response to steroids. The coefficient of beta was multiplied by steroid and CRP and the total score was obtained. This was called the SoCr (sodium+CRP) score = (sodium*0.4 – CRP*0.28) score. AUROC of the score was plotted. The score had an AUROC of 0.937. A score of >42 has a sensitivity of 93% and specificity of 83% in predicting response to steroids. The score was validated in a validation cohort of 31 patients. A score of >42 had a sensitivity of 96% and specificity of 88% in the validation cohort. All patients without pancolitis and those with a precipitating factor for colitis exacerbation responded to steroids.
Conclusion SoCr score is a simple prognostic score that can predict response to steroids in ASUC. The absence of pancolitis and lack of a precipitating factor for colitis exacerbation are strong predictors of response to steroids.
Keywords Acute severe ulcerative colitis, Predictors, Score, Steroid response
024
Advantages of routine milking of common bile duct during combined laparoscopic cholecystectomy and endoscopic retrograde cholangiopancreatography
Vinay V , Sridhar C G
Correspondence – Vinay V - [email protected]
Department of Medical Gastroenterology, GEM Hospital, Pankaj Mill Road, Ramanathapuram, Coimbatore 641 045, India
Background Approximately fifteen percent of patients with gallbladder stones also have common bile duct (CBD) stones [1]. Endoscopic retrograde cholangiopancreatography (ERCP) is combined routinely with laparoscopic cholecystectomy (LC) for concomitant CBD stone and other post-cholecystectomy complications such as bile leak and inadvertent injury. We aimed this study to evaluate the role of CBD milking to prevent complications and to increase rate of biliary cannulation in ERCPs Post-LC.
Methods This study included all cases undergoing combined LC with ERCP as one-step procedure at GEM Hospital, Coimbatore in the period from January 2021 to September 2021. All the complications with percentage of biliary cannulation were noted meticulously to compare with the conventional method of not milking CBD. Patients undergoing LC or ERCP as two-step procedure were excluded.
Results Out of total 68 cases, failed biliary cannulation was recorded in 8 patients in non-milking cases but only 1 in milking of CBD was performed intra-operatively. CBD cannulation time was longer in non-milking group as compared to milking group. Total operative time of 106.5 minutes was less than conventional 122.8 minutes but not statistically significant. Complications like inadvertent PD cannulation in 11 cases (26%) compared to milking group about one case (3%), retained calculi were noted in 6 cases in non-milking group (13.19%) as compared to 3 cases post-milking (4%). Postoperative pancreatitis were observed in 5 cases (11.9%) of non-milking group but in only one case after milking of CBD (3.82%). Average length of Hospital stay was longer in non-milking group.
Conclusions Milking of CBD although difficult in some cases of LC has definite benefit in biliary cannulation during ERCP with reduced operative time and complication rates probably due to effects on sphincter of Oddi but follow-up is required to make it standardised technique in conventional one-step combined LC with ERCP.
Keywords ERCP, Laparoscopic cholecystectomy, Milking of common bile duct
025
Exclusive enteral nutrition mediates gut microbial alterations which correlate with augmented corticosteroid response in patients with acute severe colitis
Aditya Bajaj , Manasvini Markandey, Pabitra Sahu, Sudheer Vuyyuru, Bhaskar Kante, Peeyush Kumar, Namrata Singh, Arti Gupta, Mukesh Singh, Mahak Verma, Govind K Makharia, Saurabh Kedia, Vineet Ahuja
Correspondence – Vineet Ahuja - [email protected]
Department of Gastroenterology, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029, India
Introduction Supplementation with exclusive enteral nutrition (EEN) in addition to standard corticosteroid therapy (SCT) has been proven to augment the steroid response rate in patients with acute severe ulcerative colitis (ASUC). EEN is known to alter the gut microbial composition. The present study identifies the changes in gut microbiota driven by EEN in patients with ASUC receiving standard steroid therapy and explores the correlation of the EEN-associated bacteria with changes in clinical parameters over the course of therapy.
Methods Stool samples were collected from 50 patients with ASUC who received either SCT (n=24) or SCT supplemented with EEN (n=20) for a period of 7 days, at baseline (Day 0) and post-therapy (Day 7). Microbiome characterization was carried out using 16S rRNA gene sequencing followed by data processing using QIIME2 and R packages for analysis of diversity and differentially abundant taxa.
Results Seven-day EEN supplementation of SCT in patients with ASUC resulted in enhanced Methylobacterium, Sphingomonas, Limosilactobacillus, Megamonas, Thermus, Viellonella, with a reduction in Ruminococcus gnavus, Gemmiger, Pseudomonas, and Enterococcus. The EEN-mediated enhancement in specific taxa correlated positively with patients’ serum albumin levels and negatively with fecal calprotectin levels. The microbiome abundance dataset and clinical parameters (FCP, CRP, serum albumin levels, and clinical response to EEN) correlated significantly, as analyzed by coinertia analysis. Gut microbial composition of patients who responded to the EEN-augmented SCT showed an enhanced abundance of Coprococcus, Megamonas, Oribacterium, Sediminibacterium, Acidibacter, and Thermus, and reduction in Sutterella, R. gnavus, Collinsella, Dorea, and Morganella, when compared to EEN non-responders. Baseline gut microbiome signature in patients with ASUC predicts a potential response to both the SCT and EEN-supplemented SCT in patients with ASUC.
Conclusion Augmentation of clinical response by EEN-conjugated corticosteroid therapy is accompanied by gut microbial changes in patients with ASUC.
Keywords Acute severe ulcerative colitis, Exclusive enteral nutrition, Gut microbiota
026
Molecular subtyping of pancreatic neuroendocrine tumor and its correlation with clinicopathological outcome: A single institute retrospective study
Saikat Mitra 1 , Aravind Sekar1, Divya Khosla2, Vikas Gupta3, Kim Vaiphei1
Correspondence - Saikat Mitra - [email protected]
Departments of 1Histopathology, 2Radiotherapy, and 3Surgical Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India
Introduction Pancreatic neuroendocrine tumors (PanNETs) account for ~3% to 4% of all pancreatic tumors worldwide. The WHO grading and TNM staging in PanNET do not accurately predict the clinical behavior and prognosis. We used immunohistochemistry based molecular subtyping of PanNETs and studied the relation of the mutations with clinicopathological outcome.
Methods In this single institute retrospective study, cases of PanNETs were selected. Immunohistochemistry (IHC) for ATRX, DAXX, Menin, ARX and PDX-1 markers were done on formaline-fixed tissue. FITC-labelled telomere-specific fluorescent in-situ hybridization (FISH) was performed to assess altered telomere lengthening (ALT). The tumors were subtyped based on mutation status and the subtypes were correlated with clinical, pathological features and follow-up.
Results A total of 78 cases including 75 PanNET (45 grade 1, 20 grade 2 and 10 grade 3) and 3 pancreatic neuroendocrine carcinoma were identified. ATRX and DAXX mutations were identified in 20.9% and 29.9% of PanNET cases respectively. ATRX mutation was significantly associated with nodal metastasis (p=0.007), higher TNM stage (p=0.004), higher WHO grade (p=0.014), lymphovascular invasion (p<0.001), recurrence (p=0.025). DAXX mutation was significantly associated with a larger tumor size (p=0.007), higher TNM stage (p=0.011), higher WHO grade (p=0.002), lymphovascular invasion (p=0.001), perineural invasion (p=0.046). Altogether, 26 cases (38.8%) showed either ATRX/DAXX mutation (AD mutant subtype) and showed significantly higher tumor size (p=0.035), nodal metastasis (p= 0.001), higher WHO grade (p= 0.001), lymphovascular invasion (p=0.001) perineural invasion (p=0.048) and recurrence (p=0.001). Univariate survival analysis revealed significantly lower overall follow-up in ATRX mutant (p<0.001), DAXX mutant (p=0.007) and AD mutant (p=0.011) subtypes. ALT positivity correlated with higher TNM stage, lymphovascular invasion and AD mutation. Multivariate cox-regression analysis showed ATRX mutation as independent predictor of poorer overall survival (HR=10.1, CI=1.3-76.7, p=0.025).
Conclusion ATRX/DAXX mutant PanNETs have aggressive clinical, histological behavior and are predictors of poor outcome.
Keywords Altered telomere lengthening, ATRX, DAXX, Neuroendocrine tumor, Pancreas
027
Algorithmic approach to differentiate between non-specific and specific etiologies of chronic terminal Ileitis
Karan Sachdeva, Samagra Agarwal, Peeyush Kumar, David Mathew, Sudheer K. Vuyyuru, Bhaskar Kante, Pabitra Sahu,. Sandeep Mundhra, Lalit Kurrey, Shubi Virmani, Pratap Mouli, Rajan Dhingra, Govind K Makharia, Saurabh Kedia, Vineet Ahuja
Correspondence – Vineet Ahuja - [email protected]
Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029, India
Introduction Chronic isolated terminal ileal (TI) involvement (terminal ileitis) may be seen in numerous etiologies including Crohn’s disease (CD) and intestinal tuberculosis (ITB) in addition to other etiologies that may improve with symptomatic management alone. We aimed to improve our previously suggested algorithm to distinguish patients who would merit specific treatment from those who do not.
Methods Patients (n=153) with isolated TI involvement (ulcers or nodularity) following-up at All India Institute of Medical Sciences (AIIMS) (2007-2022) were retrospectively reviewed. A specific (ITB/CD) diagnosis was made based on standardized criteria and other relevant data was collected. The cohort was utilized for validation of previously suggested algorithm while multivariate analysis with bootstrap validation was used to develop a revised algorithm.
Results We included 153 patients (mean age 36.9 years, 70% males, median duration of symptoms 1.5 years) with isolated terminal ileal involvement of whom 109 (71.2%) received a specific diagnosis (69 CD, 40 ITB). Multivariate regression and validation statistics suggested that based on a combination of clinical (blood in stools, weight loss, hemoglobin), radiological (necrotic lymph nodes, long segment ileal involvement) and colonoscopic findings (presence or absence of deep ulcers), an optimism corrected c-statistic of 0.975 and 0.958 could be reached with and without histopathological findings respectively. Based on these, a revised algorithm was developed which showed a sensitivity of 99.08% (95% CI:94.99-99.98) and a specificity of 75.0% (95% CI:59.66-86.81). The positive predictive value (PPV) was 90.76% (95% CI:85.47-94.25) and negative predictive value (NPV) was 97.06% (95% CI:82.32–99.57) with an overall accuracy of 92.16% (95% CI:86.70-95.88). This was a more sensitive and specific than the previous algorithm (accuracy 83.6%, sensitivity 95.4%, and specificity 54.4%).
Conclusion We suggested a revised algorithm to stratify patients of terminal ileitis into those who have a specific etiology and those who need only symptomatic treatment. Our algorithm has the potential to avoid missed diagnosis as well as unnecessary side effects of treatment.
Keywords Algorithm, Crohn’s disease, Terminal Ileitis
028
Significance of fibroblast growth factor receptor heterozygous genotype in the pathogenesis of non-alcoholic fatty liver disease with and without type II diabetes mellitus: A pilot study from Assam
Snigdha Jyoti Das , Purabi Bose, Sangit Dutta * , Natasha Kashyap, Aditi Kalita, Sujoy Bose **
Correspondence - Purabi Bose - [email protected]
Department of Molecular Biology and Biotechnology, Cotton University Panbazar, Guwahati 781 001, India, *Department of Medicine, Gauhati Medical College Hospital, Guwahati 781 032, India, and **Department of Biotechnology, Gauhati University, Guwahati 781 014, India
Introduction Non-alcoholic fatty liver disease (NAFLD) in lean patients is suggestive of phenotypic and apparently pathophysiologically distinct; with unsatisfactory documentation of its underlying mechanism(s) at molecular level. Type-II diabetes mellitus (T2DM) is also linked with NAFLD, and therefore a common immunological link may be present. In the present study, we intended in defining the possible role of the polymorphism of the FGFR4 receptor gene and the differential expression of its ligand, FGF19, to bring some insight towards the pathophysiology of NAFLD via molecular genetic analysis in lean patients without or with T2DM.
Methods Blood samples were obtained from clinically diagnosed lean patients having NAFLD (=50), NAFLD with T2DM (=50) and healthy volunteers (=50) with informed consent. Analysis of gene expression at mRNA level and gene polymorphism was done by Real-time-polymerase chain reaction (Real-time-PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) respectively.
Results The genotype analysis of FGFR4 gene showed higher prevalence of heterozygous genotype in patients with NAFLD compared to NAFLD with T2DM (OR=2.667) while it showed significantly lower prevalence of heterozygous genotype in controls compared to the case cohorts. The gene expression of FGF19 at mRNA level exhibited an up-regulation in both the cases in comparison to controls. Upon association with increased liver function tests (LFT) profile markers, although statistically non-significant, expression level of FGF19 was found to be negatively correlated with alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) levels and positively correlated with ALP and aspartate aminotransferase (AST) levels.
Conclusion The data suggests the association of FGFR4 heterozygous genotype with the development of NAFLD and NAFLD with T2DM. However, the upregulation of FGF19 mRNA expression in disease cohorts compared to controls was not found to be statistically significant suggesting the fact that the FGFR4 heterozygous genotype may have some role to play in the pathogenesis of either NAFLD or NAFLD with T2DM rather than its ligand FGF19.
Keywords Fibroblast growth factor (FGF19), Fibroblast growth factor receptor (FGFR4), Messenger
029
Plastic stents versus NAGI bi-flanged metal stent for endoscopic ultrasound guided drainage of walled-off necrosis - A randomized controlled study
Krithi Krishna Koduri , Nitin Jagtap, Sandeep Lakhtakia, Jahangeer Basha, Zaheer Nabi, Mohan Ramchandani, Rakesh Kalapala, Rajesh Gupta, Sana Fathimamemon, D N Reddy
Correspondence – Krithi Krishna Koduri - [email protected]
Department of Gastroenterology, Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500 082, India
Introduction Endoscopic ultrasound (EUS) guided drainage with either plastic stents or metal stents is the mainstay of walled off necrosis (WON) management. A systematic review of retrospective studies showed similar treatment success for WON by plastic or metal stents. This single center randomized controlled study was designed to evaluate the efficacy of dedicated NAGI bi-flanged metal stent (BFMS) and plastic stents for WON drainage.
Methods Patients with symptomatic WON amenable for EUS-guided drainage were randomized to either BFMS or plastic stents. Patients having altered anatomy, WON not accessible for endoscopic drainage, previous percutaneous drainage were excluded. Primary outcome was comparison of re-intervention free clinical success at 4 weeks, defined as symptom resolution and significant reduction in WON size. Secondary outcomes were treatment success, number of re-interventions, hospital stay and long-term outcomes.
Results A total of 92 patients were randomized either to BFMS (n = 46; mean age 34.9 (12.4) years) or plastic stents (n = 46; mean age 36.8 (11.1) years). There was no significant difference in terms of debris and maximum size of WON in both groups (p > 0.05). Re-intervention free clinical success at one month was observed in 31 (67.4%) in BFMS arm and 20 (43.5%) in plastic stent arm by ITT analysis (p 0.035) and 68.1% vs. 44.2% by PP analysis (p 0.0382). However, overall clinical success was equal in both groups. There was significantly lower number of re-interventions including necrosectomy sessions and hospital stay required in BFMS group. There was no difference in procedure-related adverse events or mortality. Also, there was no significant difference in clinical success, recurrence, DPDS, chronic pancreatitis and new-onset DM up to 6-month follow-up.
Conclusions The bi-flanged metal stent provides higher re-intervention free clinical success at 4 weeks with lower hospital stay without increased risk of adverse events compared to plastic stents for EUS-guided drainage of WON.
Keywords Bi-flanged metal stent, Endoscopic ultrasound, RCT, Walled off necrosis
030
Fatty liver and metabolic syndrome in patients with celiac disease: A systematic review and meta-analysis
Nishant Aggarwal 1 , Ashish Agarwal2, Hasan Alarouri3, Vignesh Dwarkanathan4, Sana Dang5, Vineet Ahuja6, Govind K Makharia6
Correspondence – Govind K Makharia - [email protected]
1Department of Internal Medicine, William Beaumont Hospital, Royal Oak, Michigan, USA, 2Department of Gastroenterology, All India Institute of Medical Sciences, Marudhar Industrial Area, 2nd Phase, M.I.A. 1st Phase, Basni, Basni, Jodhpur 342 005, India, 3Jordan University of Science and Technology Faculty of Medicine, Ar-Ramtha, Jordan, 4Department of Community Medicine, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029, India, 5Department of Medicine, Vardhaman Mahavir Medical College and Safdarjung Hospital, NH 48, Near AIIMS Hospital, Ansari Nagar West, New Delhi 110 029, India, and 6Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029, India
Objective Studies have suggested a high prevalence of fatty liver and metabolic syndrome in patients with celiac disease (CeD). We conducted a systematic review and meta-analysis to assess the prevalence of fatty liver and metabolic syndrome in treatment-naïve patients with CeD and in patients on gluten-free diet (GFD).
Methods The PubMed, Embase and the Cochrane Library databases were searched for original studies. We included full-text articles published in the English language after 1990 that used well-defined criteria for CeD, fatty liver and metabolic syndrome. Of 185 studies identified, seven were included for the analysis. Random effects model was used to calculate pooled prevalence.
Results The pooled prevalence of fatty liver in treatment-naïve patients with CeD was 15.3% (0.153 [95% CI 0.056-0.285], n=867). After initiation of GFD, the prevalence increased to 29.1% (0.291 [95% CI 0.172-0.427], n=869). The pooled prevalence of metabolic syndrome in treatment-naïve patients with CeD was 4.3% (0.043 [95% CI 0.024-0.067], n=1239), which increased to 24.2% (0.242 [95% CI 0.195-0.293], n=1239) after initiation of GFD (Figs. 1 and 2). We did not observe any significant publication bias.
Conclusions The present review has suggested a high prevalence of fatty liver and metabolic syndrome in patients with CeD which increases further with the initiation of GFD. Patients with CeD should thus be regularly screened and monitored for the development of fatty liver and metabolic syndrome. They should be counselled appropriately regarding their diet and inclusion of regular physical activity in their lifestyle.
Keywords Celiac, Fatty liver, Metabolic syndrome, Non-alcoholic fatty liver disease, Obesity
031
FDG PET CT findings in microscopic colitis and its correlation with the disease activity
Antriksh Kumar 1 , Rakesh Kochhar 1 , Kaushal Kishore Pasad 1 , Anish Bhattacharya 2 , Rajendra Kumar 2 , Shreya Shruti3, Jayanta Samanta1, Saroj Kant Sinha1
Correspondence – Saroj Kant Sinha - [email protected]
Departments of 1Gastroenterology, and 2Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India, and 3Government Medical College and Hospital, Sector 32, Chandigarh 160 030, India
Background and Aim PET-CT has been used earlier to localize the diseased segments in patients with Crohn’s disease and ulcerative colitis. There is paucity of data on its utility for the diagnosis and evaluation of disease activity in microscopic colitis (MC).
Methods Patients presenting with watery diarrhea were prospectively evaluated from July 2018 to December 2019 for the etiology using various tests including sigmoidoscopy/colonoscopy and colonic biopsy. Those suffering from MC underwent 18-FDG-PET-CT and assessment of disease activity using microscopic colitis activity index (MCDAI). A regional 18F-FDG-PET-CT scan of the abdomen and pelvis was performed, and the images were evaluated in blinded manner. Liver FDG uptake was taken as background and any uptake in large above the background liver activity was taken as abnormal. The maximum SUV (standardized uptake values) was measured in each colonic segment.
Results Fifty-three patients with chronic watery diarrhea were evaluated, of which 29 patients were found to have MC (23 LC, 2 CC and 4 mixed). Diffuse FDG uptake pattern in colon was noted in 20 (69%) patients, focal colonic uptake was present in 8 (27.6%) patients. Even in the colonic segments, diffuse FDG uptake pattern was seen predominantly. The number of patients showing such an uptake pattern were 16 (55.2%) in ascending colon, 11 (37.9%) in cecum and 8 (29.6%) in descending colon. Only four patients mounted some PET enhancement in the small intestine.
Receiver operating characteristic (ROC) curves were formulated to find maximal cut-off values of MCDAI and uptake patterns of PET scan. A significant SUVmax of diffuse uptake pattern in the descending colon had a significant correlation with MCDAI (Correlation Coefficient=0.786, p= 0.021).
Conclusion Most patients with MC show diffuse pattern of uptake in colon. Moreover, FDG-PET-CT may be useful in assessing the the disease activity of MC.
Keywords CT scan, FDG PET, Microscopic colitis, PET
032
No biopsy approach is applicable for diagnosis of celiac disease in adults
Aditya Pachisia , Nishakar Thakur, Shubham Mehta, Alka Singh, Shubham Prasad, Ankit Agarwal, Ashish Chauhan, Sachin Rajput, Rohan Malik, Prasenjit Das, Vineet Ahuja, Govind K Makharia
Correspondence – Aditya Pachisia - [email protected]
Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029, India
Introduction While European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) 2020 advocates non-biopsy pathway for the diagnosis of celiac disease (CeD) in children if IgA anti-tissue transglutaminase antibody (anti-tTG ab) titre is ≥10 folds upper limit of normal (ULN) and have a positive IgA anti-endomysial antibody (EMA), data on anti tTG Ab titre based diagnosis of CeD in adults is emerging. We planned to validate if anti-tTG Ab titre >10 folds predicts villous abnormalities of modified Marsh grade ≥2 in Asian patients with CeD.
Methods Relevant data of 937 adults with CeD was extracted from two databases including All India Institute of Medical Sciences (AIIMS) Celiac Clinic and the Indian National Biorepository. The diagnosis of CeD in them were made on basis of standard criteria including a positive anti-tTG Ab and presence of villous abnormalities of modified Marsh grade 2 or more.
Results Only 45.3% of 937 patients had anti tTG Ab titer of ≥10 folds. However, the positive predictive value (PPV) and specificity of anti tTG Ab titre ≥10 folds for predicting modified Marsh grade ≥2 was 99.8% and 98%, respectively. Further at anti tTG Ab titre ≥ 11folds, both the specificity and PPV were 100% for prediction of villous abnormalities of modified Marsh grade ≥2.06).
Conclusions Approximately only half of adult patients with CeD have anti-tTG Ab titre ≥ 10 folds hence qualifying for the non-biopsy pathway for the diagnosis. The specificity and predictive value of anti-tTG Ab ≥ 10 folds for diagnosing CeD are high even in adult patients
Keywords Anti tTG Ab, Celiac disease, Fold rise, Modified marsh score
033
The predictors of non-tumoral portal vein thrombosis among patients with decompensated liver cirrhosis using acoustic parameters of liver and spleen
Shivabrata Dhal Mohapatra, Aditya Verma, Srijaya S
Correspondence – Aditya Verma - [email protected]
Department of Medical Gastroenterology, Government Medical College, Ulloor - Akkulam Road, Chalakkuzhi, Thiruvananthapuram 695 011, India
Background and Aims Portal vein thrombosis (PVT) that occurs due to poor portal flow, complex thrombophilic disorders and factors leading to endothelial dysfunction, is an increasingly recognized complication in patients with cirrhosis. We tried to assess the acoustic parameters and stiffness of liver and spleen as risk factors associated with non-malignant PVT in decompensated chronic liver disease patients (DCLD).
Methods We prospectively enrolled 502 patients with DCLD (CHILD B/C). All patients underwent detailed clinical evaluation, baseline investigation and ultrasonography. PVT was confirmed by contrast-enhanced computed tomography (CECT) abdomen in patients with ultrasonogram (USG) evidence of PVT or alteration in portal flow dynamics. Acoustic parameters of liver and spleen were assessed by 2D Shear wave elastography (Supersonic Aixplorer). ROC was plotted to derive the best cut-off of parameters for development of PVT.
Results Thirty-nine patients were excluded. Of the 463 patients included, 51 had PVT (11%). It was observed that non-malignant PVT group patients had smaller liver size (11.8±1.8 vs. 12.4±1.5, p=0.032), higher spleen size (14.9±2.3 vs. 13.5±2.2, p<0.01), higher portal vein diameter (PVD, 14.4±3.2 vs. 12.2±1.7, p<0.01), lower portal vein velocity (PVV, 11.5±3.6 vs. 16.7±3.6, p<0.01), higher liver stiffness (61.3±21.7 vs. 55.2±17.1, p=0.02), higher splenic stiffness (50.3±15.1 vs. 36.7±7.5, p<0.01) as compared to non-PVT group. On plotting ROC; PVV <12.5 cm/sec (AUROC 0.86, sensitivity 74%, specificity 88%, NPV 95.9%), PVD >13.7 cm (AUROC 0.75), liver stiffness >66.5 kPa (AUROC 0.72), liver size <11.95 cm (AUROC 0.63) were significantly associated with development of non-malignant PVT (p<0.01). On multiple logistic analysis PVD >13.75 cm (B=1.21, OR:95%CI 3.36]1.05-10.7], p=0.04), PVV <12.5 cm/sec (B= -1.06, OR:95% CI 0.35 [0.13-0.09], p=0.03) were significant risk factors for PVT development in DCLD.
Conclusion The association of higher liver stiffness and smaller liver size as markers of extent of cirrhosis, higher splenic size and stiffness as a reflection of severity of portal hypertension, dilated PV and low PVV indicating sluggish portal flow that trigger thrombosis in the splenoportal axis, were significantly associated with non-malignant PVT in DCLD.
Keywords 2D shear wave elastography, Decompensated cirrhosis, Non-malignant PVT-Portal vein thrombosis
034
Left ventricular diastolic dysfunction: A surrogate predictor of survival in patients with decompensated cirrhosis
Rushil Solanki, Srijaya Sreesh, Krishnadas Devadas, Antony George, Vijay Narayanan, Shivabrata Dhal Mohapatra
Correspondence - Rushil Solanki - [email protected]
Department of Medical Gastroenterology, Government Medical College, Ulloor-Akkulam Road, Near SAT Hospital Medical College Junction, Chalakkuzhi, Thiruvananthapuram 695 011, India
Background and Aims Left Ventricular diastolic dysfunction (LVDD) is a primal manifestation of cirrhotic cardiomyopathy. Few studies have addressed its relationship with mortality outcomes. We evaluated the impact of LVDD along with other parameters on the short-term survival of patients with decompensated cirrhosis.
Method One hundred and ninety-two patients with decompensated cirrhosis underwent investigations including 2D echocardiography with tissue Doppler imaging. The diagnosis of LVDD was based on the American Society of Echocardiography guidelines and the patients were followed up for 6 months.
Results 42.2% (n=81) had grade 1 LVDD and 30.7% (59) had grade 2 LVDD at enrollment. 69.2% (128) were alive at 6 months. Among the non-survivors, 5.9% had no LVDD, 23.4% had grade-1 and 62.1% had grade-2 LVDD (p=<0.001). Median survival of LVDD grades 0, 1, and 2 was 177±3, 163±3, and 122±3 days respectively. Kaplan-Meier survival analysis showed poor survival in patients with LVDD (p<0.001), E/e' ≥10 (p=0.029) and pulmonary capillary wedge pressure PCWP ≥15 mmHg (p=0.003). The Cox regression model showed a hazard ratio of 10.3 for grade-2 LVDD, and 5.7 for any LVDD compared to 1.07 for model for end-stage liver disease (MELD) score as an independent predictor of mortality. MELD score cut-off for predicting mortality was 17 (84% sensitivity:62% specificity). Mortality in patients with MELD >17 was 52.9% with LVDD vs. 9.5% without LVDD (p<0.001), and MELD ≤17 was 16.7% with LVDD vs. 3.4% without LVDD (p=0.08). In multivariate analysis, the MELD score and LVDD were independent predictors of survival. Among echocardiography parameters, patients with a ratio of early filling velocity to early diastolic mitral annular velocity (E/e') ≥10 and PCWP ≥15 mmHg were significantly associated with the severity and mortality of the patients.
Conclusion The presence and severity of LVDD are better predictors of poor transplant-free survival than MELD in patients with decompensated cirrhosis. Therefore, cardiac parameters could be an add-on to the MELD score for prognostication of decompensated cirrhosis patients.
Keywords Cirrhotic cardiomyopathy, Diastolic dysfunction, Echocardiography
035
Urine neutrophil gelatinase associated lipocalin for predicting Type of acute kidney injury (AKI) in patients of decompensated cirrhosis with AKI
Roshan George , Ajay Kumar, Bhawna Mahajan, Ujjwal Sonika, Ajay Dalal, Sanjeev Sachdev
Correspondence – Roshan George - [email protected]
Department of Gastroenterology, Govind Ballabh Pant Institute of Post Graduate Medical Education and Research, 1, Jawaharlal Nehru Marg, New Delhi 110 002, India
Introduction The management and outcomes of acute kidney injury (AKI) in decompensated cirrhosis (DC) depends on type of AKI. The differentiation between types of AKI in real world setting is done by clinical adjudication, which has limitations. The present study evaluated the diagnostic accuracy of urine neutrophil gelatinase associated lipocalin (NGAL) in predicting type of AKI among patients of DC having AKI.
Methods Consecutive DC patients with AKI stage 1B or above (International Club of Ascites [ICA] 2015 criteria) seen between March 2020 to February 2021 were evaluated. AKI was typed as acute tubular necrosis (ATN-AKI), Pre-Renal (PRA-AKI) and hepatorenal syndrome (HRS-AKI). The urine NGAL levels were measured at diagnosis of AKI (Day 0) and 48hrs (Day 3) after volume expansion. The AKI type was determined by two study investigators independently using clinical data blinded to urine NGAL levels. The patients were followed up till death or 28 days.
Results Overall 388 DC patients were screened, 86 patients (PRA-AKI n=47, 55%; HRS-AKI n=25, 29%; ATN-AKI n=14, 16%) with mean age 48.73±12.53 years, 74 (86%) males were included. The area under receiver operating characteristic (AUROC) of urine NGAL for differentiating ATN-AKI and non-ATN AKI at day 0 was 0.97 (95% CI 0.95-1.0) and on day 3 was 0.97 (0.94-1.0). The optimal urine NGAL cut-off level on day 0 was 214.98 ug/g creatinine and on day 3 was 200.09 ug/g creatinine for predicting ATN-AKI. The overall mortality was 45.34% and urine NGAL levels were higher in patients who died as compared to those who survived.
Conclusion Urine NGAL has an excellent diagnostic accuracy in predicting ATN-AKI in DC patients. High urine NGAL levels are associated with increased risk of death.
Keywords Acute kidney injury (AKI), Decompensated cirrhosis, Urine neutrophil gelatinase associated lipocalin
Esophagus
036
Proton pump inhibitor therapy in patients with erosive esophagitis- A real world scenario
Mayank Jain
Correspondence – Mayank Jain - [email protected]
Department of Gastroenterology, Arihant Hospital and Research Centre, 297 Indrapuri, Near Bhanwarkuan, Indore 452 001, India
Patients with gastroesophageal reflux disease (GERD) are managed with lifestyle changes, dietary interventions, and proton pump inhibitors (PPI).
Aim To determine patterns of PPI use in patients with documented erosive esophagitis (EE).
Methods This prospective study recruited all patients with symptoms of GERD (heartburn and /or regurgitation with or without chest pain) and documented significant reflux esophagitis (Los Angeles grading LA-B or beyond on endoscopy). Lifestyle, dietary changes were initiated and all patients were prescribed twice daily PPI for 8 weeks. PPI was tapered as the requirement beyond 8 weeks. Follow-up was done at weeks 8, 12 and 24. The outcomes analyzed included number of patients where complete PPI withdrawal was possible at week 24 and determinants of continued PPI use at 24 weeks of therapy. Statistical analysis- Chi-square test, Mann–Whitney U-test, sensitivity, specificity, positive likelihood ratio, negative likelihood ratio. P<0.05 was considered as statistically significant.
Results The study cohort included 53 patients- 42 with reflux esophagitis LA-B and 11 with reflux esophagitis LA-C (median age 46 years [22-77 years]; 28 [52.3%] males). There was significant difference in consumption pattern of PPI between week 12 and 24 (p 0.008). At week 12, 15.1% were off PPI and 67% required intermittent dosing. At week 24, 45.3% of cases were off PPI therapy and 43.4% required intermittent dosing. Only 11.3% patients continued drug use at once-a-day dosing. Lower BMI (p 0.01) and age (p 0.01) were linked with complete PPI withdrawal at week 24.
Conclusion The present study highlights that PPI withdrawal is possible in 15.1% and 45.3% cases with EE after week 12 and week 24 of therapy respectively. Lower body mass index (BMI) and age are likely to be associated with PPI withdrawal at week 24.
Keywords Drugs, Esophagitis, Esophagus, Reflux, Response
037
An unusual case of dysphagia in a young male
Sumaswi Angadi, Suprabhat Giri, Sagar Gangadhar, Saidulu Chevigoni, Lohith Kumar V, Abhishek Kamuni, Sukanya Bhrugumalla
Correspondence - Sumaswi Angadi - [email protected]
Department of Medical Gastroenterology, Nizam's Institute of Medical Sciences, Speciality Block-4th Floor, Punjagutta, Hyderabad 500 082, India
Introduction Dysphagia in young individuals is commonly attributed to esophageal web, strictures, motility disorders, eosinophilic esophagitis or rarely malignancy. Extra esophageal compression as a cause of dysphagia is rarely encountered. An accurate diagnosis is essential to provide appropriate therapy.
Case Report A 39-year-old male, non-smoker, non-alcoholic, a farmer by occupation presented with intermittent fever, shortness of breath associated with cough for 1 year, hoarseness of voice, and dysphagia for 6 months. Dysphagia was progressive for solid food. Systemic examination was unremarkable except for patchy crepitations in the right chest. Cross-sectional imaging revealed a 5.9 × 10.3 × 10.8 cm heterogeneously enhancing mass lesion in the posterior mediastinum. The lesion was seen encasing the left and right main bronchi, left main pulmonary artery, and closely abutting descending thoracic aorta with pericardial involvement. A probable diagnosis of malignancy or tuberculosis was made based on clinical features including hoarseness of voice and imaging findings. Esophagogastroduodenoscopy revealed a smooth extrinsic impression in the mid-esophagus with a fistulous opening covered with necrotic debris on the opposite wall and left vocal cord palsy. Barium swallow examination confirmed a linear fistulous tract in the mid esophagus with long segment luminal narrowing. Subsequently, endoscopic ultrasound with tissue acquisition was performed. Histopathology revealed granulomatous inflammation with septate filamentous hyphal structures. Further, the patient underwent a bronchoscopy and an Aspergillus galactomannan test performed on bronchoalveolar lavage fluid was suggestive of invasive aspergillosis (0.7 ng/mL). The patient was started on intravenous voriconazole and discharged on oral formulation. Over 6 weeks, the patient reported a significant reduction in upper respiratory complaints and dysphagia.
Conclusion Extra esophageal compression is a rare cause of dysphagia. Cross-sectional imaging and endoscopic ultrasonography play an important role in its diagnosis. Invasive aspergillosis in immunocompetent individuals is rare. Prompt diagnosis and appropriate therapy is lifesaving.
Keywords Dysphagia, Endoscopic ultrasound, Invasive Aspergillosis, Mediastinal granuloma
038
Clinical, epidemiological, endoscopic profile and outcome of corrosive injuries of gastrointestinal tract
Chappidi Deepak, Sandeep Nijhawan
Correspondence – Sandeep Nijhawan - [email protected]
Department of Gastroenterology, Sawai Man Singh Medical College, New SMS Campus Road, Gangawal Park, Adarsh Nagar, Jaipur 302 004, India
Introduction Corrosive ingestion is one of the important causes of esophageal stricture and gastric outlet obstruction (GOO) in India. This study aims to explore the clinical, epidemiological, and endoscopic profile and outcomes of patients of corrosive ingestion.
Methods This prospective observational study was done on patients presenting with history of corrosive ingestion to SMS Hospital, Jaipur, Rajasthan. Detailed history was recorded, and patients were analyzed on the basis of age, sex, mode of ingestion, intention of consumption, nature of corrosive and clinical symptoms. Endoscopy was done within 24 to 48 hours of admission. Patients were serially followed up and subjected to repeat endoscopy after 6 weeks.
Results Total of 60 patients were enrolled from December 2020 to November 2021. Incidence of corrosive ingestion was higher in males than females (67% vs. 33%). The most common intention of corrosive ingestion was suicidal found in n=42 (70%). Acid ingestion (75%) was more common than alkali ingestion (25%). Chest pain and dysphagia were the most common symptoms at presentation. On endoscopy, 15 (25%) had grade 0, 5 (8%) had grade 1, 25 (41%) had grade 2 and 15 (25%) had grade 3 degree of corrosive injuries. All patients with grade 0, 1, and 2a injury recovered without sequelae. Esophageal strictures were seen in 12 (26%) patients in acid ingestion and 6 (40%) patients in alkali ingestion. GOO developed in 10 (22%) patients of acid ingestion and 6 (13%) patients of alkali ingestion. Both complications were seen in 3 (6%) patients with acid ingestion.
Conclusions Corrosive injury of the upper gastrointestinal tract is a common problem with variable complications. Acid injury is more common. Initial endoscopic grading of injury correlates with outcome. Esophageal complications were common in both acid and alkali ingestion. GOO was more common in acid ingestion.
Keywords Corrosive, Gastric outlet obstruction, Stricture
039
Experience on the diagnostic outcome of high-resolution esophageal manometry from a single-center, tertiary level hospital
Chittuluri Jagadeesh, Chezhian A
Correspondence - Chittuluri Jagadeesh - [email protected]
Department of Medical Gastroenterology, Madras Medical College, Rajiv Gandhi Government General Hospital, Poonamallee High Road, 3, Grand Southern Trunk Road, Near Chennai Central, Park Town, Chennai 600 003, India
Significance High-resolution esophageal manometry (HREM) has been the method of choice for the evaluation of esophageal motility disorders. There is no local data regarding the use and diagnostic outcome of HREM in the investigation of the patients referred for evaluation of esophageal motility.
Methodology Study Design: Retrospective, cross-sectional. Study Population: Patients referred for evaluation of esophageal motility. Intervention: HREM
Results In this study, total of 103 patients were evaluated using HREM. Majority of the patients included were females, 62 (60.195) and the mean age was 45.71 years. Most of the patients were referred for HREM because of persistent reflux symptoms despite proton pump inhibitor (PPI), 61 (59.22%), followed by dysphagia, 36 (34.95%). For the entire population, the most common HREM finding was abnormal, 66 (64.08%). Majority of patients referred for HREM because of gastroesophageal reflux related disease revealed normal results, 36 (53.73%), on the other hand majority of patients referred for HREM because of dysphagia revealed abnormal results, 35 (97.22%). Overall, an abnormal motility occurred in 66 patients (64.08%). The most common motility abnormality was weak peristaltic disorders in 33 (50.00%) followed by esophagogastric junction (EGJ) disorder in 40 (45.45%). The most common motility disorders based on symptom category were as follows: Dysphagia, Achalasia Type I in 17 out of 35 patients (48.57%); gastroesophageal reflux disease (GERD), ineffective peristalsis in 22 out of 31 patients (70.97%).
Conclusion This study confirms the overall high prevalence of weak peristaltic disorders and underscores the need to further study the pathophysiology and management of this ubiquitous disorder. The finding of achalasia in 83.33% of our patients with dysphagia is consistent with recent reports regarding the rising incidence of this disorder and underscores the need of prompt motility testing in this population.
Keywords High resolution manometry
040
Twenty-four-hour pH-metry alone is inferior to additional impedance monitoring in the diagnosis of gastroesophageal reflux disease, particularly in presence of low gastric acid secretion
Uday C Ghoshal, Sugata Narayan Biswas, Anshuman Elhence, Bushra Fatima, Anand Prakash Agrahari, Asha Misra
Correspondence - Uday C Ghoshal - [email protected]
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raibareli Road, Lucknow 226 014. India
Background Current gold standard for the diagnosis of gastroesophageal reflux disease (GERD) is 24-h pH-metry though it fails to detect non-acidic reflux. The sensitivity of 24-h pH-metry alone (both catheter-based and BRAVO capsule) is questionable, especially, if gastric acid secretion is low due to reduced parietal cell mass, Helicobacter pylori-induced gastric atrophy and antisecretory therapy. Accordingly, we analyzed the diagnostic ability of 24-h pH-metry as compared to impedance monitoring in relation to gastric acid levels without antisecretory therapy.
Methods A retrospective analysis of prospectively collected data of 150 patients with suspected gastroesophageal reflux disease (GERD) undergoing 24-h pH impedance study was done.
Results Among 150 patients with symptoms suggestive of GERD, 106 (70.6%) had confirmed GERD diagnosed either by 24-h pH-metry alone (10 [9.4%]), impedance monitoring alone (49 [46.2%]) or both (47 [44.3%]). Reflux of gastric contents was detected by 24-h pH-metry and 24-h impedance monitoring in 57/106 (53.7%) and 96/106 (90.5%) of patients, respectively (p<.00001). Patients with GERD diagnosed by 24-h impedance monitoring had a higher mean gastric pH (2.9 [median 1.3, IQR 5.3]) than those diagnosed by 24-h pH-metry (2.1 [median 1.4, IQR 2.6]) or both (1.6 [median 1.2, IQR 2.1]) (p=0.001).
Conclusion 24-h impedance monitoring detects GERD more often than 24-h pH-metry. Patients with higher mean gastric pH leading to non-acidic reflux were more often diagnosed by 24-h impedance monitoring than 24-h pH metry. Thus, 24-h pH-metry alone is inferior to additional impedance monitoring in the diagnosis of GERD, particularly in presence of low gastric acid secretion.
Keywords Gastroesophageal reflux disease, 24-h pH-metry, 24-h impedance monitoring
041
A case report of contained upper cervical esophageal perforation masquerading as retropharyngeal abscess
Dinesh Kumar Dugganapalli, Umadevi Malladi, B Ramesh Kumar, Sahithya L
Correspondence – Dinesh Kumar Dugganapalli - [email protected]
Department of Medical Gastroenterology, Osmania Medical College, 5-1-876, Turrebaz Khan Road, Troop Bazaar, Koti, Hyderabad 500 095, India
Perforation of the cervical esophagus is an infrequent but severe condition. Most patients are in their sixties, and esophageal perforation is slightly more common in males. The diagnosis and management of cervical esophageal perforation remains a challenging clinical problem. Several factors, including the difficulty of accessing the esophagus, the lack of a strong serosal layer, the unusual blood supply of the organ and the proximity of vital structures, all contribute to this condition’s high morbidity and to a mortality rate of at least 20%. We present a case of cervical esophageal perforation mimicking retropharyngeal abscess.
Keywords Cervical esophagus, Dysphagia, Esophageal perforation, Retropharyngeal abscess
042
Prevalence of eosinophilic esophagitis in patients presenting with chronic reflux symptoms at a tertiary care centre in South India
Amith Viswanath 1 , Ebby George Simon1, Anna B. Pulimood2, Kripa Varghese2, Amit Kumar Dutta1, Joseph A J1, Rajeeb Jaleel1, Anoop John1, Ajith Thomas1, Pegatraju Krishna Bharadwaj1
Correspondence – Amith Viswanath - [email protected]
Departments of 1Gastroenterology, and 2Pathology, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Introduction Eosinophilic esophagitis (EO) has been increasing in prevalence over the past decade. Previous data from India showed a prevalence of 3.2%. The purpose of this study was to determine the prevalence and clinical predictors of EO in patients presenting with chronic reflux symptoms.
Methods This was a prospective cross-sectional study which enrolled consecutive adult patients with chronic reflux symptoms from January 2022 to August 2022. Their symptoms were assessed with the reflux disease questionnaire, straumann dysphagia index and brief esophageal dysphagia questionnaire. Upper gastrointestinal endoscopy was done and endoscopic features of EO were documented. Four quadrant biopsies were obtained from the upper and lower esophagus. EO was diagnosed if the number of eosinophils was >15 per high power field.
Results Out of 197 patients analyzed, four were diagnosed with EO. Out of these, three were male patients. The median age of presentation was 44 years. Heartburn and epigastric pain were present in all four patients. Endoscopy findings were normal in 2 patients (50%). Compared to the non-EO group, EO patients were more likely to have epigastric pain (p= 0.02), higher endoscopic reference (EREFS) score (p=0.004), had microabscesses in histopathology (p =0.002).
Conclusion Prevalence of EO was 2% in this study population of reflux patients. EO should be considered in chronic reflux patients with abnormal findings typical of EO on endoscopy.
Keywords Eosinophilic esophagitis, India, Prevalence
043
Esophageal Crohn's -Always A mystery
Dhruv Shah
Correspondence – Dhruv Shah - [email protected]
Department of Gastromedicine, S V P Hospital, N H L Medical College, Ellis Bridge, Ahmedabad 380 006, India
Introduction Crohn's disease of the esophagus is rare. The estimated incidence in adult patients with Crohn's disease is 0.3% to 2%. Esophageal involvement is more common in the pediatric population. We present case of adult esophageal Crohn’s earlier misdiagnosed as esophageal duplication cyst.
Case Report A 36-year-old man with a history of dysphagia, and odynophagia from 2 months. Upper endoscopy suggestive of? Esophageal duplication cyst. Further contrast-enhanced computed tomography (CECT) thorax done suggestive of? Esophageal duplication cyst. GI surgery referred was done and transhiatal esophagectomy with gastric pull up was done and excised esophagus was sent for histopathology examination. Biopsy revealed chronic active esophagitis with noncaseating granulomas and an absence of microorganisms on special stains, which supported a diagnosis of Crohn's disease. Further colonoscopic examination with biopsies through the colon and terminal ileum was found to be insignificant. In the postoperative period patient developed esophagocutaneous fistula, patient was treated with a proton pump inhibitor, a short course of prednisone, and a maintenance regimen that included azathioprine and mesalamine. His esophageal symptoms resolved.
Discussion As illustrated by this case, most reported cases of Crohn’s disease of the esophagus are associated with disease elsewhere in the gut. However, there are rare reports in which Crohn 's disease is presented primarily in the esophagus. Patients with esophageal involvement usually complain of heartburn, odynophagia, dysphagia, and substemal or epigastric pain. Therapy is based largely on the administration of corticosteroids and immunomodulatars (Biologicals).
Conclusion Involvement of the upper gastrointestinal tract by Crohn's disease is usually under-diagnosed or falsely diagnosed. Timely diagnosis and treatment leads to good clinical outcomes. Detail evaluation of Crohn’s mimickers should always be done.
Keywords Biologicals, Dysphagia, Esophageal Crohn’s
044
Dysphagia lusoria: A rare cause of dysphagia
Arun Prasannan, Venkatakrishnan Leelakrishnan, Mukundan Swaminathan, Thirumal Perumal, Ravindra Kantanameni
Correspondence – Venkatakrishnan Leelakrishnan - [email protected]
Department of Medical Gastroenterology, P S G Hospitals, Peelamedu, Coimbatore 641 004. India
Introduction Dysphagia lusoria is a term used to describe dysphagia as a consequence of vascular compression of the esophagus. The majority of cases of dysphagia lusoria are due to aberrant right subclavian artery causing posterior esophageal compression. Decreased vascular compliance is thought to be the most predominant factor for symptoms of dysphagia. Our report describes a case of late-onset dysphagia secondary to a right aortic arch with an aberrant left subclavian artery, which represents a rare variant of dysphagia lusoria.
Presentation Seventy-two-year-old man presenting with progressive dysphagia and breathlessness for a period of 1 year. Patient is a known case of chronic kidney disease, coronary artery disease, hypertension, diabetes mellitus on treatment for 5 years. He also had abdominal distension, cough and orthopnoea. Examination revealed bilateral coarse creps, pedal edema, ascites. Investigations revealed anemia, sinus tachycardia, elevated troponins, D Dimer, S1Q3T3 in ECG. Echo showed concentric LVH, mild grade 2 diastolic dysfunction pulmonary artery hypertension. CT pulmonary angiogram revealed right sided aortic arch with abberrant origin of left subclavian artery from Kommerell diverticulum compressing esophagus with bilateral pleural effusion, bronchiactasis, dialated pulmonary artery. Endoscopy revealed extrinsic vascular compression in the mid esophagus causing luminal narrowing and pulsations. Barium swallow revealed a large extrinsic compression in the mid esophagus. Patient was adviced surgery in view of significant symptoms, but attenders opted for conservative management.
Conclusion The prevalence in the general population of an aberrant subclavian artery is estimated at 0.4% to 0.7% in the majority of the published literature. Motility abnormalities and esophageal stiffening, aortic elongation with increased traction on the obstructing artery or aneurysmal dilatation in the presence of Kommerell’s diverticulum may contribute to late symptoms. Dsyphagia lusoria due to aberrant left subclavian artery from right sided aortic arch with Kommerells diverticulum is extremely rare cause of dysphagia in elderly patients.
Keywords Aberrant left subclavian artery, Dysphagia lusoria, Right sided aortic arch
045
Leukemic infiltration of esophagus presenting as pseudoachalasia
Uday C Ghoshal, Srikanth Kothalkar, Akash Mathur
Correspondence – Uday C Ghoshal [email protected]
Department of Medical Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raibareli Road, Lucknow 226 014, India
A 38-year-old male presented with a history of dysphagia, regurgitation, and 5 Kg weight loss for ten months. He also had a history of intermittent low-grade fever every 3-4 months associated with fatigue and generalized weakness for the same duration. One month before admission, he had a history of having right upper limb cellulitis that responded to antibiotics. Examination revealed severe pallor. An esophagoduodenoscopy revealed a dilated esophagus and resistance at the gastroesophageal junction. A timed barium esophagogram showed a hold-up of contrast with distal tapering. The diagnosis of type I achalasia was confirmed on high-resolution solid-state (Sandhill Scientific, Co, USA) esophageal manometry (basal lower esophageal sphincter [LES] pressure 7.2 mmHg, integrated relaxation pressure [IRP] 25 and 27 mmHg, respectively for liquid and viscous swallow, mean distal contractile integral [DCI] 1 and 9 mmHg/cm/s, respectively for liquid and viscous swallow). His Eckardt score on presentation was 6. Given the short duration of symptoms, rapid worsening, recurrent infections and fatigue, he was subsequently evaluated to rule out secondary achalasia. On routine investigations, he was found to have bi-cytopenia (anemia and thrombocytopenia. Hemoglobin was 6 g/dL (normal 11.6 to 15 g/dL) and platelet count was 1 lakh (normal 1.5-4 lakh per cubic millimetre). A peripheral blood smear showed pseudo-rouleaux formation, reduced red blood cells, and 4% blast cells with an abnormal nuclear-cytoplasmic ratio.
Bone marrow aspiration showed particulate and hypercellular smears, constituting approximately 45% blasts and promonocytes and 20% of abnormal monocytes with reduced other hematopoietic elements; blasts positive for cytochemical staining with myeloperoxidase (MPO) stain suggestive of acute myeloid leukemia with monocytic differentiation.
Esophagal biopsy suggested leukemic infiltration. He was started on chemotherapy and nutritional support given through Rylee’s tube to which he responded with resolution of dysphagia.
Keywords AML, Dysphagia, Esophageal mannometry, Leukemic infiltration, Pseudoachalasia
046
Quality of life assessment and dysphagia relief following laparoscopic heller myotomy: Our experience
Phani Kumar Nekarakanti, Vivek Chauhan
Correspondence – Phani Kumar Nekarakanti - [email protected]
Department of Surgical Gastroenterology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, 1, Jawaharlal Nehru Marg, New Delhi 110 002, India
Background Laparoscopic Heller myotomy (LHM) can be performed by blunt dissection technique. Only a few studies have assessed the quality of life (QOL) and relief of dysphagia following LHM. The study reviews our long-term experience and correlate the QOL following LHM by blunt technique.
Methodology This retrospective study was analyzed from a prospectively maintained database (from 2013 to 2021) of a single unit of Department of Gastrointestinal Surgery at G B Pant Hospital, New Delhi. The myotomy was performed by blunt dissection technique in all patients. A fundoplication was added in selected patients. Post-operative Eckardt score >3 was considered as treatment failure. WHO QOL BREF questionnaire was used to evaluate QOL.
Results A total of 100 patients underwent surgery during study period. Of them, 65 patients underwent LHM, 27 underwent LHM with Dor fundoplication, 7 patients underwent LHM with Toupet fundoplication, and one open technique. Five patients had esophageal perforation and was repaired laparoscopically. Eleven patients developed treatment failure post-surgery. The median follow- up of the study cohort was 22 months (range 3-96 months). The mean IRP post-surgery in treatment success group was 9.15 and in treatment failure group was 15.78 (p=0.001). The mean WHO QOL score in physical well-being domain in treatment success vs. failure group 66.16 vs. 49.60 (p=0.001), psychological 55.73 vs. 41.90 (p=0.050), social 67.20 vs. 47.70 (p=0.009), environmental 64.92 vs. 43.70 (p=0.001).
Conclusion LHM by blunt technique have minimal treatment failures with good QOL with successful treatment group.
Keywords Achalasia cardia, Dysphagia, Fundoplication,Heller myotomy, Laparoscopy, Quality of life
047
Bougie versus balloon dilatation in causative-induced esophageal stricture: A retrospective analysis of two decades
Anupam Singh 1 , Yalaka Rami Reddy 2 , Pankaj Gupta 3 , Anuraag Jena 1 , Jimil Shah 1 , Saroj Kant Singh 1 , Rakesh Kochhar 1
Correspondence – Anupam Singh - [email protected]
Departments of 1Gastroenterology, and 3Radiology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India, and 2Gleneagles Global Hospital, Lakdi-ka-pul, Hyderabad 500 004, India
Introduction Endoscopic dilatation is the initial management strategy for caustic-induced esophageal strictures (CES). However, the differences in outcome for different types of dilators used are unclear. We compared the outcomes of CES for the use of bougie dilators compared to balloon dilators.
Methods Between January 1998 and December 2016, all patients with CES were included. Data collected included demographic parameters, type, and intention of caustic substance ingestion, number of strictures, number of dilatations required to achieve 15 mm dilatation, and post-dilatation recurrence. Patients were divided into 2 groups based on the type of dilator used for stricture dilatation, i.e. bougie dilator or balloon dilator. The two groups were compared for the baseline parameter, technical and clinical success, proportion of refractory strictures, recurrence rates after initial success, and major complicate rates.
Results One hundred and eighty-nine patients were included in the study with a mean age of 32.17±12.12 years and 119 (62.9%) being males. One hundred and twenty-two (64.5%) patients underwent stricture dilatation using bougie dilators while 67 (35.5 %) with balloon dilators. Technical success was higher for bougie dilators compared to balloon dilators (90.1% vs. 68.7%, p<0.001). Short-term clinical success (65.6% vs. 46.3%, p=0.01) as well as long-term clinical success (86.9% vs. 64.2%, p<0.01) was more with bougie dilators. Multivariate analysis identified the use of bougie dilators (aOR 4.868, 95% CI: 1.027 – 23.079) short-term clinical success (aOR 5.785, 95% CI: 1.203 – 27.825), and the presence of refractory strictures (aOR 0.151, 95% CI: 0.033–0.690) as independent predictors of the long-term clinical success. Twenty-four (12.7%) patients developed adverse events and were similar for the two groups.
Conclusion Use of bougie dilators increases the clinical success for CES compared to balloon dilators with similar rates of adverse events.
Keywords Controlled radial expansion balloon, Corrosive stricture, Savary Gilliard
048
Endoscopic management of a sick patient with empyema due to unusual cause of esophago-pleural fistula
Viswanath Reddy 1 , Rakesh Kumar Adi1, Ravi Shankar Bagepally1, Sai Reddy Y2
Correspondence – Viswanath Reddy - [email protected]
Departments of 1Gastroenterology, and 2Pulmonology, Yashoda Hospital, Alexander Road, Kummari Guda, Shivaji Nagar, Secunderabad 500 003, India
Introduction Esophago-pleural fistula (EPF) is an uncommon condition leading to fatal mediastinitis and empyema with sepsis. Surgery and conservative management are the options. We hereby describe an unusual cause of EPF due to accidental removal of nasogastric tube in a patient with recent cerebrovascular stroke, developed sepsis was managed by endoscopic procedures.
Methods a 52-year-old female who had recent ischemic stroke, being managed in Rehabilitation unit presented with sudden onset of breathlessness and sepsis. Evaluation was suggestive of bilateral empyema. Bilateral intercostal drains (ICD) were placed and broad spectrum antibiotics were given. Clinical suspicion of esophageal rupture was made in view of history of accidental removal of nasogastric tube preceding the catastrophic illness. Endoscopy showed a large defect (3 cm) in lower esophagus with pus draining. Options of surgery and conservative management was discussed with relatives. Due to her poor general condition and recent stroke, conservative management was considered. Esophageal defect was closed using multiple large endoclips (10). Percutaneous gastrostomy (PEG) was placed and through it, a feeding tube was placed into duodenum over guidewire under endoscopic guidance. She showed gradual improvement in terms of response to sepsis, ICDs were removed, and she tolerated PEG-D feeds. Three months later the contrast study showed closure of EPF fistula and endoscopy showed a pseudodiverticulum in the area. She was then started on oral diet and subsequently PEG-D tube was removed. Follow up in outpatient department was gratifying in terms of clinical response.
Results We describe a case of EPF with empyema due to accidental nasogastric tube removal, managed successfully with antibiotics, ICD placement and Endoscopic intervention.
Conclusion Esophago-pleural fistula due to accidental removal of nasogastric tube is rarely described. Empyema management and endoscopic therapy of the large defect with addition of alternative nutritional route helps enhancing healing of the fistula.
Keywords Empyema, Endoscopic closure, Esophago-pleural fistula, NGTube, PEGJ
049
Ugly duckling or just odd one out
Vinod Kolkunde
Correspondence – Vinod Kolkunde - [email protected]
Department of Gastroenterology, Yashoda Hospitals, Alexander Road, Kummari Guda, Shivaji Nagar, Secunderabad 500 003, India
Introduction Lichenoid esophagitis is a rare pathologic diagnosis, marked by a lichenoid pattern of inflammation in the esophagus without features of lichenoid planus. We present a case of a young male who presented with chronic progressive intermittent dysphagia and was found to have lichenoid esophagitis on esophageal biopsies.
Case Discription A 38-year-old male, no diagnosed comorbidities presented with complaints of progressive intermittent dysphagia to solids for the past 2 years and gradually progressive in nature. The episodes resolved with drinking water. He denied a history of gastroesophageal reflux, nausea, emesis, gastrointestinal bleeding or prior food impaction. He denied drug or tobacco use and reported social alcohol use. Esophagogastroduodenoscopy revealed esophageal stricture with mucosal fraibility. There was no evidence of furrowing, exudates, or findings suggestive of eosinophilic esophagitis.
Discussion Histopathology of lichenoid esophagitis shows apoptotic keratinocytes (civatte bodies) and intraepithelial lymphocytosis. A lichenoid esophagitis pattern may be seen in association with lichen planus, polypharmacy, rheumatologic diseases, and viral infections, including hepatitis and human immunodeficiency virus (HIV), but our patient does not have any history of CTD's, HIV and hepatitis. The majority of patients who present with lichenoid esophagitis pattern or lichenoid planus esophagitis are female. There was no history of lichen planus or skin involvement in our male patient and studies have shown that polypharmacy (>3 medications) and the use of immunomodulatory agents is common among patients with lichenoid esophagitis. Our patient was not taking any medications and was being managed with intermittent PPIs. With scant available literature, lichenoid esophagitis is a rare yet significant etiology of dysphagia, there is a low but documented risk of progression to malignancy.
Keywords Dysphagia, Lichinoid esophagitis, Males
050
Epidemiological study on esophageal carcinoma in south India
Shirish N D , R Selvasekaran, Ramireddy Krishna Chaitanya, R U Rajesh, T Anuvind, H Sairaman
Correspondence – Shirish N D - [email protected]
Department of Medical Gastroenterology, Thoothukudi Government Medical College Hospital, Kamaraj Nagar, Thoothukudi 628 008, India
Introduction Esophageal carcinoma is one of the common gastrointestinal malignancy. There is limited literature on epidemiology of esophageal carcinoma in south India.
Aim and Objectives To study the histological pattern of esophageal carcinoma in southern state of India. The objectives are to evaluate the relation of age, sex, substance abuse in esophageal carcinoma.
Methods We evaluated retrospectively the data of 89 patients with esophageal carcinoma in department of Medical Gastroenterology in Government Thoothukudi Medical College over a period of 3 years from June 2019 to May 2022.
Observation There were total of 89 patients with esophageal cancer, 60 (67.4%) were males and 29 (32.6%) were females, with M:F of 2.0:1. The median age was 58.8 years. Of the 89 patients, history of tobacco was found in 83 (93.3%) patients and alcohol in 26 (29.2%) patients. Majority of tumor was in upper two-third 51 (57.3%) followed by 32 (35.9%) patients in lower one-third of esophagus. In 7 patients both upper and lower esophagus are involved. Squamous cell carcinoma was the histological type involving in 63 (70.8%) patients. Adenocarcinoma was detected in 26 (29.2%) patients.
Conclusion Squamous cell carcinoma is still far more common than adenocarcinoma in India. The upper two third of esophagus is the most common site of esophageal carcinoma in southern state of India.
Keywords Adenocarcinoma of esophagus, Distribution, Sex variability, squamous cell carcinoma esophagus
051
Black esophagus treated with anti-coagulation- An interesting case report
Aastha Jha, Alok Sahu, Maitrey Patel. Apurva Shah, Shravan Bohra
Correspondence – Apurva Shah - [email protected]
Department of Gastroenterology, Apollo Hospital International Limited, Plot No, 1A, Gandhinagar - Ahmedabad Road, GIDC Bhat, Ahmedabad 382 428, India
Introduction Acute esophageal necrosis (AEN) or black esophagus, is a rare clinical entity, characterized by diffuse circumferential blackened esophageal mucosa, usually affecting the distal esophagus with abrupt normalization at the gastroesophageal (GE) junction. Here we present a case of acute esophageal necrosis, developing post stem cell transplantation.
Case Report We present a case of 59-year-old male patient who underwent autologous stem cell transplantation for multiple myeloma in February 2022. He developed sepsis on Day 10 and was started on broad spectrum antibiotics with inotropic support. On Day 15, he developed hematemesis. Upper gastrointestinal (GI) scopy showed severe ulcerative esophagitis with blackish discolouration of mucosa from 23 cm up to GE junction (Fig. 1a). Biopsy findings were suggestive of inflammation, ulceration, and necrosis, without evidence of granuloma, malignancy, or fungus. He did not have any history of alcohol intake, non-steroidal anti-inflammatory drug use, corrosive agent ingestion or GE reflux history. A contrast CT chest was not done due to presence of acute kidney injury. He was treated with anticoagulation in renal dose (low molecular weight heparin- 40 mg once daily), proton pump inhibitors (PPI) and sucralfate. Patient improved with the same, and injury completely healed within 14 days of initial scopy (Fig. 1c).
Conclusion Probable etiological factors include sepsis, hypo-perfusion related to shock and malnutrition. Treatment relies on aggressive resuscitation, correction of underlying medical conditions, institution of therapy with proton pump inhibitors and sucralfate but use of anti-coagulation for GI bleed paradoxically decreased the bleed in our case considering lower esophageal necrosis due to hypoperfusion/thrombosis. No such case report has been done yet, as per our knowledge for use of anticoagulation in AEN.
Keywords Black esophagus acute necrotizing esophagitis anticoagulation
052
A rare case of esophageal actinomycosis- Case report
Paila Ramesh , A Chezhian, Stefan Agera, Shubha I, Caroline Selvi, Prem Kumar, Aravind A
Correspondence – Stefan Agera - [email protected]
Department of Medical Gastroenterology, Madras Medical College, Poonamallee High Road, Park Town, Chennai 600 003, India
Introduction Esophageal actinomycosis is rare and has been reported in immunocompetent and immunocompromized patients. We reporting an unusual case of esophageal actinomycosis in limited cutaneous systemic sclerosis patient on immunosuppressants.
Case Report A 55-year-old female known limited cutaneous systemic sclerosis on immunosuppressants, ILD with pulmonary hypertension, CKD on medical treatment, systemic hypertension presented with difficulty in swallowing since 1-year, insidious onset, progressive, solids >liquids, grade 2, associated with pain during swallowing and occasional vomitings. She denied any recent chemical or foreign body injury of esophagus and physical examination unremarkable. Upper gastrointestinal endoscopy showed multiple well defined round ulcers about 0.5 to 0.5 cm in diameter scattered in the distal esophagus. Histopathological examination of biopsy specimen showed that stratified squamous epithelium with basal cell hyperplasia, extensive areas of hemorrhage, necro inflammatory exudates, sulfer granules and filamental bacterial colonies consistent with actinomycetes. Intravenous penicillin G (20 million units per day) injection was given for 2 weeks, followed by oral amoxicillin 2 gm per day for 6 months on outpatient basis. A repeat upper gastrointestinal endoscopy after 4 weeks of antibiotic treatment was begun showed a remarkable reduction in ulcer size and activity. After 6 months of antibiotic treatment repeat endoscopy revealed no ulcers or microorganisms.
Summary Esophageal actinomycosis is uncommon, but it has been reported in immunocompetent and immunocompromised patients. Esophageal histology should be carefully observed for sulfer granules and filamentous actinomycetes colonies. In this case patient responded to penicillins, but treatment may fail in patients with poor compliance or complicated disease.
References
1. Brown JR. Human actinomycosis: a study of 181 subjects. Hum Pathol. 1973; 4:319-33.
2. Arora AK, Nord J, Olofinlade O, Javors B. Esophageal actinomycosis: a case report and review of the literature. Dysphagia. 2003; 18:27-31.
Keywords Esaphagus actinomycosis
Stomach
053
Bovine Colostrum as an alternative long-term management option in patient of common variable immunodeficiency: A case study
Ganesh Muniappan
Correspondence – Ganesh Muniappan - [email protected]
Department of Gastroenterology, Kovai Medical Centre and Hospital, 99, Avinashi Road, Peelamedu, Indira Nagar, Civil Aerodrome Post, Coimbatore 641 001, India
Introduction Common variable immunodeficiency (CVID), also known as hypogammaglobulinemia is a primary immune deficiency disease characterized by low levels of protective antibodies and an increased risk of infections. CVID is treated with I.V. or S.C. immunoglobulin injections to partially restore immunoglobulin levels. However, due to compliance and cost issues of Ig additional treatments are the need of the hour, which are unfortunately rare. Oral Bovine Colostrum containing IgG, lactoferrin, lysozyme, lactoperoxidase and other nutrients may be a promising potential agent in managing long-term Common Variable Immunodeficiency Disease-associated gastrointestinal (GI) symptoms.
Case presentation A 41-year-old male suffering from CVID since lasts 10 years presented with severe recurrent uncontrollable GI infections requiring IVIG therapy. He was reluctant to continue IVIG, hence considering the evidence of oral hyperimmune bovine Colostrum on immune function and GI symptoms, the combination of bovine colostrum with zinc was selected as an exploratory option. The patient’s improvement of GI symptoms with regular use of combination was assessed through patient-reported outcome measures.
Result The patient showed marked clinical improvement from two months onwards. During the regular follow-up to 20 months, the patient showed an increase in his body weight and an improvement in his biochemical parameters along with gradual normalization in his GI symptoms with no reported adverse event.
Conclusion These results suggest that bovine colostrum improves clinical management of patients with GI symptoms due to CVID, when conventional therapies are not feasible. It should be investigated further with randomized controlled trials (RCTs) for more robust data as an effective and safe alternative therapy.
Keywords Common variable immunodeficiency, Gastrointestinal infection, Hypogammaglobulinemia, Intravenous immunoglobulin, Primary immunodeficiency
054
A rare case of giant fundic polyp in Peutz-Jegher syndrome presenting as gastric outlet obstruction
Srikanth Reddy Keesari , Govind Verma, Sudhir Mysore
Correspondence – Dhiraj Agrawal - [email protected]
Department of Medical Gastroenterology, Pace Hospital, HUDA Techno Enclave, Hitech city, Hyderabad 500 081, India
Affiliation Peutz-Jegher syndrome (PJS) is a rare polyposis syndrome commonly affecting a small bowl with recurrent obstruction due to polyp related intussusception. Here we present a rare case of giant fundic polyp presented as gastric outlet obstruction.
Introduction PJS characterized by mucocutaneous pigmentation and hamartomatous polyps which can occur anywhere in the GI tract. Commonly it presents as small intestine obstruction1(42.8%), abdominal pain (23.4), rectal bleeding (13.5%), extrusion of polyp (7.2).
Case Report A 58-year-old female presented with pain abdomen, vomiting, bloating sensation since 15 days. Her endoscopy showed large fundal polyp with a large pedicle obstructing pylorus. Contrast-enhanced computed tomography (CECT) showing polypoidal mass from fundus of stomach extending posteriorly into D2 and causing obstruction. She underwent laparoscopic gastrostomy+ reduction of intussusception +stapled partial gastrectomy done. Histopathology revealed hamartomatous polyp, favoring Peutz-Jegher polyp.
Discussion PJS with an incidence of 1 in 200000 live births. It is caused by mutation in the STK11(LKB1) gene. Those affected have multiple hamartomatous polyps, commonest2 sites are small bowel (50%), stomach (36%), colon (21%). Additionally, individuals with PJS have a significantly increased lifetime risk of gastroesophageal, small bowel, colonic and breast cancer. common presentation is obstruction due to intussusception within small bowel occurs more frequently in the jejunum compared to ileum. although the stomach is the second most common site for PJS polyps, gastric outlet obstruction due to gastro-gastric intussesception is extremely rare phenomena. such as in our patient who was admitted with gastric outlet obstruction.
Conclusion PJS with fundic polyp rarely presented as gastric outlet obstruction managed by laparoscopic gastrostomy + reduction of intussception + stapled partial gastrectomy.
References
1. Utsunomiya J, Gocho H, Miyanaga T, Hamaguchi E, Kashimure A. Peutz-Jeghers syndrome: its natural course and management. Johns Hopkins Med J. 1975; 136:71-82.
2. Shalaby S, Akbari K, Spilsbury C. Gastric outlet obstruction in Peutz-Jegher syndrome. Clin Surg. 2020; 5:2886
Keywords Gastric outlet obstruction, Hamartomatous polyp, Peutz-Jegher syndrome
055
Successful closure of bronchogastric fistula with Ovesco clips
Srikanth Reddy Keesari, Govind Verma, Sudhir Mysore, Dhiraj Agrawal
Correspondence – Dhiraj Agrawal - [email protected]
Department of Medical Gastroenterology, Pace Hospital, HUDA Techno Enclave, Hitech City, Hyderbad 500 081, India
Affiliation A bronchogastric fistulas are rare following transhiatal esophagectomy incidence less than 1% and incidence is higher following transthoracic esophagectomy 5.6% [1]. We present a case of 60 female presented with bronchogastric fistula following transhiatal esophgagectomy for carcinoma esophagus.
Introduction Bronchogastric fistula is a rare complication which occurs between the tracheobronchial tree and stomach in patients who undergo esophagogastric anastomoses. In the early postoperative period [2], the most likely cause of gastrobronchial fistula is dissection injury or post operative mediastinitis. When occur late, the commonest cause is tumor recurrence. others radiation necrosis and tracheobronchial erosion caused by the gastric staple line.
Case Report A 60-year-old female who underwent esophagectomy for carcinoma esophagus followed by chemoradiotherapy in October 2020. Came with cough on intake of food for last 2 years, which increases in supine position. Chest X-ray PA view showed gastric pull up and fibroatelectatic opacity in right mid zone. UGI endoscopy showing ulcer with fistulous opening at 30 cms from incisors. Bronchoscopy showing bronchogastric fistula in right middle bronchi. Endoscopic guided 12 mm Ovesco clips were applied over the fistulous opening. She tolerated oral food intake well after 2 days.
Discussion The management of gastrobronchial fistula following esophagectomy was not well defined. The options available are endobronchial stenting [2] which may not seal of fistula completely, surgical closure have high morbidity and endoscopic closure is new and safe approach.
Conclusion This is one of few reports on successful closure of gastrobronchial fistula using the OTSC-Ovesco clips. Therefore, this case highlights the use of a novel endoscopic approach as a safe and effective modality for bronchogastric fistula closure.
Reference
1. Dugan K, Frye L, Bronchogastric fistula a rare complication following transhiatal oesophagectomy. Chest J. 2017; 8: 903.
2. Dogan E, Turan N, Cobanogie U. American Journal of Cancer Prevention 2015.
Keywords Bronchogastric fistula, Esophagectomy, Ovesco clips
056
Congenital gastric diverticulum in antrum
Ramesh Avula , L R S Girinadh, Vamsi D Yadav
Correspondence - Ramesh Avula - [email protected]
Department of Medical Gastroenterology, Andhra Medical College, Medical College Road King George Hospital, Opp. Collector Office, Maharani Peta, Visakhapatnam 530 002, India
Introduction Gastric diverticula are outpouchings of gastric wall. They are rare anatomical abnormalities with prevalence of 0.02% to 0.04%. They are usually found in fundus during routine endoscopy. We herein present a rare case of gastric diverticulum in prepyloric region.
Case Presentation A 40-year-old male patient presented with right upper quadrant pain for last 5 days, increasing postprandially. On evaluation, patient was found to have choledocholithiasis with cholelithiasis. No associated findings of cholecystitis were found. An endoscopic retrograde cholangiopancreatography guided bile duct stone retrieval was planned prior to cholecystectomy. Routine screening upper gastrointestinal endoscopy showed 3 cms x 3 cms gastric wall outpouching in the prepyloric area, associated with few erosions. Patient did not have any symptoms/signs of gastric outlet obstruction, suspicious ulcers or intraabdominal infections. Radiologic investigations did not reveal any adhesions around the diverticulum indicating it to be congenital in nature and unlikely to be the cause of present symptoms in the patient. Biopsy from diverticulum showed nonspecific inflammation. Hence, further treatment was directed towards gallstone disease and gastric diverticulum was managed conservatively.
Conclusion Gastric diverticula, least common type of gastrointestinal diverticula, are mostly congenital (70%) and usually found in fundus. Acquired gastric diverticula are usually found in antrum. Our patient had a congenital gastric diverticulum in antrum, an extremely rare finding. Most gastric diverticula can be managed conservatively like in this patient. However symptomatic large gastric diverticula might require surgical excision.
Keywords Acquired, Congenital, Gastric diverticulum, Gastrointestinal diverticula
057
A rare case report of mantle cell lymphoma presenting as a gastric growth
Harish Kulkarni, Sumit Kumar, Prafulla Kumar, Sai Krishna Katepally, P Shravan Kumar
Correspondence - Harish Kulkarni - [email protected]
Department of Medical Gastroenterology, Gandhi Medical College, Gandhi Hospital, Musheerabad, Padmarao Nagar, Secunderabad 500 003, India
The gastrointestinal (GI) tract is the most common site of extra nodal non-Hodgkin lymphoma (NHL), accounting for 20% to 40% of all extra nodal lymphomas [1]. Mantle cell lymphoma is a type of aggressive mature B cell non-Hodgkin lymphoma comprising 2% to10% of all adult NHL2. It can involve GI tract in 10% to 28% cases. Colon is the most involved site but both the upper and lower GI tract from the stomach to the colon can be involved.
Here we present a rare case of 75-year-old male presenting with dyspepsia and significant weight loss for 3 months. Endoscopy showed a proliferative growth in the antrum of the stomach, biopsy study showed atypical lymphoid proliferation and immunohistochemistry showed CD20-positive (+)/CD5+/cyclin D1+/CD23-negative which was suggestive of Mantle cell lymphoma. Patients with mantle cell lymphoma can be asymptomatic or present with abdominal pain, obstruction, diarrhea, or bleeding. A high index of suspicion is mandatory in elderly patients with GI symptoms. Standard treatment includes a regimen comprising of Rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Median overall survival is 5 to 7 years [3]. A recent study showed that 2-year overall survival rate is 92% and 85% for those younger and older than 65 respectively [4].
References
1. Peng JC, Zhong L, Ran ZH. Primary lymphomas in the gastrointestinal tract. J Dig Dis. 2015; 16:169–76.
2. Shah BD, Martin P, Sotomayor EM. Mantle cell lymphoma: a clinically heterogeneous disease in need of tailored approaches. Cancer Control. 2012; 19:227-35.
3. Leukemia and Lymphoma Society. Mantle Cell Lymphoma Facts. July 2012
4. Karmali R, Switchenko JM, Goyal S, et al. Multi-center analysis of practice patterns and outcomes of younger and older patients with mantle cell lymphoma in the rituximab era. Am J Hematol. 2021; 96:1374-84.
Keywords Mantle cell lymphoma, Non-Hodgkin lymphoma
058
Unusual gastric ulcers (mucormycosis and IgG4 disease related)
Sunil Raviraj Kothakota, Srinivas Nistala
Correspondence - Sunil Raviraj Kothakota - [email protected]
Department of Gastroenterology, Medicover Hospital, MVP, Visakhapatnam 530 022, India
We would like to present two cases of gastric ulcers of unusual etiologies. The first patient was 45-year-old man, recovering from severe Corona virus disease – 19 (COVID-19) pneumonia presented with hematemesis. Upper gastrointestinal (GI) endoscopy showed two large necrotic ulcers in gastric fundus and antrum. Biopsy was taken and histopathology examination was suggestive of mucormycosis. He was managed with amphotericin B for two weeks followed by posoconazole for 4 weeks. Repeat endoscopy showed completely healed ulcer. The second case was 39-year-old man, presented with abdomen pain and jaundice. He was diagnosed as sclerosing cholangitis on basis of obstructive jaundice and magnetic resonance cholangiopancreatography (MRCP) findings. Gastroduodenoscopy was done, suggestive of malignant looking ulcers in gastric fundus and D2. Histopathology examination and immunohistochemistry (IHC) were suggestive of IgG4 disease. His serum IgG4 level was also on higher side. He improved well with steroid therapy.
Keywords Gastric mucormycosis, IgG4 disease
059
A rare case of primary gastric tuberculosis presenting as linitis plastica
Abhishek Pandey, Monika Jain, G S Lamba
Correspondence - Abhishek Pandey - [email protected]
Department of Gastroenterology, Sri Balaji action Medical Institute, C6 New Multan Nagar, Near Paschim Vihar, New Delhi 110 056, India
Gastric tuberculosis is a rare disease and usually presents as gastric outlet obstruction. Other uncommon presentations include gastrointestinal bleed and gastric perforation.
A case of gastric tuberculosis presenting as linitis plastica is reported here.
A 35-year-old male patient presented with early satiety, anorexia, occasional vomiting, and weight loss of two months duration. Physical examination was essentially normal. Routine investigations including contrast-enhanced computed tomography (CECT) thorax were normal. CECT whole abdomen was done which showed thickness of wall of fundus, body and antrum of the stomach with luminal narrowing along with loss of normal mucosal pattern with multiple enlarged mesenteric lymph nodes, likely suggestive of Carcinoma Stomach- Linitis Plastica.
Upper gastrointestinal endoscopy (UGIE) revealed normal esophagus. Stomach showed diffuse involvement of mucosa, with decreased distensibility, fine granularity and friability of mucosa. Multiple gastric biopsies were taken, which showed acute-on-chronic inflammation, ulceration, dilated crypts, and a few crypt abscesses. Several discrete epithelioid cell granulomas with prominent Langhans giant cells were seen. There was no evidence of caseation. Acid-fast bacilli (AFB) staining was negative. Histological impression of granulomatous gastritis was made with the most likely etiology of tuberculosis.
Patient was initiated on standard 4 drug anti-tubercular therapy (ATT) regimen with advice to follow-up regularly. On the second monthly follow-up there was definite improvement in symptoms.
Patient had improved appetite. Symptoms of early satiety, post meal vomiting were significantly reduced. Patient had also gained weight. At 6 monthly follow-up after initiation of ATT, patient had complete resolution of symptoms. ATT was continued for total duration of 12 months. Upon completion of ATT, repeat UGIE was conducted which showed normal distensibility of stomach, normal nmucosa with normal mucosal thickness.
To conclude, tuberculosis is a endemic disease with high prevalence in India. Its rare presentation as Linitis Plastica on imaging and endoscopy is depicted in this case.
Keywords Gastric carcinoma, Gastric tuberculosis, Linitis Plastica
060
A big fish in a small pond - A rare case of autoimmune gastritis
Shruti Keyal, Shine Sadasivan, Manoj Unni, Roopa Paulose
Correspondence – Shine Sadasivan - [email protected]
Department of Gastroenterology, Amrita Institute of Medical Sciences, Peeliyadu Road, Ponekkara, Edappally, Ernakulam, Kochi 682 041, India
We present a case of a 57-year-old lady who presented initially with complaints of heat intolerance and weight loss, followed by complaints of tiredness and fatigue. Subsequently, 2 months later she developed complaints of dyspepsia, abdominal discomfort, and reflux.
Evaluation upon presentation was consistent with Grave’s disease and refractory anemia with B12 deficiency. Further work up was carried out as anemia was refractory to nutritional supplementation. Upper gastrointestinal endoscopy showed features of corpus and funds restricted erythema and edema with thinning of the mucosal folds (Fig.1). Anti-parietal cell and anti-intrinsic factor antibodies were positive. Upper endoscopic biopsies taken as per gastric biopsy mapping protocol showed features of corpus and funds restricted chronic atrophic gastritis with intestinal metaplasia and antralization (Figs. 2, 3). With these findings, we confirmed a diagnosis of autoimmune gastritis (AIG). She was treated with B12 and iron supplementation (oral and parenteral) and neomercazole and had significant clinical improvement upon follow-up.
AIG is an underestimated disease owing to unawareness and under-reporting. Inappropriate biopsy sampling, high number of asymptomatic cases and lack of clarity on the pathogenesis are some of the reasons why the recorded incidence of the disease is about 0.5% to 4% globally. Like with other autoimmune diseases, it very frequently co-exists with at least one other autoimmune illness, most commonly thyroid related (“thryo-gastric syndrome”). Also of concern, is the predisposition to develop gastric NET and gastric adenocarcinoma in about 4% to 12% of these patients.
To the best of our knowledge, there are no such reported cases of AIG from Indian subcontinent. A diagnostic delay is attributed to both physician and patient’s unawareness of AIG. We thus aim at highlighting the need for a proper case finding strategy and hope to attract more attention towards AIG to improve standard of care in our patients.
Keywords Atrophic gastritis, Autoimmune gastritis, H. pylori
061
A curious case of acute gastric dilatation in an infant
Zahabiya Nalwalla, Shivangi Tetarbe, Ruchi Mishra, Ira Shah
Correspondence - Zahabiya Nalwalla - [email protected]
Department of Pediatric Gastroenterology, Hepatology and Nutrition, Bai Jerbai Wadia Children's Hospital, Acharya Donde Marg, Parel East, Parel, Mumbai 400 012, India
Introduction Acute gastric dilatation is characterized by a gut-brain disconnection disorder leading to gradual atony and stretching of the gastric mucosa causing intestinal obstruction. We present a case of an infant with acute gastric dilatation requiring surgical intervention.
Case Report A 1-year-old infant presented with abdominal distension, intermittent abdominal pain and sensation of retching, but inability to vomit since 1 week. X-ray erect abdomen suggestive of gastric dilatation (Fig. 1). Ryle’s tube inserted and 1 liter fluid drained. Baseline investigations were normal. CT abdomen (Fig. 2) was suggestive of grossly over-distended stomach, left dome of diaphragm seems to be elevated by distended stomach. Focal defect 5 × 3.5 cm in posterior aspect of diaphragm. Malposition spleen along long axis of tail of pancreas. Suspected CDH (congenital diaphragmatic hernia) with volvulus. Patient was taken up for a gastropexy with left CDH repair. Child recovered and was discharged.
Discussion Acute gastric dilatation is commonly seen in children secondary after spine, abdominal or thoracic trauma, central or peripheral nervous system conditions such as bulimia and anorexia nervosa. Acute gastric dilatation associated with acute gastric volvulus as a late presentation of congenital diaphragmatic hernia is a rare presentation. An important sign is the sensation of retching but inability to vomit which is attributed to the occlusion of gastroesophageal junction by the distended stomach. Gastric decompression and immediate surgery helps halt the vascular congestion and ischemia.
Conclusion Acute gastric dilatation associated with acute gastric volvulus as a late presentation of congenital diaphragmatic hernia is a rare presentation. Abdominal distension with inability to vomit is a subtle symptom of acute gastric dilatation.
Keywords CDH, Dilatation, Gastric, Infant, Volvulus
062
Parietal cell carcinoma- A rare cause of gastric mass and upper gastrointestinal bleed
Sarthak Malik 1 , Shreya Shruti2, Kim Vaiphei3, Anupam Lal4, Jayanta Samanta1, Saroj Kant Sinha1
Correspondence - Saroj Kant Sinha - [email protected]
Departments of 1Gastroenterology, 3Histopathology, and 4Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh 160 012, India, and 2Government Medical College and Hospital, Sector 32, Chandigarh 160 030, India
Case Presentation We present a case of parietal cell carcinoma presenting with melena and pain abdomen. A 57-year-old Indian male, known diabetic and reformed smoker/alcoholic presented with upper abdominal pain and generalized weakness for three months. He also reported passage of black tarry stools for 3–4 days, about 15 days back, following which he started having general weakness and easy fatigability. Physical examination showed pallor with normal abdominal examination. Investigations revealed hemoglobin to be 10 g/dL and peripheral blood film showed microcytic hypochromic anemia. Liver and renal function test were normal. Contrast-enhanced computed tomography scan of abdomen revealed arterial phase enhancing polypoidal lesion on greater curvature of the stomach. Esophagogastroduodenoscopy showed a six cm size ulcerated, friable mass in proximal body of stomach. Biopsies showed evidence of parietal cell carcinoma. The cells showed glandular arrangement, abundant granular eosinophilic cytoplasm, along with positive immunohistochemistry for pan-cytokeratin. Patient underwent exploratory laparotomy with total gastrectomy, distal pancreatectomy, splenectomy, Roux-en-Y esophagojejunostomy. He received adjuvant chemoradiotherapy. Patient recovered well and became asymptomatic.
Discussion Parietal cell carcinoma is a rare malignant tumor of stomach with a strikingly male (9:1) preponderance. It generally occurs in older males and runs a relatively indolent course. These well to moderately differentiated tumors are usually diagnosed by pathology. Lymph node and distant metastasis occur rarely, hence prognosis is generally favorable.
Conclusion Parietal cell carcinoma is rare cause of gastric mass and upper gastrointestinal bleeding. It is rarely considered in differential diagnosis clinically and diagnosis invariable emerges on histopathology.
Keywords GI bleed, Parietal cell carcinoma, Stomach cancer
063
It’s not malignancy, its menetrier’s !!!
Chitikeshwarapu Sai Kumar, Praveen Reddy Vasepalli
Correspondence – Praveen Reddy Vasepalli - [email protected]
Department of Gastroenterology, Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500 082, India
Introduction Menetrier’s disease (MD) is a rare disease that was first described by the French pathologist Pierre Menetrier in 1888. is characterized by the huge expansion of the gastric mucosa, thick mucus secretion, protein loss, and hypochlorhydria [1].
Case Report A 41-year-old female presented with complaints of admitted with loss of appetite, loss of weight (8 kg in 2 months), progressive h/o postprandial vomiting since 2 months. H/o generalized swelling present and loose stools since 2 weeks. Examination showed mild pallor and pedal edema, puffy face. CBP, RFT were normal, LFT showed hypoproteinemia (1.6). INR was normal. Thyroid profile showed elevated TSH (69.3). 2D ECHO was normal. USG abdomen showed dilated stomach with significant thickening of walls of gastric mucosa extending from GE junction to pylorus of stomach and duodenum, thickening of mucosa in the colon from cecum to rectum. Contrast-enhanced computed tomography (CECT) abdomen was more in favor of malignancy? linitis plastica. UGI endoscopy showed grossly hypertrophy mucosal folds with poor distensibility in the body of stomach. Histopathology showed focal hyperplastic and hypermucinous changes, menetrier disease. Evalaution for H pylori was nagetive. Ilio colonoscopy showed edematous colonic mucosa with superficial erosions. Managed conservatively with NJ feeds and thyroxine. Triple regimen for H pylori. She improved symptomatically.
Conclusion Despite having strong clinical and radiological suspicion of malignancy, MD should be one of the differentials of the hypertrophied gastric mucosa with or without H. pylori or hypoalbuminemia.
References
1 Rich A, Toro TZ, Tanksley J, et al. Distinguishing Ménétrier's disease from its mimics. Gut. 2010; 59:1617-24.
Keywords Malignancy, Menetrier’s
064
A study of compliance with Helicobacter pylori eradication therapy in patients with Helicobacter pylori infection
Gauri Kumbhar, Sudipta Dhar Chowdhury, Ajith Thomas, Amit Kumar Dutta, Ebby George Simon, A J Joseph
Correspondence – Sudipta Dhar Chowdhury - [email protected]
Department of G.I. Sciences, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Introduction Compliance with therapy is the single most important factor in Helicobacter pylori (H. pylori) eradication which influences treatment failures and subsequent development of antibiotic resistance. The present study was done with an aim to study compliance with H. pylori eradication therapy (HPET) in patients with H. pylori infection.
Methods This was a prospective study conducted between June 2019 to August 2022 at a tertiary care centre in South India. Patients with H. pylori infection who were treated with HPET were interviewed using structured questionnaire. Baseline data as regards demographic variables, presenting symptoms, diagnostic methods of H. pylori infection, HPET regimen details, its side effects, and compliance was noted.
Results A total of 110 patients were included out of which 73 (66.4%) were males. The mean age was 41.39 (SD 12.91) years. Thirty-six (32.7%) patients had presented with postprandial fullness, another 36 (32.7%) had epigastric pain, 23 (20.9%) had epigastric burning whereas 12 (10.9%) had retrosternal burning sensation. H. pylori infection was diagnosed in 71 (64.5%) patients by histopathology, 30 (27.3%) with rapid urease test, and 9 (8.2%) using H. pylori stool antigen by ELISA. One hundred and seven (97.3%) patients were treated with Clarithromycin triple therapy, whereas the remaining three received Bismuth quadruple therapy. Forty-eight patients (43.6%) reported various side effects of HPET. Diarrhea (14.5%) was the most common side effect followed by nausea (10.9%), dysgeusia (10%), abdominal pain (8.2%), vomiting (4.5%), headache (3.6%) and skin rashes (2.1%). Fifteen (13.6%) patients discontinued the treatment owing to side effects. Amongst them, nausea (26%) and headache (26%) were the most common side effects. Majority of them (66.7%) discontinued HPET within three days of initiation while one patient took half the daily dose for two weeks.
Conclusions Side effects of HPET are very common and are the major cause leading to non-compliance. Further studies are warranted focusing on measures to improve compliance with HPET, to increase eradication rates, and reduce the emergence of resistance.
Keywords Compliance, Clarithromycin, Diarrhea, H. pylori eradication therapy, HPET, Side effects
065
Efficacy of clarithromycin based triple therapy for two weeks for eradication of Helicobacter pylori infection
Rajeeb Jaleel, Tintu Varghese
Correspondence – Rajeeb Jaleel - [email protected]
Department of Gastroenterology, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Introduction Multiple regimens are used for treatment of H. pylori infection. Success of eradication depends on compliance of medications and antibiotic resistance data. Clarithromycin triple therapy is commonly used. We aim to assess the efficacy of this regimen in the current study.
Methodology This was a retrospective observational study among adult (>18 years) patients who had H. pylori eradication therapy for 14 days with clarithromycin 500 mg BD, Amoxycillin 1 gm BD and PPI BD. Patients who underwent testing to confirm eradication of infection after therapy were finally included. The clinical and investigation details were recorded. The test for eradication was based on H. pylori stool Antigen assay. Those with negative test considered to have successful eradication. This test was done in patients who were not taken PPIs for last 2 weeks. The proportion of patients with successful eradication of infection was the primary outcome of the study. stool Ag analysis
Results Sixty-two patients were included in this study. Their mean age of the study population was 42.6 year and 41 (74.1%) were Men. Initial H. pylori prior to starting antibiotic regimen was identified based on Gastroscopy biopsy in 36 (58.06%). Post HPET 39/62 (62.9%) of patients were positive for H. pylori stool Ag. In H. pylori non eradication group 32 (82.05%) and 19 (48.7%) were from eastern and southern part of India respectively. Indication for treatment PUD in 11/39 (28.2) in H. pylori eradication and 9/23 (39.1%) in non-eradication group. Amoxycillin, Clarithromycin and Pantoprazole for duration of 14 days was most common regimen used to treat H. pylori infection 60/62 (96.77%). Mean stool Ag level in patients who were stool Ag positive post HPET were 37.14 ng/mL.
Conclusion The failure of clarithromycin based triple therapy was present in significant number of patients with H. pylori infection. This necessitates rethinking of initial regimen of choice.
Keywords H. pylori eradication therapy, H. pylori stool antigen, Triple therapy
Small intestine
066
Prevalence of collagenous ileitis in microscopic colitis: A single-center experience
Kaushal Prasad, V Devraj, Saroj K Sinha, Uma Devi1
Correspondence – Kaushal Prasad - [email protected]
Departments of Gastroenterology and 1Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012, India
Introduction Involvement of the terminal ileum (TI) in microscopic colitis (MC) rarely been systematically studied and prevalence of collagenous ileitis (CI) in MC is not reported. Aim of present study was to investigate the TI mucosal alterations and to determine the prevalence of CI in cases of MC.
Methods In this prospective study TI mucosa of 55 patients with MC (37 with lymphocytic colitis [LC: male/female ratio 2.7, median age 37 years] and 18 with collagenous colitis [CC: male/female ratio 1.6, median age 37 years]) were examined for TI mucosal alterations. Results were compared with 36 patients with ulcerative colitis (UC) as controls.
Results The TI mucosal biopsies revealed varied histologic pattern with normal mucosa in 5 (9%), intraepithelial lymphocytosis without crypt hyperplasia 24 (43.6%), intraepithelial lymphocytosis with crypt hyperplasia 14 (25.5%), villous atrophy 6 (11%), villous atrophy with CI 2 (3.6%) and CI without villous atrophy in 4 (7.3%) patients. Overall, 6 (10.9%) cases of MC were associated with CI. Out of 8 (14.5%) cases with primary ileal villous atrophy 6 were associated with LC and 2 were associated with CC and both had associated CI. All cases with LC revealed intraepithelial lymphocytosis and/or associated villous atrophy whereas 6 (33.3%) cases of CC were associated with CI.
Conclusions The TI is frequently involved in MC. Intraepithelial lymphocytosis, villous atrophy or CI may be helpful in diagnosing these conditions. Results suggest that the TI may be involved by a similar pathogenic process as the colon in LC and CC.
Keywords Biopsy, Collagenous ileitis, Ileum, Microscopic colitis,
067
A case of chronic diarrhea due to common variable immune deficiency related enteropathy
Ramesh Avula, L R S Girinadh, Vamsi D Yadav, Gangu Ghanashyam, Abhishek S Y
Correspondence - Ramesh Avula - [email protected]
Department of Medical Gastroenterology, Andhra Medical College, Medical College Road, King George Hospital, opp. Collector Office, Maharani Peta, Visakhapatnam 530 002, India
Introduction Common variable immune deficiency (CVID), a form of primary immune deficiency disease (PIDD), is a disease presenting with recurrent sino-pulmonary infections in twenties and thirties with estimated prevalence of 1 in 25,000 to 50,000. CVID enteropathy is a phenotypic variant presenting with chronic diarrhea and weight loss. We present herein a rare patient of CVID enteropathy without any history of recurrent sino-pulmonary infections.
Case Presentation A 44-year-old male patient presented with complaints of chronic watery diarrhea and significant unintentional weight loss for last 18 months. Despite treatment with empirical antibiotics anti protozoals and anti diarrheals, he continued to have 10-12 large volume stools per day. On examination, he had severe sarcopenia, loss of subcutaneous fat and oedema. Investigations revealed anemia, hypoprotenemia (both serum albumin and globulin levels were decreased), hypocalcemia, decreased vitamin D levels and increased TSH (8.5 mIU/L). Stool routines were normal. Viral markers were negative. Upper GI endoscopy revealed chronic Helicobacter pylori related gastritis. Biopsy of second part of duodenum showed giardiasis. As patient did not improve on metronidazole, colonoscopy was done which showed few rectal ulcers. Blind biopsy of terminal ileum showed non-necrotizing granuloma. Anti-tTG was negative. Serum immunoglobulin levels were decreased (IgA 401 mg/dL, IgG <21 mg/dL, IgM <3 mg/dL). Absolute CD4 count was decreased (408/uL) and CD4/CD8 ratio reversed (0.34). Antibody levels for diphtheria and pertussis were decreased (non-protective). A diagnosis of CVID related enteropathy was made and patient was suggested treatment with intravenous immunoglobulins (IVIG) and repeat vaccination with killed vaccines.
Conclusion Our case demonstrates that CVID enteropathy should be considered a differential in chronic diarrheas with malabsorption features not responding to routine therapies even in the absence of recurrent sinopulmonary infections. Early diagnosis and treatment can improve the prognosis of the patient.
Keywords Chronic diarrhea, Common variable immune deficiency, Enteropathy, Giardiasis, Intestinal granuloma
068
Ileal stricture due to endometriosis – A case report
Varun Wagle , Sandeep Gopal, Suresh Shenoy, Anurag Shetty, G V Chaithra, Bailuru Vishwanath Tantry
Correspondence - Varun Wagle - [email protected]
Department of Medical Gastroenterology, Kasturba Medical College Hospital, Ambedkar Circle, Mangalore, Manipal Academy of Higher Education, Manipal, India
Endometriosis is a benign disease which has been described in about 15% of premenopausal women with a peak incidence in the third and fourth decades of life [1]. It is characterized by presence of endometrial glands and stroma located in an extrauterine environment [2]. Although endometriosis is most commonly located in the pelvic cavity, the incidence of bowel involvement ranges from 3% to 37%, primarily in the sigmoid colon and the rectum [3]. Ileal involvement in endometriosis is quite rare with an incidence of only about 7.1% of all intestinal endometriosis cases [4]. Further, small bowel obstruction due to endometrial lesions is an extremely uncommon situation, representing only 0.7% of surgical procedures for endometriosis [5]. Here we present a case of a 34-year-old lady, known case of hypothyroidism, who presented with chief complaints of pain in abdomen, vomiting and constipation of one month duration. Baseline investigations revealed raised C-reactive protein. X-ray abdomen showed multiple air fluid levels. Contrast-enhanced computed tomography (CECT) abdomen was done which was suggestive of inflammatory thickening of terminal ileum. She underwent a colonoscopy which showed ileal obstruction beyond which the scope could not be negotiated. A diagnostic laparoscopy was done which showed dense adhesions in the terminal ileum with fibrotic stricture. Hence right hemicolectomy with ileo-ascending colon anastomosis was achieved surgically. The histopathological analysis of the excised terminal ileum and ileocecal valve was suggestive of ileocecal endometriosis. In this paper, we report this unusual presentation of endometriosis.
Keywords Endometriosis, Ileum, Stricture
069
An unusual cause of a refractory duodenal ulcer
Addagarla Varun, P Shravan Kumar, Sai Krishna Katepally, Tejaswini Tumma, Snehitha Nalluri
Correspondence - Addagarla Varun - [email protected]
Department of Medical Gastroenterology, Gandhi Medical College, Musheerabad, Padmarao Nagar, Secunderabad 500 003, India
A duodenal ulcer which does not respond to 6 weeks of proton pump inhibitor (PPI) therapy or 8 weeks of H2B therapy is termed a refractory duodenal ulcer. The common causes of a refractory duodenal ulcer include use of tobacco, alcohol, drugs (NSAIDS, Steroids), persistent H pylori infection. Rare causes include Zollinger-Ellison syndrome, malignancy, Crohn’s disease, mesenteric ischemia and atypical infections like Cytomegalovirus (CMV), syphilis, etc.
Here we present a case of a 75-year-old female who presented with dyspepsia and black tarry stools. Endoscopy revealed a Forrest class 1b ulcer in the first part of duodenum. Ulcer was managed with local adrenaline injection, hemoclip application and anti H pylori therapy. She was readmitted with symptoms of hematemesis after 8 weeks. Repeat endoscopy revealed persistent duodenal ulcer hence biopsy was taken which showed cells with high N/C ratio and salt and pepper appearance with suspicion of neuroendocrine tumor (NET), however immunohistochemistry (IHC) was negative for synaptophysin and chromogranin and positive for cytokeratin 7 and 20 and her gastrin levels were normal. Computed tomography (CT) abdomen revealed a lesion in the head of the pancreas with liver SOL and periportal lymph nodes. Ca 19-9 levels were 4307 U/L. endoscopic ultrasound (EUS) guided fine needle biopsy (FNB) of the pancreatic mass revealed Pancreatic adenocarcinoma.
Pancreatic malignancy presenting as a GI bleed is rare (1.6% according to Wang et al.). Mechanisms include direct invasion (most common), splenic or portal vein invasion causing variceal bleed, bleeding from the pancreatic duct through the ampulla and pseudocyst with pseudoaneurysm formation. According to few recent case series' such cases have a poor prognosis with a 6-month survival rate of only 35%. Most cases are inoperable at presentation and only supportive therapy may be possible. There should be a high index of suspicion of malignancy in cases of refractory duodenal ulcers especially in the elderly.
Keywords GI bleed, Pancreatic adenocarcinoma, Refractory duodenal ulcer
070
Once in a blue moon: Brown bowel syndrome
Siddharth Shukla 1 , Shreya Shruti2, Anupam Lal3, Kaushal Kishore Prasad1, Jayanta Samanta1, Kim Vaiphei4, Saroj Kant Sinha1
Correspondence - Saroj Kant Sinha - [email protected]
Departments of 1Gastroenterology, 3Radiodiagnosis, and 4Histopathology, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh 160 012, India, and 2Government Medical College and Hospital, Sector 32, Chandigarh 160 030, India
Background Evaluation of chronic diarrhea requires multiple investigations in stepwise manner yet the final diagnosis may remain elusive in 10% to 15% of case. Here we present a case of chronic diarrhea due to a rare cause.
Case Presentation A 29-year-old male with bloating, early satiety, and frequent stools for last 8 years. He reported loss of around 30 kg weight in the past 6-8 years. His physical examination showed gross emaciation and body mass index (BMI) of 11.75 kg/m2. He had pallor, edema, and bradycardia with heart rate of 46–54 per minutes.
Investigations Blood investigations showed hemoglobin 8 gm%, total protein 4.8 gms with albumin 2.1 gms. Serum tissue transglutaminase antibody was negative. Contrast enhanced computed tomography showed multifocal symmetric mural thickening involving short segment of small bowel with proximal dilatation and mild thickening of ileocecal junction. Barium meal-follow through and enteroclysis corroborated these findings. Colonoscopy and upper gastrointestinal endoscopy were normal. Diagnosis of Crohn’s disease was considered and oral prednisolone and mesalamine were started. He continued to be symptomatic over next two years. Laparotomy showed multiple dilated small bowel loops and no stricture. Ileal biopsy showed lipofuscinosis.
Diagnosis The final diagnosis was confirmed to be brown bowel syndrome. Patient was then started on vitamin E, multivitamins, antioxidants and mesalamine.
Discussion Intestinal lipofuscinosis is a rare disorder that presents as brown pigmentation, occasionally with bowel dilatation and pseudo-obstruction. It co-exists with malabsorption of fat-soluble vitamins, especially vitamin-E. Pathologically, mitochondrial malfunction and degeneration lead to lipofuscin deposition followed by smooth muscle mitochondrial myopathy. Clinical features show motility disorders along with malabsorption features. Treatment involves treating the underlying cause and early initiation of vitamin-E supplementation.
Conclusion We report a rare intestinal disorder, brown bowel syndrome, characterized by the deposition of lipofuscin in the intestinal cells following chronic malabsorption syndrome and vitamin E deficiency.
Keywords Brown bowel syndrome, Chronic diarrhea
071
A case series of eosinophilic gastroenteritis
Jasmeet Singh Dhingra , Nirmaljit Singh Malhi, Rajiv Grover, Achal Garg
Correspondence – Jasmeet Singh Dhingra - [email protected]
Department of Gastroenterology, Advanced Gastroenterology Institute-The Gastrociti, Ludhiana Road, Vth Floor, Orison Hospital, Barewal Road, Ludhiana 141 008, India
Introduction Eosinophilic gastroenteritis (EG) is an inflammatory disorder of the gastrointestinal (GI) tract due to infiltration of bowel wall layers with eosinophils and associated inflammatory changes. The aim of this study is to describe clinical characteristics and treatment response in a series of EG patients from Iran.
Methods This is a retrospective study of all patients diagnosed with eosinophilic gastroenteritis at Advanced Gastroenterology Institute: AGI The GASTROCITI in Ludhiana for a 30-month period from February 2020 to July 2022. Cases were identified using the Department of Endoscopy database. Data were obtained from medical records that included clinical manifestation, endoscopic findings, and histopathological features.
Results Three patients with EG were identified during 30 month period. Two were males and one female. Mean age of the patients was 30 years (ages: 24, 30 and 36). Median duration between symptom onset and diagnosis was 6 (range 3- 9) months. All patients had mucosal involvement in form of ileocolonic ulcers with biopsy specimen showing > 30 eosinophils/HPF. One had subserosal involvement also as diagnosed with bowel wall thickening on CT enterography. All patients had peripheral eosinophilia with mean eosinophil counts approx. 1100. Patients were followed for a median duration of 5 (range 3-12) months. Two patients had remission with oral budesonide treatment and one patient required systemic steroids for response. The relapse rate was 33% as one patient had repeat symptoms 3 months after stopping therapy. Episode of relapse was successfully controlled with a repeat course of corticosteroids.
Conclusion Clinical characteristics and treatment responses of EG patients are variable. Patients need to undergo close follow-up after treatment to detect early signs of relapse.
Keywords Eosinophilic bowel disorder, Eosinophilic enteritis
072
A peculiar endoscopic appearance of duodenal diverticulosis with unusual presentation of iron deficiency anemia
Brij S, Bilal Mir, Rajesh Sharma, Tahir Majeed
Correspondence - Bilal Mir - [email protected]
Department of Gastroenterology, Indira Gandhi Medical College, Ridge Sanjauli Road, Lakkar Bazar, Shimla 171 001, India
Background A duodenal diverticulum is commonly encountered in clinical practice and can be found incidentally in 23% of normal people undergoing imaging. Most duodenal diverticulosis is found at the second or third part of duodenum, around the ampulla of Vater with a reported incidence of 67%. In the majority of cases, they are completely asymptomatic and only 5% of patients develop symptoms related to diverticular complications. Duodenal diverticula presenting as iron deficiency anemia (IDA) is rare entity.
Case Report We reported an unusual case of duodenal diverticulosis presenting as iron deficiency anemia. A 50-year-old female with no underlying comorbidity was admitted for evaluation of anemia with a hemoglobin of 9.2 gm/dL. She denied any history of non-steroidal anti-inflammatory drugs and obvious blood loss. Her physical examination revealed thin built, conjunctival pallor. Her baseline blood work was unremarkable except for hypochromic microcytic anemia. Her iron profile was suggestive of IDA, and stool for occult blood was negative. Subsequently she was planned for gastrointestinal endoscopic examination for further evaluation. Her upper endoscopy revealed normal esophagus, stomach, first part of duodenum, and showed the presence of multiple periampullary adjacent diverticula in 2nd part of duodenum with a peculiar ‘net like’ appearance with normal overlying mucosa. Her colonoscopy was normal, and CT enterography revealed findings suggestive of duodenal diverticula. IDA was attributed to duodenal diverticulosis given the extensive duodenal luminal and mucosal deformity and possible iron malabsorption. Conclusion The present case emphasizes upon the varied and rare presentation of a predominantly asymptomatic condition like duodenal diverticula and the diagnosis should not be disregarded while evaluating unexplained IDA.
Keywords Duodenal diverticula, Endoscopy, Iron deficiency anemia,
073
Endoscopic resection of foregut neuroendocrine tumors
Ajay B R, Varun Kesar, Jaseem Ansari, Mangesh Borker, Sanjana Bhagawat, Yash Kanani, Rajendra Pujari, Harshal Gadhikar, Amol Bapaye
Correspondence – Amol Bapaye - [email protected]
Department of Gastroenterology, Deenanath Mangeshkar Hospital, Deenanath Mangeshkar Hospital Road, Erandwane, Pune 411 004, India
Introduction Carcinoids, a type of neuroendocrine neoplasm most commonly found in the pulmonary and gastrointestinal system. Neuroendocrine tumors (NETs) arise from enterochromaffin cells [1]. Endoscopic resection is now gaining prominence over surgery, traditionally considered the treatment of choice [2]. We aimed to analyze the outcomes of endoscopic management (EMR/ESD/EFTR) of foregut (stomach/duodenum) NET given limited published evidence.
Methods Retrospective analysis of 52 patients who underwent endoscopic resection of histologically confirmed Foregut NET at Deenanath Mangeshkar Hospital (DMH), Pune (tertiary hospital) over a period of 10 years (August 01, 2012 to July 31, 2022).
Results Average age of presentation-58.75 years (range 33-82 y). Total of 84 NETs in 52 (M-38, F-14) patients. Location- First part of duodenum (n=59), second part of duodenum (n=17) and stomach (n=8). Presentation-six as carcinoid syndrome (chronic diarrhea and weight loss) and rest incidental. Macroscopically all were sub mucosal lesions. Average size -11.7 mm (range 7-50 mm). Layer of origin on EUS-Sub-mucosa (3 indenting muscularis propria) Pre-op histopathology of all lesions-NET. None had metastatic disease on imaging (CECT/DOTA). Resection was done by ESD (36), Band EMR (20), EMR (10), EFTR (9), Hybrid ESD (6) Cap EMR (3). Average procedure time-74 mins (range:40-220 mins) Adverse events-8 ESDs (muscle defect) and 1 EMR (bleeding) all managed endoscopically. 64 lesions removed En Bloc and had tumor free margins (Rest 20 underwent Band EMR). Histologically 57 lesions-NET G1 and 7 -NET G2. Median follow-up-18 months (range 1-94 mo). All had complete healing but 3 patients had new lesions-one resected by FTRD and 2 lost to follow-up.
Conclusion Endoscopic management appears safe and effective for management of small foregut NETs with no recurrence. Further large studies are needed to validate our data.
References
1. Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med. 1999; 340:858-68.
2. Fujishiro M, Yahagi N, Nakamura M, et al. Successful outcomes of a novel endoscopic treatment for GI tumors. Gastrointest Endosc. 2006,63:243-9.
Keywords Endoscopic resection, Foregut NET
074
A rare case of primary squamous cell carcinoma of duodenum
Shiv Pathak, Sandip Pal
Correspondence – Shiv Pathak - [email protected]
Department of Gastroenterology, NH-R N Tagore Hospital, Premises No: 1489, Mukundapur Main Road, 124, Eastern Metropolitan Bypass, Mukundapur, Kolkata 700 099, India
Primary malignancies of small intestine are itself rare and maximum cases are of adenocarcinoma in type arising in 2nd part of duodenum. We report here a primary malignancy of 1st part of duodenum of squamous cell carcinoma type and that too growing circumferentially causing gastric outlet obstruction.
Keywords Duodenum, Squamous cell cancer
075
Opioid enteropathy: A common cause of ulceroconstrictive disease of bowel in western Rajasthan
Pranav S Kumar, Chhagan Lal Birda, Taruna Yadav, Binit Sureka, Ashish Agarwal
Correspondence – Ashish Agarwal - [email protected]
Department of Gastroenterology, All India Institute of Medical Sciences, Marudhar Industrial Area, 2nd Phase, M.I.A. 1st Phase, Basni, Basni, Jodhpur 342 005, India
Introduction Opium addiction is common in western Rajasthan. Opioid-induced bowel dysfunction and narcotic bowel syndrome are well-described gastrointestinal (GI) disorders in patients with opioid abuse. We describe patients with long-term opium addiction presenting with ulceroconstrictive disease of the GI tract (GIT).
Methods We performed a retrospective review of prospectively maintained records of patients with opioid addiction who were diagnosed with opioid enteropathy in the Gastroenterology Department at All India Institute of Medical Sciences, Jodhpur, Rajasthan between July 2021 and June 2022. Opioid enteropathy was diagnosed in patients where all the other possible causes of ulceroconstrictive disease of the bowel were excluded by meticulous evaluation.
Results Twelve patients (mean age: 53.5±6.9 years; 10/11 [90.9%] males) with opioid addiction were diagnosed with opioid enteropathy. The median duration of opioid consumption was 20 (IQR:10-25) years. N=4/11 (36.4%) consumed opium, while n=7/11 (63.6%) consumed opium husk (doda) with the median expenditure of 4000 (IQR: 3000-7000) Rs. per month for opioid purchase. Common symptoms were pain abdomen (100%), slow transit constipation (45.5%), gola formation (45.5%), weight loss (81.8%) and loss of appetite (72.7%). On evaluation, patients had iron deficiency anemia (90.9%), hypoalbuminemia (72.7%), positive stool occult blood (54.6%) with ESR (90.9%) and CRP levels (90.9%). Endoscopy was normal in 81.8% of patients, while pyloric and duodenal stricture and ileocecal valve stricture were found in 1 patient (9.1%) each. Contrast-enhanced computed tomography (CECT) enterography showed multiple short segment jejunal and ileal strictures in 100% of patients. Conservative management with opioid deaddiction, iron supplements, rifaximin and laxatives was done in all patients with endoscopic balloon dilatation of pyloric stricture needed in one patient. Only 5 patients agreed and could undergo successful opioid deaddiction.
Conclusion Long-term addiction to high-dose opium can lead to ulceroconstrictive disease of the GIT. Considering the high prevalence of opium addiction, there is a need to recognize this entity and encourage opium deaddiction.
Keywords Enteropathy, Inflammatory bowel disease, Opium, Strictures, Ulceration, ulceroconstrictive disease
076
A rare case of chronic diarrhea due to eosinophilic enterocolitis with coexisting eosinophilic esophagitis
Ramesh Reddy Avula, L R S Girinadh, Vamsi D Yadav
Correspondence - Ramesh Reddy Avula - [email protected]
Department of Medical Gastroenterology, Andhra Medical College, Kukatpally 500 072, India
Introduction Eosinophilic gastrointestinal disorders (EGID) is a rare spectrum of disorders including eosinophilic esophagitis (EOE), eosinophilic gastroenteritis (EGE) and eosinophilic colitis (EC). Around 10% of patients with EGE and EC also have esophageal involvement. We intend to report an extremely rare case of EGID involving esophagus, small intestine and large intestine simultaneously.
Case Presentation A 38-year-old male patient presented with chronic diarrhea, abdominal pain and unquantified weight loss for last 2 months not improving with routine empirical treatment with antibiotics, anti-protozoals and anti-diarrheals. Endoscopy revealed erosions in stomach, duodenum, terminal ileum and proximal colon. Biopsy revealed eosinophilic infiltration in esophagus, terminal ileum and proximal colon. contrast-enhanced computed tomography (CECT) showed multiple skip areas of short and long segment circumferential mural thickening with enhancement in the jejunum and ileal loops in upper mid and lower abdomen causing mild luminal narrowing with pelvic ascites indicating involvement of muscular and probably serosal layer to a lesser degree (absence of obstructive symptoms with minimal ascites) along with predominant mucosal involvement (responsible for clinical symptoms). Patient was treated with elimination diet, systemic corticosteroids and monteleukast. Diarrheal episodes decreased, steroids were tapered after two weeks and shifted to oral budesonide.
Conclusion There is scant data on simultaneous involvement of different segments of gut in EGIDs. Most commonly, esophagus has shown to be involved with eosinophilic gastroenteritis and eosinophilic colitis. We believe it to be one of the first reports to show a simultaneous involvement of esophagus, small intestine, and large intestine along with mucosal and mural involvement. Patient’s symptoms were attributed to predominant small intestinal mucosal involvement. It strengthens the fact that a common underlying pathogenesis causes EGIDs, suggests some degree of underlying muscular layer involvement in patients with predominant mucosal disease and that oral budesonide may be used to successfully treat the disease with minimal systemic adverse effects.
Keywords Eosinophilic gastroenteritis, Eosinophilic gastrointestinal disorders, Streroids
077
A rare case of primary sclerosing cholangitis with celiac disease – Fact or fancy?
Vikas Bharti , Animesh Shah, Prabha Sawant
Correspondence – Vikas Bharti - [email protected]
Department of Gastroenterology, Gleneagles Global Hospital, 35, Dr Ernest Borges Road, Parel East, Parel, Mumbai 400 012, India
A 50-year-old male, known case of primary sclerosing cholangitis (PSC) since last 5 years, asymptomatic and on treatment Tab. Ursodeoxycholic acid 300 mg TDS, now presented with chronic small bowel diarrhea since last 5 months with weight loss and malabsorption syndrome. Diagnosed with celiac disease (CD) based on serology and histology. Patient did not have associated inflammatory bowel disease (IBD). On endoscopic ultrasound (EUS) patient was found to have a large gallbladder polyp. Patient was started on gluten-free diet (GFD) in view of CD and had significant improvement in diarrhea and weight gain. Though asymptomatic for PSC his liver biochemistries remained unchanged in spite of GFD. Currently patient is better and on follow up for PSC.
Conclusion CD has been found in 2% to 3% of patients with PSC therefore it should be considered as a differential in patients with PSC having malabsorption syndrome. The relationship between the two diseases remains unknown, although an immunologic connection is suspected.
Keywords CD, HLA, PSC
078
Indian national biorepository of well-phenotyped cohort of patients with celiac disease
Alka Kumari 1 , Sanjay Kumar 2 , Divya Sharma 3 , Kunj Bihari Gupta 1 , Sachin Rajpoot 1 , Anam Ahmed 1 , Sushil Falodia 3 , Saroj Kant Sinha 2 , Rakesh Kochhar 2 , B S Ramakrishna 4 , Vineet Ahuja 1 , Govind K Makharia 1
Correspondence – Govind K Makharia - [email protected]
1Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029, India, 2Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India, 3Department of Medicine, Sardar Patel Medical College, S P Medical College Road, P B M Hospital, Bikaner 334 001, India, and 4Department of Gastroenterology, SRM Institutes for Medical Science, Vadapalani, Chennai 600 026, India
Objective There are several fundamental questions that needs exploration using animal models, cell-culture system, and biological material of well-phenotyped longitudinally followed patients with celiac disease (CeD). With support of Department of Biotechnology, we established a national celiac disease-specific biorepository.
Methods The diagnosis of CeD is being made on the standard criteria using standard Indian guidelines. Biological materials including blood (serum, plasma, DNA), duodenal biopsies (blocks, RNA, DNA, microbiome), urine and stool samples in multiple aliquots are being collected and labelled in a way that could survive all potential storage conditions. The samples were maintained and distributed to central biorepository through laboratory information management system (LIMS). Specimens are labelled with a unique number (human-readable forms of barcode), providing a direct link to protected database software including compliance with data privacy.
Results This is an ongoing activity and between September 2017 and March 2022, we have recruited 363 biopsy-proven treatment-naïve patients with CeD and (47 six-months post gluten-free diet), first-degree relatives of CeD (n=135) and controls (n=83). Fasting blood samples (10-12 mL) (separated as serum, plasma and whole blood and aliquoted), stool, urine, and duodenal mucosal biopsies (10-12 peices for RNA, DNA, proteomics, metagenomics etc.) have been collected and stored. Overall, 8148 aliquots of various biological material from 628 subjects has been stored in the biorepository including 12-13 aliquots per patient. We plan to continue recruiting patients and nurture the biorepository.
Conclusion Our national biorepository is likely to be useful for exploring many fundamental questions related with celiac disease.
Keywords Biobank, Gluten, Laboratory information management system, Storage
079
Diagnostic characteristics of anti-endomysial antibody in the diagnosis of celiac disease
Alka Kumari 1 , Aditya V Pachisia 1 , Rimlee Dutt 2 , Kunj Bihari Gupta 1 , Sanjay Kumar 3 , Divya Sharma 4 , Anam Ahmed 1 , Vignesh Dwarkanath 5 , Prasenjit Das 2 , Sushil Falodia 5 , Saroj Kant Sinha 1 , Vineet Ahuja 1 , Govind K Makharia 1
Correspondence – Govind K Makharia - [email protected]
Departments of 1Gastroenterology and Human Nutrition, 2Pathology, and 5Community Medicine, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029, India, 3Department of Gastroenterology, Post graduate Institute of Medical Education and Research, Chandigarh 160 012, India, and 4Department of Medicine, Sardar Patel Medical College, S P Medical College Road, PBM Hospital, Bikaner 334 001, India
Background The systematic review and meta-analysis has shown the sensitivity and specificity of anti-endomysial antibody (AEA) in adults to be 88% and 99.6, respectively for the diagnosis of celiac disease (CeD). In our clinical experience, we also found a relatively lower sensitivity of AEA. We prospectively evaluated the diagnostic accuracy of AEA.
Methods In a prospective study, we tested the AEA in patients with CeD who were recruited under an Indian National CeD Biorepository. The gold standard for the diagnosis of CeD was a combination of positive anti-tissue transglutaminase antibody (TG2) and presence of villous abnormalities of modified Marsh grade 2 or more. AEA was detected using immunofluorescence-based assay (Inova Diagnostic IFA kit, USA). The sample size to test the sensitivity and specificity of AEA was 277 and 93 respectively. Patients suspected to have CeD, with negative TG2 were taken as controls. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive and negative likelihood ratio (LR) were calculated.
Results Mean fold rise in TG2 titer in treatment-naive patients with CeD was 11.04±7.58 U/mL. The AEA was positive only in 50.9% (141 of 277) patients with CeD and 2 of 93 (2.15) % controls. The sensitivity, specificity, PPV and NPV were 52%, 98%, 98.6% and 42.7%, respectively. Diagnostic odds ratio, positive LR and negative LR for AEA were 52.6, 26 and 0.49, respectively.
Conclusion Only half of Indian adult patients with CeD have AEA positive. If positive, it has high specificity, diagnostic odds ratio, and positive predictive value.
Keywords Anti-tissue transglutaminase antibody, Biorepository, Diagnostic accuracy
080
Role of mycobacteria growth indicator tube and Xpert mycobacterium tuberculosis tests in diagnosing intestinal tuberculosis
Hemanth Chinthala 1 , Polavarapu Jagadish 1 , Joy Sarojini Michael 2 , Lalji Patel 1 , Shaleen Dass 3 , Ajith Thomas 1 , Anoop John 1 , Reuben Thomas Kurian 1 , Rajeeb Jaleel 1 , Sudipta Dhar Chowdhury 1 , Ebby George Simon 1 , A J Joseph 1 , Anna Pulimood 4 , Amit Kumar Dutta 1
Correspondence – Amit Kumar Dutta - [email protected]
Departments of 1Clinical Gastroenterology and Hepatology, 2Microbiology, 4Pathology, 3Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Introduction Newer microbiological diagnostic tests like mycobacteria growth indicator tube (MGIT) (culture for mycobacterium tuberculosis [MTB] and gene Xpert test (molecular test for detecting MTB) have been found to be useful in diagnosing pulmonary tuberculosis. However, their role in diagnosing intestinal tuberculosis (ITB) is less well studied. We aimed to study the utility of these tests in the diagnosis of ITB.
Methods In this retrospective study, we evaluated the case records of patients with diagnosis of ITB. The disease was in the small and/or large intestine in all the cases. The lesions were detected on colonoscopy or enteroscopy and sample was sent for histopathology and microbiological tests MGIT/Xpert. Clinical details, histopathology findings along with MGIT and Xpert test results were recorded. Final diagnosis of ITB was based on presence of histopathology findings or positive culture or presence of extraintestinal tuberculosis or response to ATT. Diagnostic yield of MGIT and Xpert tests were calculated.
Results Forty patients with a final diagnosis of ITB were included. Their mean age was 37.1+13.4 years and 30 (70%) were males. Median duration of symptoms was 4 months (IQR, 2-11.3 months). Abdominal pain (80%) was the commonest symptom. Fever was noted in 37.5% and diarrhea in 17.5% cases. MGIT culture was positive in 5 (12.5%) cases. Xpert test was positive in two of the five cases with positive MGIT culture report. Another patient had Xpert positive, but MGIT culture was negative. The sensitivity of MGIT culture was 12.5% and Xpert was 7.5%. The combined sensitivity of MGIT and Xpert test was 15%.
Conclusion Newer microbiological tests (MGIT, Xpert) help in the diagnosis of about one-sixth of cases with ITB. The faster availability of results compared to conventional culture is the key advantage but due to the paucibacillary nature of ITB, their yield is quite low.
Keywords Intestinal tuberculosis (ITB), Mycobacteria growth indicator tube (MGIT) test, Xpert
081
Duodeno-duodenal intussusception in a patient with chronic pancreatitis
Srikanth Kothalkar , Akash Mathur, Anshuman Elhence * , Uday C Ghoshal
Correspondence – Uday C Ghoshal - [email protected]
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raibareli Road, Lucknow 226 014, India, *All India Institute of Medical Sciences, Gate No, 1, Great Eastern Road, AIIMS Campus, Tatibandh, Raipur 492 099, India
Introduction Duodeno-duodenal intussusception, characterized by distal invagination of a segment of the duodenum into the duodenum itself, is rare because of the retroperitoneal fixation of the duodenum. We present a case of duodeno-duodenal intussusception in a patient with chronic pancreatitis.
Case Presentation A 53-year-old female with chronic pancreatitis underwent a Frey's procedure along with lateral pancreaticojejunostomy (LPJ) in 2016. However, four years after the surgery, she developed a lower common bile duct (CBD) stricture and was on endotherapy for the same. On presentation, she had recurrent post-meal bilious vomiting, approximately 15 bouts a day, loss of appetite, retrosternal burning sensation and a localized abdomen swelling. On examination, she had epigastric fullness with a BMI of 14.7 Kg/m2. Esophagogastroduodenoscopy (EGD) showed mucosal invagination in the first part of the duodenum, suggestive of duodeno-duodenal intussusception, and the scope was negotiated across with difficulty into the second part of the duodenum (Fig. 1A, B and C). A triphasic computerized tomography (CT) scan showed CBD stents in situ, atrophic pancreas and an ill-defined soft tissue in the region of the pancreatic head; also, the duodenum was thickened with doudeno-duodenal intussusception with upstream dilatation of the stomach (Fig. 1D). Tumor marker CA 19-9 was >1200 U/mL (normal 0-37 U/mL). For gastric outlet obstruction due to duodenal intussusception, a nasojejunal tube (NJ) was placed to maintain nutrition. Given the high suspicion of pancreatic malignancy and duodeno-duodenal intussusception, definitive surgical management was planned.
Conclusion This case highlights that duodeno-duodenal intussusception should always be thought of as a cause of gastric outlet obstruction, especially in a patient with post-surgical status and typical endoscopic findings.
Keywords Duodenum, Esophagogastroduodenoscopy, Lateral pancreaticojejunostomy
082
Celiac disease associated with non-cirrhotic portal fibrosis: A case series of three cases
Sayan Malakar , Akash Mathur, Uday C Ghoshal
Correspondence – Uday C Ghoshal - [email protected]
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raibareli Road, Lucknow 226 014, India
Introduction Celiac disease (CeD) is known to be associated with portal hypertension as it has been described with chronic liver disease, Budd-Chiari syndrome, and non-cirrhotic portal fibrosis (NCPF). This is the third case series revealing the association between CeD and NCPF.
Results Three patients (all females, median age of 24.67 years ranging from 17-27 years) were evaluated based on their symptoms. On evaluation, they had iron deficiency anemia and other features of malabsorption. So, they were investigated accordingly. The patients were diagnosed with CeD, based on high anti-tissue transglutaminase antibody titer and duodenal biopsy. On ultrasonography, they had splenomegaly and dilated portal veins without any evidence of chronic liver disease and ascites. Two patients revealed small esophagal varices on upper gastrointestinal endoscopy. The possibility of NCPF was kept. Two patients underwent hepatic venous pressure gradient (HVPG) measurement and transjugular liver biopsies. The mean HVPG was 7.5 mmHg. All the other alternative etiologies were ruled out. On liver biopsy, there was no evidence of chronic liver disease or cirrhosis consistent with NCPF according to the Asia Pacific Association for the Study of Liver (APASL) criteria. They were started on a gluten-free diet (GFD). On follow-up patients’ symptoms, hemoglobin and weight improved after strict adherence to GFD.
Conclusion Association between liver diseases and CeD is well known. The presence of splenomegaly in patients with CeD should prompt clinicians to look for NCPF.
Keywords Celiac disease, Gluten-free diet, Non-cirrhotic portal fibrosis, Splenomegaly
083
Spot stool a1 antitrypsin/elastase ratio as a marker of protein losing enteropathy
Anoop John , Ajith Thomas, Rajeeb Jaleel, Reuben Kurien, Sudipta Chowdhury, Amit Dutta, Ebby Simon, A J Joseph, Gagandeep Kang, K A Balasubramanian, Dilip Abraham, Julie Hephzibah, Junita John
Correspondence – A J Joseph - [email protected]
Department of Gastroenterology, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Introduction Diagnosis of protein losing enteropathy (PLE) is most commonly based on the determination of fecal α1 antitrypsin clearance, which is a cumbersome and time-consuming procedure. The aim of the study was to investigate whether spot stool α1 antitrypsin/elastase ratio can be used as a substitute marker in screening patients for PLE.
Methods Patients aged more than 1 year who were suspected as having PLE over a period of 3 years from October 2016 to September 2019 were included. Patient’s stool sample was tested for fecal alpha 1 antitrypsin and elastase by a standard ELISA assay. The patients were given three days of oral Lansoprazole prior to the day of the test and would be asked to take 50 grams of butter daily for three days prior. The study was approved by the Institutional Review Board (IRB No. 10253).
Results Over the study period, 33 patients underwent a scintigraphy scan and the diagnosis was confirmed in 20 patients (60%) with a positive scan. Among the positive patients, median age was 34 years (range: 3-69 years) and 7 (35%) were female. Median serum protein and albumin was 4 g/dL and 1.6 g/dL respectively. The cause of the protein loss were Crohn’s disease 5 (25%), intestinal lymphangiectasia (3), abdominal tuberculosis (2), celiac disease (1), SLE (1), Cronkhite-Canada syndrome (CCS) (1), congestive enteropathy (1) and idiopathic (6). Spot α1 antitrypsin had AUROC of 0.79 for diagnosing PLE and for a cut-off of 0.846 mg/g, sensitivity was 85%, specificity was 70%, compared to AUROC for spot stool α1 antitrypsin/ elastase ratio of 0.78 and for a cut-off of 0.01 mg/g the sensitivity was 85%, specificity was 70%.
Conclusion Spot stool α1 antitrypsin/elastase ratio was comparable to spot stool α1 antitrypsin as screening test for diagnosing protein losing enteropathy.
Keywords a1 antitrypsin, Protein losing enteropathy, Scintigraphy
084
Study of association between duodenal eosinophilia with functional dyspepsia and its subtypes
Mrinal Gogoi, Haribhakti Seba Das, Chittaranjan Panda, Prajna Anirvan, Pankaj Barali, Buddhi Prakash Meena, Padmalochan Prusty, Samir Kumar Hota
Correspondence – Mrinal Gogoi - [email protected]
Department of Gastroenterology, Srirama Chandra Bhanja Medical College, Behera Colony, Mangalabag, Cuttack 753 001, India
Background Functional dyspepsia (FD) is a chronic GI disorder with no structural disease. Increased duodenal eosinophilia has been linked to FD worldwide.
Aims and Objectives Study the association of duodenal eosinophilia with functional dyspepsia and its subtypes.
Methods An observational study between January 2020 to December 2021. Detailed clinical information, investigation reports, were collected from all patients diagnosed with functional dyspepsia and were included in the study after considering inclusion and exclusion criteria. Biopsy specimens were collected from the distal esophagus, gastric body, duodenal bulb, and the second portion of the duodenum.
Results Seventy-six patients with FD were included in the study among them 41 and 35 patients fulfilled the criteria for epigastric pain syndrome and postprandial distress syndrome respectively as per ROME IV criteria. Mean tissue eosinophil count in the duodenal bulb and D2 was higher than stomach and esophagus. In the duodenal bulb, 20 (26.3%) patients had a high eosinophil count and 32 (42.1%) patients were in the D2. Overall, 44.7% of patients had either duodenal bulb or D2 eosinophilia or combined duodenal bulb and D2 tissue eosinophilia. 29.3% and 31.7% of EPS patients have increased tissue eosinophils at the duodenal bulb and D2 respectively. 29.3% and 31.7% of PDS patients had increased tissue eosinophils in the duodenal bulb and D2 respectively. There is no statistically significant difference in mean tissue eosinophil count in EPS and PDS patients both at duodenal bulb and D2. On multivariate analysis, BMI, High AEC, PPI use, NSAIDs use, and dietary pattern were not associated with increased duodenal eosinophil count.
Discussion In our study mean tissue eosinophil count in the duodenal bulb and D2 was higher than stomach and esophagus. No significant association was found between duodenal eosinophilia with the dietary pattern, BMI, blood absolute eosinophil count, NSAIDs, and PPI intake.
Keywords Duodenal eosinophilia, Functional dyspepsia,
085
Use of a gastroscope for distal duodenal stent placement in patients with malignant obstruction
Saurabh Gaur , Komal Kalla, Mukesh Kalla, Ramesh Roop Rai, Pankaj Shrimal, Nikhil Atoliya, Anant Gupta, Vinayak Kalla, Sumit Patter, Suresh Kumawat, Shreyansh Jain
Correspondence – Saurabh Gaur [email protected]
Department of Medical Gastroenterology, S R Kalla Memorial Gastro and General Hospital, 78-79, Dhuleshwar Garden, C Scheme, Jaipur 302 001, India
Introduction Duodenal stent placement can be performed effectively and safely by using a Gastroscope in patients with an obstruction at the level of the distal duodenum. Patients with gastrointestinal malignancies may develop an obstruction at the level of the duodenum. Stent placement is a commonly used palliative treatment, because this modality is less invasive. However, stent placement in the distal part of the duodenum (second half of the horizontal part and ascending part of the duodenum) with a therapeutic gastroscope can be difficult. The main factors limiting the use of a gastroscope for distal duodenal stenting are the relatively short endoscope length, and shaft flexibility, which may cause looping of the scope into the stomach.
Method A 75-year-old male, presented to us with c/o recurrent vomiting, patient was evaluated on imaging USG abdomen s/o- large lobulated soft tissue mass lesion in tail region of pancreas abutting DJ flexure/ proximal jejunum, finding confirmed by gastrograffin swallow, contrast-enhanced computed tomography (CECT) abdomen done s/o large pancreatic tail malignancy, infiltrating DJ flexure / proximal jejunum. USG guided fine needle aspiration cytology (FNAC) s/o well differentiated adenocarcinoma. Self-expandable metallic stent (SEMS) placement done and hemoclip applied to prevent stent migration, as compared to earlier cases, the approach and negotiation was much easier. The length of the stricture was determined using contrast fluoroscopy of the duodenum during the procedure. A guide wire was then introduced through the stricture and the stent was advanced over the wire. Stent length was chosen to aim at a length of 1–2 cm more than the stricture. Endoscopy and fluoroscopy were used to follow stent deployment. Immediately after the procedure, an upright abdominal X-ray was performed to assess that no perforation had occurred during the procedure.
Results Success of deployment of SEMS, Easy deployment and minimal negotiation requirement.
Keywords Gastroscope, SEMS
Large intestine
086
An interesting case of inflammatory bowel disease and malignant melanoma
Sandeep Kumar Reddy G
Correspondence - Sandeep Kumar Reddy G - [email protected]
Department of Gastroenterology, Madras Medical College, Chennai 600 003, India
Inflammatory bowel disease (IBD) patients are at increased risk of skin cancer and lymphoma. Among skin cancer non melanoma skin cancer are more common compared to melanoma in IBD. IBD patient with malignant melanoma is an uncommon/rare finding. Here we present a case of IBD not on biologicals (but on immunomodulatory) developing malignant melanoma. IBD perse and usage of biologicals increase risk of malignant melanoma but immunomodulators are not associated with malignant melanoma. Immunomodulators increase risk of non-melanoma skin cancer (NMSC).
Keywords Biologicals, IBD, Malignant, Melanoma
087
Assessment of anemia profile in patients of ulcerative colitis and correlation with its severity
Manjri Garg, Pranjjal Sindhu, Sandeep Goyal
Correspondence - Sandeep Goyal - [email protected]
Department of Medicine, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak 124 001, India
Introduction Anemia is most common extraintestinal manifestation in ulcerative colitis (UC) and is associated with mortality. Anemia in inflammatory bowel disease (IBD) is a result of combination of iron deficiency anemia (IDA) and anemia of chronic disease (ACD) with complex pathogenesis. We looked for anemia, its subtypes and correlation with disease severity.
Methods Seventy-five patients were enrolled in this study. Fifty-two patients had moderate,15 had mild and 8 had severe disease activity as per Mayo score. Hemoglobin (Hb), MCV, MCH, MCHC, serum iron, total iron binding capacity (TIBC), transferrin saturation (TfS), CRP and serum ferritin were estimated. Anemia was defined as per WHO criterion. Anemia was classified as IDA, ACD, and mixed as per European Crohn's and Colitis Organisation (ECCO) guidelines. Anemia and iron indices were compared in patients with moderate (group I) and mild + severe (group II) disease activity.
Results The mean age of patients was 34.8±14 years. The mean duration of disease and onset were 28.8±33.8 months (median 12 months) and 32.5±11.5 years respectively. Extent of disease could be assessed only in 43 patients (E3:22, E2:12: E1:11). Forty-five (60%) patients had anemia. IDA and mixed anemia were present in 43 (57.3%) and 18 (24%) patients respectively. None of the patient had ACD. There was no statistical difference in Hb. MCV, MCH, MCHC in group I and II (11.6±1.6 vs. 11.5±2.6 g/dL; 80.3±7.9 vs. 81.0±7.8 fL; 26.3±3.8 vs. 26.0±5.0 pg; 32.3±2.3 vs. 31.2±3.0 g/dL). Similarly no difference was found in serum iron (59.8±26.3 vs. 57.5±39.8 mcg/dL), ferritin (25.8±26.0 vs. 27.3±25.3 ng/mL), TIBC (338±84.4 vs. 316.3±64.8 mcg/dL) and TfS (14.3±10.5 vs. 14.7±14.4%).
Conclusion Anemia was present in 45 (60%) of patients, However, 61 (81.2%) patients had IDA or mixed anemia. Hb, IDA, mixed anemia were independent of disease severity. We stress that the anemia should be evaluated in UC patients with iron indices and not merely Hb levels.
Keywords Hemoglobin, Iron Indices, Ulcerative Colitis Disease Severity
088
Non-invasive markers for predicting endoscopic disease activity in ulcerative colitis
Ahammed M C, Srijith K, Sithara K B, Sunil Kumar K
Correspondence - Sunil Kumar K - [email protected]
Department of Medical Gastroenterology, Government Medical College, Kozhikkode, Malappuram 673 639, India
Ulcerative colitis (UC) is a chronic inflammatory bowel disease that diffusely involves various parts of the colon. The Truelove–Witt’s criteria requires many clinical and laboratory parameters which is cumbersome. Moreover, the assessment of mucosal activity via endoscopy is invasive, inconvenient, costly and may be inappropriate in patients with severe UC. No ideal biomarker has been identified to assess mucosal activity in UC.
Aim Whether neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), CRP and CRP to albumin ratio (CAR) is useful in predicting endoscopic severity of UC
Methods Patients with UC, who underwent colonoscopy/ Flexible sigmoidoscopy at Government Medical College, Calicut were enrolled. NLR, PLR, CRP and CRP to albumin ratio were measured at the time of procedure.
Results Thirty-two patients (Male:20, Female:12) were enrolled in the study. Mean age at flare was 43.6 ± 15.3 year. Mean disease duration was 4.38 ± 5.35 years. All the patients were on mesalamine. 34.3% were on Azathioprine at time of flare. Mean time to colonoscopy from symptom onset of flare was 13.9±8.73. 34.3% had severe disease. Patients with moderate disease differed significantly with patients with severe disease in terms of CRP (15.9±13.0 vs, 25.49±5.24, p:0.005) and CAR (4.28±3.29 vs. 7.25±1.25, p:<0.001) and. There were no difference in NLR (3.16±1.18 vs. 3.39±1.68, p:0.775), PLR (196.89±57.3 vs. 164.78±50.48, p:0.327), Hb (10.42±1.83 vs. 9.85±1.33, p:0.235) or albumin 3.77±0.55 vs. 3.51±0.53, p:0.661). When ROC was plotted to differentiate between moderate and severe disease, AUC was highest for CRP (0.746 [0.572-0.921], p:0.02) and CAR (0.753 [0.582-0.924], p:0.02). Performance of NLR (0.515 [0.286-0.743], p:0.88) and PLR (0.662 [0.455-0.868], p: 0.13) was poor.
Conclusion In our study CRP and CAR predicted severity of ulcerative colitis while NLR and PLR did not.
Keywords CAR, CRP, NLR, PLR
089
The role of platelet to lymphocyte ratio and neutrophil to lymphocyte ratio as non-invasive markers of mucosal activity in ulcerative colitis at a tertiary care hospital of Coimbatore
Arshiya Mubin
Correspondence – Arshiya Mubin - [email protected]
Department of Medical Gastroenterology, Govt. Coimbatore Medical College and Hospital, No 42, Beside Kovai Litho Press, V C K Layout, Trichy Road, Coimbatore 641 018, India
Introduction Ulcerative colitis (UC) causes idiopathic, chronic, and relapsing inflammation of the gastrointestinal tract. The incidence of UC has rapidly increased in Asia. Endoscopy plays an important role in the diagnosis, treatment, and monitoring of disease activity in UC. However, the assessment of mucosal activity via endoscopy is invasive, inconvenient, and costly, and may be inappropriate in patients with severe UC. Non-invasive inflammatory biomarkers of IBD, such as the WBC count, ESR, and CRP are used in clinical practice. However, no ideal biomarker has been identified to assess mucosal activity in IBD as the currently used biomarkers are nonspecific. Therefore, there is an unmet clinical need to identify biomarkers that can replace the need for an endoscopy to assess mucosal disease activity. This study aims to study the role of platelet to lymphocyte ratio and neutrophil to lymphocyte ratio as biomarkers in UC.
Methods Fifty patients with UC (2 lost follow-up) who underwent measurement of fecal calprotectin (FC) and endoscopy and 96 matched healthy controls. NLR and PLR were compared between the patients and healthy controls. The endoscopic activity was divided into 2 groups: group 1 (mild to moderate inflammation) and group 2 (severe inflammation) according to the Mayo endoscopic score in UC.
Results To diagnose UC, the optimal cut off of NLR and PLR was 2.26 (sensitivity 54.2%; specificity 90.6%) and 179.8 (sensitivity 35.4%; specificity 90.6%) respectively. The optimal cut off to differentiate group 1 and group 2 was 3.44, 175.9, and 453 μg/g for NLR, PLR, and FC, respectively (sensitivity, 63.6% vs. 90.9% vs. 81.8%; specificity, 81.1% vs. 78.4% vs. 73.0%; positive likelihood ratio, 3.364 vs. 4.205 vs. 3.027; AUC, 0.714 vs. 0.897 vs. 0.813). PLR had the highest AUC and positive likelihood ratio.
Conclusion NLR and PLR help differentiate patients with UC from healthy controls. NLR, PLR, and FC indicate endoscopic activity and may reflect intestinal mucosal conditions.
Keywords IBD, Markers, NLR, PLR, UC
090
Hepatobiliary and pancreatic manifestations in inflammatory bowel disease: Data from tertiary referral center
Mayur Satai, Arun Vaidya, Aditya Kale, Amrit Gopan
Correspondence - Mayur Satai - [email protected]
Department of Gastroenterology, Seth G S Medical College and K E M Hospital, Acharya Donde Marg, Parel East, Parel, Mumbai 400 012, India
Background and Aims There are various hepatobiliary and pancreatic manifestations seen in Crohn’s disease (CD) and ulcerative colitis (UC). We evaluated their prevalence in inflammatory bowel disease (IBD).
Methods Prospectively collected IBD clinic data from January 2012 to June 2022 was reviewed retrospectively.
Results Two hundred and ninety-five IBD patients (180 [61%] males, median age 39 y). The majority (247, 83.7%) were UC. Hepatic manifestations were seen in 38 (13.2%, 23 [60.5%] males), 10.9% UC and 22.9% CD (p=0.023) (Table 1). Radiological evidence of fatty liver was present in 27 (9.2%), liver cyst 4 (1.4%), hemangioma 3 (1%), cirrhosis 3 (1%) and portal vein thrombosis in 1 (0.3%). Seropositive status for hepatitis B and C were seen in 4 (1.4%) and 2 (0.7%) cases respectively. Raised liver enzymes were: AST (11.2%), ALT (7.4%) and alkaline phosphatase (2.3%). UC, but not CD with hepatic manifestations had significantly lower albumin levels (3.1g/dL vs. 3.4 g/dL, p=0.05). Biliary manifestations were seen in 16 (5.1%, 11 [68.7%] males), 5.3% in UC and 6.2% in CD. Cholelithiasis was present in 12 (4.1%), cholecystitis 2 (0.7%), gallbladder polyps 2 (0.7%) and primary sclerosing cholangitis (PSC) in 3 (1%) patients. One patient had an AIH-PSC overlap. There was no significant association of severity of IBD with any manifestation. Pancreatic manifestations were seen in 5 (1.7%). 4 patients had azathioprine induced and 1 had idiopathic acute pancreatitis.
Conclusion Hepatobiliary and pancreatic manifestations were present in nearly one-fifths IBD patients without any gender predilection. Hepatic manifestations, most common being fatty liver, were more common in CD than UC, with lower albumin levels in UC with liver involvement.
Keywords Fatty liver, Hepatobiliary, IBD, Pancreatic
091
Clinical utility of rifaximin in Indian gastroenterology practice – Results of a nation-wide survey among >200 gastroenterologists
Shailesh Pallewar, R V Lokesh Kumar, Kamlesh Patel
Correspondence - Shailesh Pallewar - [email protected]
Lupin Ltd, Kalpataru Inspire, Opp Grand Hyatt, Santacruz East, Mumbai 400 055, India
Introduction Functional gastrointestinal disorders (FGIDs), now called as disorders of gut brain interactions are very common conditions across the world and are associated with poor quality of life and high healthcare utilization. Irritable bowel syndrome (IBS) is one of the most common forms of FGID and in India, reported prevalence of IBS based on several population-based studies varies between 4.2% to 7.5%. Rifaximin is a broad-spectrum, non-absorbable antibiotic used in the treatment of several GI disorders. In India, approved indications of rifaximin include non-invasive bacterial diarrhea and hepatic encephalopathy (HE), rifaximin’s approval for IBS in India is still awaited.
Methods This nation-wide structured questionnaire-based survey was conducted through an online platform (EnSight –Imagica Health) to ascertain the views of Indian gastroenterologists regarding role and clinical utility of rifaximin in managing various GI disorders.
Results Overall, 232 gastroenterologists completed this survey. It was observed that, rifaximin was prescribed primarily for the treatment of HE and diarrhea by 18.1% and 18.5% gastroenterologists respectively. Importantly, 21.9% and 24.1% gastroenterologists prescribed rifaximin primarily in patients with small intestinal bowel overgrowth (SIBO) and IBS-D respectively. For managing IBS-D, only 23.3% clinicians prescribed rifaximin at 550 mg TID for 14 days (as per the USFDA prescribing information), however, approximately 64% clinicians use 400 mg strength TID for 14 days. For managing IBS, 57.3% gastroenterologists reported that 2-week rifaximin treatment provided adequate symptomatic relief for up to 10 weeks. In relapsed patients, 8.5% gastroenterologists reported no clinical benefit of 2-week repeat rifaximin treatment whereas 79.2% gastroenterologists reported that 2-week repeat-treatment with rifaximin is effective and well tolerated.
Conclusion Among various GI indications, rifaximin is most commonly used in the management of IBS-D in Indian gastroenterology settings and is an effective and well tolerated.
Keywords Diarrhea, Irritable bowel syndrome, Rifaximin, SIBO
092
A cross-sectional observational study of self-reported treatment adherence in inflammatory bowel disease (ulcerative colitis) patients attending SMS Hospital, Jaipur
Hitesh Sharma , Rupesh Pokharna
Correspondence - Hitesh Sharma - [email protected]
Department of Gastroenterology, Sawai Man Singh Medical College, New S M S Campus Road, Gangawal Park, Adarsh Nagar, Jaipur 302 004, India
Introduction Ulcerative colitis (UC) is characterized by periods of relapse and remissions, so maintenance therapy is required lifelong by patients. Due to frequent dosing and sometime inconvenient methods of administration (enema, suppositories) and medication side effects non-adherence to treatment in UC patients is emerging problem. Non–adherence to treatment is important factor for occurrence of relapse in future, increase healthcare cost, high risk of disability and complications. The aims of our study were to find the prevalence, reason, and predictor of non-adherence to medical therapy in inflammatory bowel disease (UC) patients.
Methods This cross-sectional study included the patients of UC recruited between January 2020 to March 2022. Adherence was assessed with questionnaire (interview based) that also includes patients clinical, personal, and sociodemographic profile and reason of non–adherence.
Results A total of 112 patients of UC were included, there were 66 (58.9%) males and 46 (41.1) were females; mean age was 33.4±12.4 years; mean duration of disease was 3.8±3.96 years. Eighty-one (72.3%) patients were non-adherent (taking 80% or less of advised-dose) to medication. The reason for non-adherence were:cost of treatment 39 (48.1%), felt better 19 (23.5%), forgetting dose 5 (6.1%), frequent drug dosing 2 (2.5%), life-long treatment 3 (3.7%), alternative treatment 8 (9.8%) and adverse effects of medication 5 (6.2%). Patients socioeconomic class (p=0.013), occupation (p<0.001) and education (p=0.001) have positive association with adherence. Patients in upper-middle and lower -middle socioeconomic class with educated and employed were highest adherent (66.6%), whereas patient from lower socioeconomic class who were illiterate and unemployed were least adherent (15%). Conclusion Over 70% patients with UC was non-adherent in our study, cost of treatment and felt better was commonest cause. So proper counselling and improving knowledge about UC is must and gastroenterologist should also focus on it.
Keywords Inflammatory bowel disease, Non-adherence, Ulcerative colitis
093
Melanosis coli - A case report
Jitendra Singh , Jitendra Kumar Singh
Correspondence - Jitendra Singh - [email protected]
Department of Gastroenterology and Hepatology, M L N Medical College, George Town, Prayagraj 211 002, India
Introduction A 65-year-old male presented to our department with 5 year history of constipation along with laxative intake for last 5 years on daily basis.
Methods His physical examination was normal. His ultrasound did not show any significant abnormalities. His routine blood investigation were also normal. We planned him for a full length colonoscopy. His colonoscopy showed blackish pigmentation of colonic mucosa which was more in the right colon. Multiple biopsy were taken throughout colon. His histopathology report showed macrophage in lamina propria with brown-black pigmentation in the cytoplasm. Histochemical staining showed these pigments stained to Fontana- masson and was suggest of Melanosis coli. Patient was advised to stop the laxative. Melanosis coli is a benign condition seen in patients using anthraquinone- based laxative which is more common on right side of colon.
Conclusion Elderly people are at risk of developing Melanosis coli especially those with chronic constipation [1]. In our case patient was consuming a laxative which contained senna as active ingredient. Since mucosa appear to be brown, black it can be easily confused with ischemic colitis. Histologic finding of ischemic colitis which differentiate it from Melanosis coli includes distortions of crypts, edema, hemorrhagic changes in mucosa and submucosa [2]. There is increased incidence of adenoma in patients with melanosis coli due to easier detection of adenoma against the dark staining of colonic mucosa [3].
(Blackish brown pigmentation of colonic mucosa)
References
1. Ahasan HM, Khan MAI, Mahbub S, et al. Melanosis coli- an atypical presentation. J Med. 2010; 11:183-5.
2. Theodoropoulou A, Koutroubakis IE. Ischemic colitis- clinical practice in diagnosis and treatment. World J Gastroenterol. 2008; 14: 7302-8.
3. Blackett JW, Rosenberg R, Mahadev S, Green PHR, Lebwohl B. Adenoma detection is increased in the setting of Melanosis coli. J Clin Gastroenterol. 2018;52:313-8.
Keywords Constipation, Melanosis
094
Environmental risk factors for inflammatory bowel disease- Ulcerative colitis
Nadiya M E , Rupesh Pokharna
Correspondence – Rupesh Pokharna - [email protected]
Department of Gastroenterology, Sawai Man Singh Medical College, New S M S Campus Road, Gangawal Park, Adarsh Nagar, Jaipur 302 004, India
Introduction Inflammatory bowel disease (IBD) both ulcerative colitis (UC) and Crohn’s disease are rising in India. Environmental factors and westernization of diet and lifestyle have been associated. This study was aimed to assess the risk factors for IBD UC from Western Indian state of Rajasthan.
Methods Prospective, single center, case control study including 165 IBD UC patients and 165 asymptomatic healthy controls. A simple printed questionnaire assessing the risk factors and disease characteristics of UC was prepared and both the patients and controls were asked to fill. Odds ratio (OR) and 95% confidence interval was calculated and p value less than 0.05 was considered significant.
Results The study didn't show any difference in prevalence of UC in urban or rural population. The disease was more prevalent in men compared to women (OR 1.071, 0.82-1.38) and presented in third decade of life in majority (1.830, 1.52-2.19). Patients with UC had lower body mass index (OR 2.185, 1.52-3.14). In this study toxin abuse like smoking and surgery like appendicectomy were seen as risk factors for UC (OR 4.5, 3.19-8 and 3.1, 1,5-5). Consumption of milk was associated with higher risk of UC in this study population. This study didn't find cooking oil, high fiber diet, consumption of fruits and vegetables OR junk food to be protective OR causative for UC.
Conclusion This study highlights the environmental risk factors for IBD UC from a single center in western state of Rajasthan.
Keywords IBD UC
095
Unusual rectal foreign bodies – Challenges in management
Mamindla Kiran, Govind Verma, M Sudhir, Dhiraj Agrawal
Correspondence - Dhiraj Agrawal - [email protected]
Department of Medical Gastroenterology, PACE Hospital, Metro Pillar Number C1775, 18, Hitech City Road, HUDA Techno Enclave, HITEC City, Hyderabad 500 081, India
Introduction Rectal foreign bodies diagnosis and management is difficult, Due to wide variations in type of object, host anatomy, time from insertion, injuries, and local contamination. Reluctant to seek medical advice and provide details makes situation more difficult.
Case Report Twenty-four-year-old male presented to emergency department with anal pain, on history he had inserted a foreign object into the rectum. CT shows non – metallic foreign body located high in the rectum Without any evidence of free air in the peritoneum. colonoscopy- 15 × 6 cms size plastic cylindrical tube observed in the rectum, under mild sedation anal canal dilated with anal dilator and foreign body removed with both endo and flouro guidance with artery forceps. Patient discharged in a stable condition.
Twenty-seven-year-old male presented with severe pain abdomen and anal pain. On history he had inserted handheld bidet shower into the rectum. CT – abdomen shows metallic hand held shower confirmed in the rectum with free fluid in the pelvis. ?Perforation, patient taken for emergency laparotomy. Intra operatively multiple (3) perforations in the upper and mid rectum with free fluid in the pelvis with contamination observed. Removal of foreign body done. Resection of segment of rectum with rectosigmoid anastomosis with peritoneal lavage with loop ileostomy done. Patient discharged in a stable condition.
Discussion Rectal foreign body diagnosis and management varies widely with each patient. systematic approach for diagnosis, assessment for foreign body size and location should be mandatory.
Keywords Foreign body, Laparotomy, Rectum
096
Extensive invasive mucormycosis in post liver transplant patient
Mamindla Rakesh Kiran, Govind Verma, M Sudhir, Dhiraj Agrawal, Phani Krishna Ravula, Suresh Kumar S, Santhosh Kumar Ganapathi
Correspondence - Dhiraj Agrawal - [email protected]
Department of Medical Gastroenterology, Pace Hospital, Metro Pillar Number C1775, 18, Hitech City Road, HUDA Techno Enclave, Hitec City, Hyderabad 500 081, India
Introduction Fungal infections are rare and feared complication in liver transplant recipient, with high rates of morbidity and mortality. Current estimates are about 5%. Most common organisms are Candida and Aspergillus, both constitutes 80% of cases. Rare causes are Mucor, Cryptococcus, Histoplasma.
Case Report A 44-year-old male with decompensated chronic liver disease with MELD- Na score 28, underwent living donor liver transplantation. intra operatively he had requirement of inotropic support. patient started on immunosuppression. On POD-6 patient developed rejection (moderate cellular rejection – RAI score–6/9) treated with methyl prednisolone pulse therapy, after that Patient developed low grade fever and reduced consciousness, black necrotic discharge around surgical site, with drop in hemoglobin, underwent colonoscopy – findings of terminal ileum shows nodularity, cecum and ascending colon shows a large circumferential ulceration with sloughed out/ballooned necrotic mucosal layer, he underwent debridement of wound with limited ileo-cecal resection. Histology suggestive of invasive mucormycosis of intestine with angio and muscular invasion.
Patient treated with liposomal amphotericin – B, his condition gradually worsened with increased requirement of ionotropes, decreased urine output, raise in creatinine and decreased level of consciousness, despite intensive care management and regular monitoring patient not survived.
Discussion Mucor rarely involves the gastrointestinal (GI) tract. In GI most common site of involvement is stomach than colon. Abdominal pain, altered bowel habits, fever are the presenting symptoms, it may rarely present as mass lesion mimicking carcinoma colon, sometimes leads to bowel necrosis and perforation.
Conclusion Invasive fungal infections leads to high mortality in transplant patient, identification of high risk group and prophylactic anti-fungal therapy decreases devastating complications in this patients.
Keywords Fungal infection, Mucor, Tranplant
097
Non-inflammatory bowel disease colitis: Uncommon cause of a common presentation
Nirmaljit Singh Malhi, Jasmeet Singh Dhingra, Rajiv Grover, Achal Garg
Correspondence - Nirmaljit Singh Malhi - [email protected]
Department of Gastroenterology, Advanced Gastroenterology Institute-The Gastrociti, Opposite Grandwalk Mall, Barewal Road, BRS Nagar, Ludhiana 141 008, India
Introduction Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1-INH) is a rare disease, which induces an acute attack of angioedema mediated by bradykinin. It can cause serious abdominal pain when severe edema develops in gastrointestinal (GI) tract. Such patients with repeated episodes can have presentation like aubacute intestinal obstruction (SAIO).
Methods We herein present a 48-year-old female patient with HAE-C1-INH, who underwent recurrent episodes of SAIO with abdominal colic in past. She frequently needed hospitalizations with the administration of opioids due to severe abdominal pain.
Result HAE-C1-INH should be considered, when evaluating patients with unidentified recurrent abdominal pain. Characteristic bowel findings were non-inflammatory edema, normal acute phase reactants (ESR/CRP/PCT) and severe pain. On evaluation, serum C4 was 9.8 (10-40 mg/dL), serum C3 was 49.7 (90-170 mg/dL) and C1 Esterase inhibitor protein was 164 (195-345 mg/L). Computed tomography (CT) enterography scan findings of mucosal enhancement, extensive submucosal oedema of the intestinal tracts, mesenteric congestion and edema and colectasia during acute attack.
Fig 1: Abdominal computed tomography scan in this patient during acute attack shows bowel wall edema.
Medical interview focusing on past history revealed history of minimal facial and upper extremity edema. She did not have a positive family history or any such episodes in childhood. Patient was started on prophylactic daily Danazol (200 mg) and remained symptom free for 1 year follow-up. On recovery as she was symptom free all medications were stopped by herself and after 2 months of stopping medications, she had a relapse requiring admission and opioid administration. Icatibant, a selective bradykinin B2 receptor antagonist, available for self-administration during an acute attack could not be used due non availability in our country.
Conclusion HAE-C1-INH can present like SAIO. High index of suspicion is necessary for identification and prompt therapy leads to excellent treatment response.
Keywords Intestinal angioedema, NIBDC
098
Colonoscopic intralesional injection of Coca-Cola for evacuation of large rectal fecaloma
Avnish Kumar Seth , Jitendra Mohan Jha
Correspondence - Avnish Kumar Seth - [email protected]
Department of Medical Gastroenterology, Manipal Hospital, Sector 6, Dwarka, Delhi 110 075, India
Introduction Fecaloma is a large mass of organized hardened feces causing impaction, usually in rectum and sigmoid colon. Management includes digital evacuation, use of clearance enema or oral laxatives. We present use of intralesional injection of Coca-Cola for evacuation of large rectal fecaloma refractory to other treatment modalities.
Case Report A 81-year-old male with long standing constipation, presented with inability to pass stool and severe pain in rectum for one month and difficulty in passing urine for one day. Examination of abdomen was unremarkable. Per-rectal examination revealed rounded 10 cm diameter hard non-pitting fecaloma in rectum that could not be crushed digitally. Abdominal X-ray and non-contrast computerized tomography (NCCT) scan confirmed presence of solid stool with distension of rectum and sigmoid colon. Attempts at clearance of stool with conventional methods were unsuccessful. At colonoscopy (Olympus CF-H180AL), large mobile fecaloma was noted in distal rectum with presence of solid fecal matter in proximal rectum and sigmoid colon. Following informed consent, two liters of Coca-Cola was instilled with 50 mL syringe through the working channel of colonoscope into descending and sigmoid colon, leading to evacuation of stool, but the rounded fecaloma was retained in the rectum. 50 mL of Coca-Cola was then injected into the fecaloma with 21-G endoscopic sclerotherapy needle. After 5 minutes, the hard fecaloma could now be crushed against the sacrum and was successfully evacuated digitally.
Discussion We have described previously published the use of colonoscopic instillation of Coca-Cola for clearance of fecaloma. However, large fecaloma may be refractory to available methods and may need disintegration prior to successful evacuation. Technique of intra-lesional injection of Coca-Cola has been previously described in a single report from South Korea.
Conclusion Colonoscopic intralesional injection of Coca-Cola followed by digital evacuation is effective for removal of rectal fecaloma refractory to conventional treatment.
Keywords Colonoscopic injection Coca-Cola, Colonoscopic removal, Fecaloma
099
Use of indigenous Dr Seth’s fecaloma basket along with Coca-Cola instillation for colonoscopic clearance of large colonic fecaloma
Avnish Kumar Seth , Jitendra Mohan Jha
Correspondence - Avnish Kumar Seth - [email protected]
Department of Medical Gastroenterology, Manipal Hospital, Sector 6, Dwarka, Delhi 110 075, India
Introduction Fecaloma, large masses of organized hardened faeces in rectum and distal colon, are often refractory to conventional treatment. We present use of Indigenous Fecaloma Basket, designed by us, for fragmentation of large fecaloma followed by evacuation with Coca-Cola instillation.
Case Report Six-year-old male with constipation since infancy presented with inability to pass stool for two weeks. There was no history of pain abdomen or vomiting. The child was differently abled and was previously operated for congenital hydrocephalus and undescended testes. On examination the child weighed 18 Kg and was confined to bed. Abdominal examination revealed multiple non-pitting hard masses in hypogastrium, left iliac fossa, umbilical and left lumbar regions. Oral polyethylene glycol and sodium phosphate enema showed no result. Non-contrast CT scan confirmed large fecaloma in rectum, sigmoid and descending colon with density up to 184.5 HU. Under sedation, a large rectal fecaloma was disintegrated digitally and evacuated. Colonoscopy (Olympus, PCF-PH190L/I) revealed multiple large fecaloma of up to 5 cm dia till splenic flexure. Dr Seth’s Fecaloma basket (Manish Medi Innovation, 3 steel wires, basket opening length 1500 mm, basket diameter 60.75 mm, catheter dia 2.3 mm) was introduced through the working channel and the fecaloma were captured and crushed. Instillation of 540 mL of Coca-Cola (30 mL/Kg) at splenic flexure resulted in complete evacuation of fragmented fecaloma, aided by abdominal compression. Parents did not consent for full-thickness rectal biopsy.
Discussion We have previously published the use of colonoscopic instillation of Coca-Cola for clearance of fecaloma. However, large fecaloma may be refractory to treatment with available methods. Commercially available endoscopic baskets, designed for use in polyps and bile duct stones, may be too small to capture large fecaloma.
Conclusion Indigenous Fecaloma Basket enables colonoscopic capture and disintegration of large fecaloma. Colonoscopic instillation of Coca-Cola then results in complete clearance of fecaloma fragments.
Keywords Colonic fecoloma, Dr Seth’s Fecoloma basket
100
A case report on multiple polyps of gastrointestinal tract
Uday Vadicherla, Muthu Kumaran, I Shubha, A Aravind, Caroline Selvi, A Chezhian, R Murali
Correspondence - Uday Vadicherla - [email protected]
Department of Medical Gastroenterology, Madras Medical College, Poonamallee High Road, Park Town, Chennai 600 003, India
Introduction The liberal use of endoscopy leads to an increase in detection of polyps in gastrointestinal tract. Incidence of polyps during endoscopy 6%, 4.6% and 7% to 42% in stomach, duodenum, and colon respectively.
Case Discussion A 27-year-old male patient presented with dyspeptic symptoms on examination found to be having macrocephaly, on face patient having multiple tiny papules (trichilemmomas) on face and also on hands. On 0ral examination patient having multiple oral papillomas on tongue and gum hypertrophy. On genital examination hyper pigmented flat lesion seen on glans penis.
On esophagogastroduodenoscopy (EGD) we noticed multiple tiny polyps in distal esophagus and in second part of duodenum. Then we proceeded to colonoscopy, found multiple polyps in entire colon. On histopathology examination confirms polyps as hamartomatous type. Ultrasonography (USG) of neck, which shows multiple colloid cysts in both lobes of thyroid. Fine needle aspiration cytology (FNAC) of this showed nodular colloid goiter. USG of scrotum showed multiple hypoechoic lesions, suggest hamartomas or lipomatosis of testis. With all these above findings patient fits into Cowden syndrome diagnostic criteria by Pilarski et al.
Keywords Hamartomatous polyp, Papilloma, Trichilemmomas
101
Roots of a colonic tree- A rare endoscopic finding in ulcerative colitis
Aastha Jha, Alok Sahu, Maitrey Patel, Apurva Shah, Shravan Bohra
Correspondence – Apurva Shah- [email protected]
Department of Gastroenterology, Apollo Hospital International Limited, Plot No, 1A, Gandhinagar - Ahmedabad Road, GIDC Bhat, Estate, Ahmedabad 382 428, India
Introduction Although usual endoscopic findings in ulcerative colitis consist of mucosal erythema, edema, ulcerations and pseudo polyposis, other uncommon presentations have also been noted. Filiform polyposis is a rare entity noted in cases of inflammatory bowel disease, which is characterized by multiple, long, slender, worm like projections, consisting of submucosal core lined with normal mucosa. Here we present a case with multiple intertwined filiform polyposis noted in a case of ulcerative colitis.
Case Report We present a case of 41-year-old male patient, known case of ulcerative colitis for 5 years, who presented with persistent diarrhea. Patient was on oral mesalamine for a few years and was not taking steroids or immune suppressants. Upon endoscopic evaluation, patient was found to have multiple, thin, long (5-6 cm in length), slender, worm-like projections, resembling the stalk of polyps, without the heads. These were very similar to those like roots of a tree. Patient also had an entire area of erythema and loss of vascular pattern in the left colon, suggestive of ongoing inflammatory activity. Histopathology of the polypoidal projections showed normal colonic mucosa, although that of the erythematous mucosa was suggestive of chronic active inflammation. He had evidence of flare.
Conclusion This type of giant filiform polyposis is formed by chronic inflammation of the large bowel mucosa, with repeated ulceration and healing leading to the formation of worm-like polypoid projections. They may mimic adenomatous polyps or may even be mistaken for a malignancy. It is important in such cases to take multiple biopsies, to rule out dysplasia or invasive malignancy, although it has rarely been reported. If asymptomatic, requires periodic observation and follow-up. However, if associated with active IBD, surgical resection should only be considered for severe active colitis.
Keywords Filiform polyposis, Ulcerative colitis
102
Fecal calgranulin is an alternate stool biomarker to differentiate inflammatory bowel disease from irritable bowel syndrome (diarrheal type)
Santhosh Kumar 1 , Rajeeb Jaleel 2 , Tintu Varghese 3 , Stephen Benny 2 , Ira Praharaj 3 , Sudipta Chowdhury 2 , Reuben Thomas 2 , Ebby Simon 2 , A J Joseph 2 , Amit Kumar Dutta 2
Correspondence – Amit Kumar Dutta - [email protected]
Departments of 1Hepatology, 2Gastroenterology, and 3Wellcome Research Unit, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Background Calgranulin C (S100 A12), a novel biomarker was reported to be stable in stored stool (at room temperature) for longer duration (7 days) compared to calprotectin (2-3 days). We aimed to compare the diagnostic accuracy of calgranulin with calprotectin for differentiating inflammatory bowel disease (IBD) from irritable bowel syndrome with diarrhea (IBS-D).
Methods We prospectively studied patients (≥18 years) with active IBD (Asia-Pacific consensus criteria) and IBS-D (Rome III criteria). We excluded patients with blood in stools. All patients had colonoscopy in addition to other laboratory tests. Sample size of 55 patients in each group was needed to detect 15% difference in diagnostic accuracy between calprotectin and calgranulin. Informed consent was taken and the study was Institutional Review Board approved. Fecal samples were collected prior to colonoscopy preparation and stored at -80° celsius. Calgranulin was measured using IDK® S100A12 ELISA and calprotectin using EDI quantitative fecal calprotectin ELISA Kit. The laboratory staff were blinded.
Results We studied 113 patients, aged 38.3 (±13.6) years with 84 men (74.3%), 56 IBD patients (30 Crohn’s disease [CD], 25 ulcerative colitis [UC] and one indeterminate colitis) and 57 IBS-D patients. The baseline symptomatology and BMI of the patients were comparable. The median calgranulin was significantly different between IBD (19.5 [3.9-54] ug/g) compared to IBS-D patients (1.9 [0.26-6.25] ug/g), p<0.00001. Calgranulin had AUROC of 0.77 for differentiating IBD from IBS-D and for a cut off of 8 ug/g, sensitivity was 66.1%, specificity was 79% with diagnostic accuracy of 78.9%, compared to AUROC for calprotectin of 0.88 and for a cut-off of 92.6 ug/g the sensitivity was 82.1%, specificity was 75.4% with diagnostic accuracy of 75.4%. AUROC of calgranulin for differentiating CD and IBS-D was 0.74 and for differentiating UC from IBS-D was 0.84.
Conclusion The diagnostic accuracy of fecal calgranulin is comparable to fecal calprotectin for differentiating IBD from IBS-D.
Keywords Calgranulin, Calprotectin, Inflammatory bowel disease, Irritable bowel syndrome
103
Colorectal carcinoma presenting as pyogenic liver abscess
Antony George , Devika Madhu, Nidhin R, Prasanth T S, Krishnadas D
Correspondence – Antony George - [email protected]
Department of Medical Gastroenterology, Government Medical College, Ulloor - Akkulam Road, Chalakkuzhi, Thiruvananthapuram 695 011, India
Introduction Colorectal carcinoma is a common malignancy worldwide with well-established symptoms. Liver abscess as the presenting sign of occult colorectal malignancy has rarely been reported. We present a case of colorectal carcinoma presenting as pyogenic liver abscess.
Case Summary We report a 60-year-old healthy male, chronic smoker, and alcoholic, who presented with complaints of abdominal pain in the right hypochondrium, which was associated with high-grade fever with chills of 2 weeks duration. General examination revealed features of SIRS, with temperature – 101 Fahrenheit, tachycardia (pulse-96/minute), and resting tachypnea (respiratory rate – 24/minute). Abdominal examination revealed tenderness in the right hypochondrium. Blood workup revealed a total leukocyte count of 17,900 cells/microlitre with a neutrophil count of 87%, ESR of 120, and elevated ALP -209 (125). His procalcitonin levels were 14.7 (0.25). He was treated with broad-spectrum antibiotics after obtaining blood cultures. Tumor marker analysis revealed high carcinoembryonic antigen (CEA) levels – 132. contrast-enhanced computed tomography (CECT) abdomen revealed multiple ill-defined peripherally enhancing hypodense lesions in the left lobe of the liver suggestive of pyogenic liver abscess, 2 well defined hypodense lesions in the right lobe of the liver suggestive of metastatic lesions, and a focal asymmetric wall thickening of 6.1cm length involving the distal transverse colon and splenic flexure, with multiple enlarged pericolic lymph nodes; suggestive of colorectal carcinoma. Colonoscopy the following day revealed a circumferential polypoidal growth at splenic flexure beyond which scope could not be negotiated and a pedunculated polyp in descending colon. Histopathology revealed moderately differentiated adenocarcinoma. He was given 6 weeks of antibiotics and planned for radiotherapy.
Conclusion Increased awareness that pyogenic liver abscesses can be the initial presentation of colorectal carcinoma is imessential. Timely diagnosis and early treatment can improve the outcome of colorectal neoplasm. Colonoscopy is necessary to identify the origin of unexplained liver abscess.
Keywords Abdominal pain, Colorectal carcinoma, Pyogenic liver abscess, SIRS
104
Frequency of thiopurine induced myelosuppression in Indian patients with inflammatory bowel disease: A randomized controlled trial comparing full dose initiation versus gradual escalation
Alok Singh , Sanjeev Sachdeva, Siddharth Shrivastava, Ajay Kumar, Ashok Dalal, Ujjwal Sonika, B C Sharma
Correspondence – Alok Singh - [email protected]
Department of Gastroenterology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, 1, Jawaharlal Nehru Marg, New Delhi 110 002, India
Background and Aim Myelosuppression is most dreaded adverse reaction to Azathioprine (AZA) treatment with a reported 7% cumulative incidence. We aimed to compare the incidence of myelosuppression in patients with full dose initiation versus gradual escalation of AZA.
Methods Forty patients of inflammatory bowel disease (IBD) were recruited over one year. They were randomized into two groups (group A, group B) of 20 each. Randomization was done in 1:1 ratio based on computer generated tables. Group A received full dose initiation of AZA at 2 mg/kg and group B (gradual escalation) received 1 mg/kg and the dose was uptitrated to 1.5 mg/kg and 2 mg/kg at 4 weeks and 8 weeks respectively. All patients were clinically followed for 24 weeks.
Results Seventeen patients were included in analysis in each group as 3 patients were lost to follow-up in each group. Median age was 32 years and 30 years in group A and B, respectively. Fourteen and 15 patients were of UC; 3 and 2 patients were of CD respectively in group A and B. During follow-up post AZA initiation, 2 (11.8%) patients in group A and 4 patients (23.5%) in group B relapsed (p=0.65). Two patients (11.8%) in each group developed myelosuppression. Median time to development of leucopenia was 10 weeks (range 4-12 weeks). Absolute neutrophil counts (ANC) in group A showed a trend towards lower median values as compared to Group B particularly after 4 weeks of initiation of AZA. On univariate analysis serum protein, albumin and bilirubin were found to significantly associated with leucopenia. However, on multivariate analysis none of these factors were significant.
Conclusions Patients with full dose initiation had comparable relapses in follow-up period as compared to gradual escalation group. Incidence of myelosuppression was similar in both the groups.
Keywords Azathioprine, Leucopenia, Ulcerative colitis
105
Case series of colonic mucormycosis in covid pandemic
Vinod Raman , Ravi Shankar B
Correspondence – Ravi Shankar B - [email protected]
Department of Medical Gastroenterology, Yashoda Hospitals, Alexander Road, Kummari Guda, Shivaji Nagar, Secunderabad 500 003, India
Introduction Mucormycosis-fungal infection (ubiquitous). Class – Zygomycetes (1). Predisposition in COVID infection. Gastrointestinal (GI) mucormycosis is rare. Outcome is usually fatal.
Case 1 A 54-year-old male, presented with lower GI Bleed. Treated with remdesivir and Oxygen support. Colonoscopy: Cecal ulceration and black pigmentation (Fig. 1). KOH stain – Aseptate Hyphae (Fig. 2).Treated with Liposomal amphotericin B. Semiurgent surgery: right hemicolectomy done, Succumbed to death.
Case 2 A 58-year-old male came for lung transplantation. K/C/O –DM2, Hypertension. On ECMO day 38, CT abdomen showed sigmoid colon perforation with fecal peritonitis. Emergency laparotomy+sigmoid colon resection +end colostomy. Histopathology confirmed mucormycosis (Fig. 3). Deteriorated and succumbed.
Discussion 2nd wave Covid – several cases of rhino-orbito cerebral mucormycosis.GI mucor rarely reported. Complaints of fever, nausea, abdominal pain, GI bleed and perforation. Predisposing factors: diabetes, steroids, immunocompromised states. Endoscopy : large ulceration with necrosis, black pigmentation
Diagnosis KOH mount, PCR, Treatment – Inj. Liposomal amphotericin B – 5 mg/kg/day for 3 weeks followed by oral posaconazole (2). Prognosis is usually poor (3).
Conclusion GI mucormycois is a rare disease and should be considered in patients with lower GI bleed and perforation. Prompt attention needs to be given for early diagnosis and appropriate treatment.
Keywords Colitis, GI bleed, Perforation
106
A rare case of primary cecal lymphoma
Lohith Kumar V R , Suprabhath Giri
Correspondence – Lohith Kumar V R - [email protected]
Department of Medical Gastroenterology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad 500 082, India
Introduction Gastrointestinal tract is the most common site of extranodal lymphoma, of which non-Hodgkin’s lymphoma (NHL) comprises 4% of total cases. Primary lymphoma arising from the colon is very rare accounting only 0.2% to 1% of all colonic malignancy.
Case Report Sixty-three-year-old old gentleman presented with 2 months history of mass in the right iliac fossa with mild dragging pain, progressive weight loss and anorexia with no change in bowel habits, GI bleed, fever. On examination 8 × 6 cm firm, tender mass with restricted mobility noted extending from right lumbar region to RIF. CT scan showed circumferential wall thickening in the caecum and terminal ileum with loco-regional lymph nodal mass of 16 × 10 cm. Colonoscopy revealed proliferative lumen occluding polypoidal growth in the cecum. Histopathology was suggestive of cecal lymphoma. Further, immunohistochemistry (IHC) markers showed CD10, CD 20,CD3 and Bcl2 positivity, cyclin D1-negative, Ki67-42% diagnostic of diffuse large B cell lymphoma. Whole body PET CT showed FDG avid abdominal (SUV max 29.6) and mediastinal lymphadenopathy (SUV max 8.02) with diffuse circumferential wall thickening of right colon (SUV max35.97). He was diagnosed to have ceacal lymphoma-DLBCL, stage III (Lugano).The patient was started on R-CHOP regimen.
Conclusion Primary ceacal lymphoma is very rare, it should always be considered in the differential diagnosis. Management depends on the clinical features and staging; requiring multi-disciplinary approach including surgery, chemotherapy.
Keywords Ceacal lymphoma, Colon, Extra nodal lymphoma, R-CHOP
107
Cytomegalovirus colitis in inflammatory bowel disease: A case series
Rishabh Agarwal , Naresh Bhat, Anupama N K, Amit Yelsangikar, Kayal Vizhi N, Raghu B M
Correspondence – Rishabh Agarwal - [email protected]
Department of Gastroenterology, Aster CMI Hospital, No. 43/2, New Airport Road, NH.7, Hebbal, Sahakara Nagar, Bengaluru 560 092, India
Cytomegalovirus (CMV), is an opportunistic pathogen, known to complicate the course of treatment in patients with inflammatory bowel disease (IBD). It has been found to exist more in immunocompromised than immunocompetent individuals, more in ulcerative colitis than in Crohn's disease.
We present a series of 5 cases where CMV was encountered in the course of IBD, and our experience with the treatment, complications, and outcome. Diagnosis is based on suspicious endoscopic lesions, serology, histopathological features, and tissue PCRs. Effective antiviral drugs are available, but they come with a set of frequent adverse events. Hence, the treatment of CMV colitis should be supervised.
Humans are the only reservoirs for CMV. CMV replication should be differentiated from CMV mediated disease. It is also important to differentiate IBD flare from CMV. CMV increases the risk of hospitalization in IBD patients. It may reduce response to biologicals. It has also been reported that IBD patients with CMV mediated disease have higher rates of colectomy. However, some studies have showed no effect of CMV infection on IBD in remission. CMV and its treatment, both are known to cause bone marrow suppression, which can be lethal if unchecked. Nevertheless, it should be actively looked for and treated for better outcomes.
Keywords Colitis, Cytomegalovirus, IBD
108
Relationship of mucosal urease producing organisms and disease activity in patients of ulcerative colitis: A prospective cross-sectional study
Bigyan Maharaj 1 , Anurag Jena2, Pallab Ray3, Neelam Taneja3, M R Shivaprakash3, Mini P Singh4, Anupam Kumar Singh2, Vishal Sharma2, Kaushal Kishor Prasad2, Arun Kumar Sharma2, Rakesh Sehgal5, Usha Dutta2
Correspondence – Usha Dutta - [email protected]
Departments of 1Internal Medicine, 2Gastroenterology, 3Medical Microbiology, 4Virology, and 5Medical Parasitology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India
Introduction Microbial dysbiosis in inflamed areas in patients of ulcerative colitis (UC) signifies the role of ongoing infection leading to perpetuation of disease activity. We planned a study to compare the prevalence of mucosal urease producing bacteria in patients with UC and study its relationship with disease activity.
Methods A prospective cross-sectional study was conducted at our tertiary care hospital from February 2021 to June 2022. All patients underwent clinical evaluation, endoscopy (Mayo score assessment) and blood investigations after informed consent. Patients undergoing colonoscopy for indication other than UC without any colonic inflammation were taken as controls. A mucosal biopsy specimen taken from the inflamed mucosa and adjacent visually non-inflamed mucosa was placed in the rapid urease test (RUT) media (Pylo Dry® Kit, India). After 1/2-hour, positive result (color change yellow to pink) indicated the presence of a urease-producing organism]Results A total of 78 UC cases and 33 controls were recruited. Fifty-one patients of UC had active disease (22 patients had severe disease). In UC, mucosal biopsy from inflamed areas more often had evidence of RUT positivity as compared to adjacent non-inflamed areas in the same patient (p=0.039). RUT performed using mucosal biopsy in severe UC more often showed positivity as compared to controls (18/22 [81.8%] vs. 18/33 [54.5%]; p=0.037). RUT performed using mucosal biopsy in patients of UC more often showed positivity as compared to controls (57/78 [73.1%] vs. 18/33 [54.5%]; p=0.056).
Conclusion Mucosal biopsy in patients with severe UC had more often evidence of urease producing organisms than controls. Mucosa associated microbiota profile may have a role in driving inflammation.
Keywords Inflammatory bowel disease, Microbiota, Multiplex PCR
109
Gastrointestinal mucosa associated microbial profile and disease activity in patients of ulcerative colitis: A prospective study
Bigyan Maharjan 1 , Anurag Sachan 2 , Anuraag Jena 2 , Pallab Ray 3 , Neelam Taneja 3 , M R Shivaprakash 3 , Mini P Singh 4 , Devyani Sharma 5 , Anupam Kumar Singh 2 , Vishal Sharma 2 , Kaushal Kishor Prasad 2 , Arun Kumar Sharma 2 , Rakesh Sehgal 5 , Usha Dutta 2
Correspondence – Usha Dutta - [email protected]
Departments of 1Internal Medicine, 2Gastroenterology, 3Medical Microbiology, 4Virology, 5Medical Parasitology, Level 4, F Block, Post Graduate Institute of Medical Education and Research, Nehru Hospital Extension Block, Sector-12, Chandigarh 160 012, India
Introduction Mucosa associated microbiota (MAM) are shown to drive gut inflammation. Their role in disease activity in ulcerative colitis (UC) is largely unknown. We planned to study fecal and MAM profiles in UC and compare them with controls.
Methods A prospective study was conducted at our university from February 2021 to June 2022. Patients underwent clinical evaluation, endoscopy (Mayo-Score assessment) and blood investigations after consent. Patients undergoing colonoscopy for indication other than UC without colonic inflammation were taken as controls. Mucosal biopsies were taken from inflamed and adjacent non-inflamed areas for bacterial and fungal culture. Stool was evaluated for microscopy, culture, and PCR (E coli and Entamoeba histolytica).
Results Seventy-eight cases (51 active; 27 in remission) and 33 controls were included. Mucosal bacterial culture in patients with severe UC more often grew organisms than controls (15/18 [83.3%] vs. 14/30 [46.7%]; p=0.01). Mucosal bacterial culture in severe UC more often grew organisms than non-severe disease (15/18 [83.3%] vs. 30/52 [57.7%]; p= 0.05). Stool bacterial culture was similar between cases and control (p=0.97). Patients with UC more often had stool PCR positivity for E. histolytica compared to controls (14/54 [25.9%] vs. 2/25 [8%]; p=0.065). Stool fungal culture was more often positive in those with active UC compared to controls (23/31 [74.3%] vs. 14/28 [50%]; p=0.055). Patients with severe UC more often grew pathogenic organisms either one of bacteria/fungi/E. histolytica or both or all compared to controls (p=0.037). Inflamed mucosa more often grew pathogenic bacteria and fungi compared to adjacent normal looking mucosa (p= 0.039).
Conclusion Mucosal culture from patients grew more often pathogenic organisms and stool PCR positivity for E. histolytica than controls. Inflamed areas more often grew pathogenic organisms compared to adjacent normal mucosa. Careful assessment to exclude infection is required before starting immunosuppression.
Keywords Inflammatory bowel disease, Microbiota, Multiplex PCR
110
Clinical profile and outcomes of Cytomegalovirus colitis in acute severe ulcerative colitis
Ashis Choudhury , Anoop John, Rajeeb Jaleel, Reuben Thomas Kurien, Sudipta Dhar Chowdhury, Amit Kumar Dutta, Ebby George Simon, A J Joseph
Correspondence – Anoop John - [email protected]
Department of Gastroenterology, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Introduction Cytomegalovirus (CMV) infection is common in ulcerative colitis and has been shown to be potentially harmful. This 12-year retrospective observational study aims to find o the prevalence, clinical profile and outcomes of CMV colitis in patients admitted with flare of ulcerative colitis.
Methods All patients admitted to Department of Gastroenterology, Christian Medical Collge, Vellore between 2010 and 2022 with a flare of ulcerative colitis were included. Data analysis was done with regards to their clinical presentation, diagnostic profile, treatment, and outcomes. CMV superinfection was diagnosed if any of the three tests were positive i. e. CMV PCR in colonic biopsy or blood and colonic histopathology.
Results Among 360 patients with acute flare of ulcerative colitis, 127 (35.2%) had confirmed CMV infection and in 188 (52.2%) CMV was ruled out. Forty-five (12.5%) patients were excluded due to incomplete evaluation. Eleven patients with histological evidence of CMV improved without any antiviral treatment. Twenty-seven (21.2%) patients were treated for CMV with antivirals. Among the patients treated, 16 were female (59.2%), mean age was 36.7 years (15-63), median duration of hospital stay was 19 days (4-56) and antivirals were initiated at median 8th day (2-26) of hospital stay. Patients were treated with ganciclovir and/or valganciclovir. Out of the 27 patients who were treated for CMV, 20 (74.07%) patients improved, 4 (14.8%) patients underwent subtotal colectomy, 2 (7.4%) patients discharged in a moribund state after failure of medical treatment and 1 (3.7%) patient died. 8 (29.6%) patients developed leukopenia/thrombocytopenia on treatment of which one required G-CSF treatment, one required withholding antivirals for a few days and remaining 6 were continued on the drug with careful monitoring.
Conclusion Medical antiviral therapy for CMV was usually well tolerated among ulcerative colitis patients; however, CMV superinfection was associated with poor outcomes.
Keywords CMV colitis, Superinfection, Ulcerative colitis
111
Relationship of colonic mucosa associated microbial profile and disease activity in patients of ulcerative colitis
Bigyan Maharjan 1 , Anurag Sachan 2 , Anuraag Jena 2 , Pallab Ray 3 , Neelam Taneja 3 , M R Shivaprakash 3 , Mini P Singh 4 , Devyani Sharma 5 , Anupam Kumar Singh 1 , Vishal Sharma 1 , Kaushal Kishor Prasad 1 , Arun Kumar Sharma 1 , Rakesh Sehgal 5 , Usha Dutta 2
Correspondence – Usha Dutta - [email protected]
Departments of 1Internal Medicine, 2Gastroenterology, 3Medical Microbiology, 4Virology, and 5Medical Parasitology, Level 4, F Block, Nehru Hospital, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh 160 012, India
Background and Aim Mucosa associated microbes are shown to drive the gut inflammation and their role in disease activity in ulcerative colitis (UC) is largely unknown. We planned to study fecal and mucosa associated microbial profile in these patients and compare with those in remission and controls.
Methods Prospective study was conducted at our university hospital (February 2021-June 2022). Patients underwent clinical evaluation, endoscopic assessment, and laboratory investigations after informed consent. Patients without any colonic inflammation undergoing colonscopy were enrolled as controls. Mucosal biopsies were taken from inflamed mucosa and adjacent non-inflammed areas for bacterial and fungal culture. Stool was evaluated for microscopy, culture, Multiplex PCR for diarrhogenic E. coli and PCR for Entamoebahistolytica.
Results The mean age and gender of the cases (n=78; 51 active disease and 27 in remission) and control (n=33) was similar. Mucosal bacterial culture in patients with severe UC more often grew organisms than controls (15/18 [83.3%] vs. 14/30 [46.7%]; p=0.01) and those with non-severe disease (15/18 [83.3%] vs. 30/52 [57.7%]; p=0.05). Inflammed mucosa more often grew pathogenic bacteria and fungi compared to adjacent normal looking mucosa (p= 0.039). Patient with UC had numerically higher stool PCR positivity for E. histolytica compared to controls (14/54 [25.9%] vs. 2/25 [8%]; p=0.065). Stool fungal culture positivity was numerically higher in those with active UC compared to controls (23/31 [74.3%] vs. 14/28 [50%]; p=0.055). Patients with severe UC more often grew pathogenic bacteria/fungi were PCR positive for E. histolytica compared to controls (20/22 [90.9%] vs. 23/33 [69.7%]; p=0.037). However, stool bacterial culture was similar between cases and control (p=0.97).
Conclusion Mucosa associated microbial profile in patients with UC more often showed presence of infection than controls. Inflammed segments of colon more often grew pathogenic bacteria and fungi compared to adjacent relatively normal looking mucosa.
Keywords Inflammatory bowel disease, Microbiota, Multiplex PCR
112
Ulcerative colitis-associated inflammation and fecal microbiota transplantation drive compositional alterations in the relatively conserved human colonic crypt-associated microbiota
Manasvini Markandey 1 , Aditya Bajaj 2 , Mahak Verma 2 , Preksha Gaur 3 , Shubi Virmani 2 , Mukesh Singh 2 , Prasenjit Das 2 , Chittur Srikanth 3 , Dhiraj Kumar 4 , Saurabh Kedia 2 , Vineet Ahuja 1
Correspondence – Vineet Ahuja - [email protected]
Departments of 1Gastroenterology, New Private Ward, 2All India Institute of Medical Sciences, Ansari Nagar East, New Delhi 110 029, India, 3Regional Centre for Biotechnology, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad Road, Faridabad 121 001, India, and 4Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110 067, India
Introduction Intestinal crypts form a pristine gut biogeographical niche, homing the intestinal stem cells and being the closest neighbours to underlying lamina propria. Initially believed to be sterile, the crypt lumen was recently shown to inhabit a conserved microbial population. However, identity of the crypt-associated microbiota (CAM) remains elusive. Present study is among the first to illustrate the CAM composition in health and its deviation during ulcerative colitis (UC), and the effect of fecal microbiota transplantation (FMT) on the structure of this community.
Methods Recto-sigmoidal biopsies from controls, and from patients with mild-moderate UC before and after FMT, (n=26) were subjected to methacarn-fixation, followed by paraffin-embedding, sectioning and laser-capture microdissection-assisted crypt isolation. DNA isolated from micro-dissected samples was subjected to 16S rRNA gene sequencing. The bacterial presence in colonic crypts was confirmed using fluorescence in-situ hybridization. Microbiome data analysis was carried out by using QIIME2 and R packages.
Results Colonic crypts were found to be sparsely inhabited by bacterial cells in both control and diseased tissue samples. 16S-amplicon sequencing revealed a unique bacterial community, distinct from MAM, with an over-representation of aerobic Actinobacteria (Cutibacterium, Rothia, Prausenella) and Proteobacteria (Sphingobium, Paracoccus, Skermanella) members. The community displays significant resilience to UC-associated inflammation and also to the microbiome restorative effects of FMT, except for minor alterations, as evident from the similar α and β-diversity indices and unperturbed core members across the control, disease and treatment groups. UC mediated addition of Prauserella and loss of Cutibacterium from CAM, while FMT resulted in addition of Sphingobium, Paracoccus, Kocuria and Cutibacterium, accompanied by loss of Lawsonella and Paracoccus.
Conclusions A gut bacterial community, enriched in aerobic bacteria, resides in the colonic crypts, and undergoes taxa-level alterations during UC and in response to FMT.
Keywords Crypt-associated microbiota, Fecal microbiota transplantation, Laser capture microdissection, Ulcerative colitis
113
Fecal microbiota transplantation in patients with mild to moderate ulcerative colitis is associated with early clinical response in a real-world setting
Vineet Ahuja , Shubi Virmani, Bhaskar Kante, Sudheer Kumar, Peeyush Kumar, Mukesh Singh, Govind K Makharia, Saurabh Kedia
Correspondence – Vineet Ahuja - [email protected]
Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029, India
Background Fecal microbial transplantation (FMT) is efficacious in patients with ulcerative colitis (UC). There is a large knowledge gap in the number of FMT sessions required for the response and timing of the response to FMT.
Methods In this open-label, single center (All India Institute of Medical Sciences, New Delhi, 2019-2022) study, patients with mild-moderate UC who were refractory to conventional therapy were subjected to FMT. Patients received up to 7 sessions of freshly prepared FMT once a week, administered colonoscopically. Clinical assessment using SCCAI (simple clinical colitis activity index) was done at each follow-up FMT session for 8 weeks. Clinical remission is defined as SCCAI ≤ 3 and response as the decrease in SCCAI scores by 3 points.
Results Forty-one patients of active UC (mean age 33.9±11.05 years, 61% males, the median duration of disease 48 months, 63.4% left side colitis, 36.6% pancolitis, median SCCAI at baseline 6) were included, of which 26 (63.4%) had a clinical response, and 23 (56%) had clinical remission at week 8. Twenty patients (48.8%) were early responders with the median time to achieve clinical response as early as 1 week. There was no significant difference in baseline demographic, clinical, endoscopic and laboratory features between responders and non-responders at week 1. There was a significant improvement in PRO (patient reported outcome) scores at week 1 correlating the early clinical response.
Conclusion Half of the patients with mild to moderate UC refractory to conventional therapy achieved clinical response on FMT as early as 1 week. Studies including a large number of patients are required to assess the predictors of early response including the microbiota characteristics.
Keywords Fecal microbiota transplantation, Ulcerative colitis
114
Long-term efficacy and safety of fecal microbiota transplantation in patients with mild to moderate ulcerative colitis
Vineet Ahuja , Shubi Virmani, David Mathew, Bhaskar Kante, Sudheer Kumar, Peeyush Kumar, Sandeep Mundhra, Mukesh Singh, Govind K Makharia, Saurabh Kedia
Correspondence – Vineet Ahuja - [email protected]
Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029, India
Background Studies on fecal microbiota transplantation (FMT) as induction therapy in patients with ulcerative colitis (UC) have shown success yet reports on long-term outcomes including efficacy and safety are lacking, which were evaluated in this study.
Methods In this retrospective analysis, patients with mild-moderate UC were administered weekly/twice weekly FMT (freshly prepared through colonoscopy) in addition to standard of care between July 2017-March 2020. Short-term response was assessed using clinical/endoscopic indices and long-term response was assessed in terms of steroid use, biological requirement, colectomy, or hospitalization. Primary outcome was long-term safety (multi-drug resistant infection (MDR), infection requiring hospitalization or development of any new medical condition) and efficacy (long-term composite relapse requiring biologicals/oral steroids/colectomy/hospitalization).
Results Twenty-six patients were included (mean age-33.42±9.47 years, males-50%, median SCCAI 7 [5-8] and UCEIS-5 [3-6]). Patients received median of 5 (2-7) FMT sessions. Fifty percent and 30.7% patients achieved clinical response and remission, and endoscopic response and remission were noted in 46.1% (n=12/26) and 26.9% (n=7/26) patients respectively at 8 weeks. Median follow-up duration after FMT was 42 (range - 27–57) months. Fourteen patients (53.8%) experienced composite long-term relapse at a median duration of 6 months (range:3 – 40). Among clinical responders, the proportion of patients free of long-term relapse at 6, 12, 24, 36 and 48 months were 92.3%, 76.9%, 69.3%, 80%, and 66.7% respectively. No patient developed MDR infection, infection requiring hospitalization or any new medical condition.
Conclusion No new safety signal was reported after a reasonably long follow-up period of FMT. However, <50% were free of long-term composite relapse requiring biologicals/oral steroids/colectomy/hospitalization.
Keywords Fecal microbiota transplantation, Ulcerative colitis
Liver
115
Real-world evaluation of response to conventional hepatitis B vaccination strategy in cirrhosis- A brief report
Mayank Jain
Correspondence - Mayank Jain - [email protected]
Department of Gastroenterology, Arihant Hospital and Research Centre, 297 Indrapuri, Near Bhanwarkuan, Indore 452 001, India
Introduction The response rates to hepatitis B vaccination in adult patients with cirrhosis range from 16% to 79% in different populations. The aim was to determine response rates to hepatitis B vaccination and its determinants in adult patients with cirrhosis of liver.
Methods Patient inclusion-Adult patients (>18 years) with cirrhosis of liver were screened for HBsAg, anti-HBc and anti-HBs. Those who were negative for all were advised vaccination. Patient exclusion- We excluded patients who were known HBsAg positive, on oral antiviral drugs, who did not complete the recommended vaccination schedule and those who were lost to follow-up. Vaccination strategy-for vaccine naïve patients, dose of 20 mcg intramuscular in deltoid region was administered at 0, 1 and 6 months. For those with prior history of vaccination but negative anti-HBs titres, dose of 40 mcg was used at 0, 1 and 6 months.
Definition of response-Patients with anti-HBs titres >10 IU/L were considered responders and those with titres <10 IU/L were labelled as non-responders.
Baseline demographic parameters, anthropometry, Model of end-stage liver disease (MELD) score and history of prior vaccination were compared between the two groups.
Statistical tests used were numbers, percentages, Chi-square test and Mann-Whitney U test. A p value of <0.05 was considered significant.
Results The study cohort included 164 patients- median age 43 (18-68) years and 67% males (110). On follow-up at 2 months after last dose of vaccination, 103 (62.8%) had anti-HBs titre >10 IU/L. Of these, 54 (52.4%) had titres >100 and 49 (47.6%) had titres ranging from 10-99. Non-responders were significantly older than responders (48 vs. 41 years, p 0.01).
Conclusion The response rate to hepatitis B vaccination in adult patients with cirrhosis of liver is 62.8%. Older patients are more likely to be non-responders.
Keywords Cirrhosis, Hepatitis, Infection, Prevention, Vaccination
116
Standard volume plasma exchange is safe and effective for patients with acute liver failure
Moiz MD Vora, Anand V Kulkarni, Nagaraja Rao Padaki, Kalyan Rakam, Pragati Naik, Baqar Ali Gora, Sameer Shaikh, Anand Gupta, Sowmya Iyenger, Mithun Sharma, Rajesh Gupta, Nageshwar Reddy
Correspondence – Moiz Vora - [email protected]
Department of Gastroenterology and Hepatology, Asian Institute of Gastroenterology, Mindspace Road, AIG Hospital, Hyderabad 500 032, India
Background Plasma exchange (PLEX) is an effective bridging therapy for patients with acute liver failure (ALF).There are no studies comparing the efficacy of standard volume (SV) vs. high volume (HV) PLEX. Therefore, we aimed to compare the safety and efficacy of SV with HV-PLEX.
Methods Patients with ALF who underwent PLEX were included in this retrospective study. The primary outcome was to compare the transplant-free survival among SV and HV-PLEX groups at 30-days. Secondary objectives were to compare the effect of SV and HV-PLEX on total bilirubin, INR, ammonia levels, SOFA and MELD Na scores, and to assess the adverse events related to PLEX.
Results A total of 17 patients underwent PLEX:SV-8 and HV-9. The mean age and severity scores were similar among both the groups. Most common cause of ALF was viral (50% in SV vs. 44.45% in HV) in each group. 50% in SV and 34% in HV group satisfied King’s College Criteria for liver transplantation (p=0.41). Each patient in both the groups underwent a median of 2 sessions of PLEX. There was a significant decrease in serum bilirubin levels and prothrombin time in both the groups post-PLEX. Post-PLEX, the change in total bilirubin, INR, ammonia, SOFA, and MELD Na score was comparable (Fig. A). Mortality at seven days was similar among both groups (SV-12.5% vs. 33.3% in HV; p=0.57). Mortality at day 30 was 25% in SV compared to 67% in the HV group (p=0.1). On Kaplan Meier analysis, transplant-free survival at day 30 was similar in both the groups (p=0.26) (Fig. B). Two patients in the HV group developed volume overload features and were managed conservatively compared to none in the single volume group.
Conclusions Standard volume plasma exchange has similar efficacy as high-volume plasma exchange on severity scores. Standard volume plasma exchange is safe and effective for patients with acute liver failure.
Keywords Acute liver failure, Effective, High volume and single volume plasma exchange
117
Prevalence of sarcopenia in patients with chronic liver disease and its correlation with Child-Turcotte-Pugh and model for end-stage liver disease scores
Nitin Bhople , Deepak Lahoti
Correspondence - Deepak Lahoti - [email protected]
Department of Gastroenterology, Max Super Speciality Hospital Patparganj, A-108, Indraprastha, Extn, Patparganj, Delhi 110 092, India
Introduction Sarcopenia is common problem in patients with chronic liver disease (CLD). There is scarcity of data in Indian population. To study prevalence and correlation of sarcopenia with model for end-stage liver disease (MELD) and Child-Turcotte-Pugh (CTP) score in Indian population. A total of 103 patients with CLD were enrolled over a period of 18 months.
Methods Sarcopenia was evaluated by Hand grip strength (HGS), Psoas muscle index (PMI) using CT scan, 4-meter walk test (4 MW - Gait speed) and the results were taken into consideration for calculation of probable, confirmed, severe sarcopenia respectively. Correlation of sarcopenia with various stages of CLD was based on CTP and MELD scores obtained. Statistical analysis was done using Statistical Package for the Social Sciences (SPSS) version 20.0 software using appropriate tests. For all statistical tests, p value less than 0.05 was taken to indicate a significant difference.
Results Study group comprised of 35% female and 65% male. Mean average PSOAS area was 704.44, mean PMI was 254.73, mean HGS was 25.78, mean 4 MW was 1.77 and mean MELD score was 18.03. Sarcopenia prevalence was 55.3% in CTP C, 31.6% in CTP B and 13.2% in CTP A. Significant worsening of sarcopenia was noted with higher scores of CTP class and MELD scores. We found the prevalence of sarcopenia based on HGS (probable) to be 36.89%, according to PMI (confirmed) to be 33.1%, 4 MW (severe) test to be 19.4%.
Conclusions Sarcopenia is very common in patient with CLD in Indian population. Its severity seems to be worsened with stage of liver disease.
Keywords CTP score, MELD score, Sarcopenia
118
Treatment of amebic liver abscess: Comparison of catheter drainage and single time percutaneous needle aspiration: Randomized controlled trial
Kapil Mohata, Sandeep Nijhawan
Correspondence – Sandeep Nijhawan - [email protected]
Department of Gastroenterology, Sawai Man Singh Medical College, New SMS Campus Road, Gangawal Park, Adarsh Nagar, Jaipur 302 004, India
Background and Aims Treatment of liver abscesses comprises combination of antibiotics and image guided percutaneous needle aspiration (PNA) or percutaneous catheter drainage (PCD). There is debate regarding choice of these interventions as first line of management. Aim was to compare results of ultrasound guided PCD with single time PNA to evaluate the clinical and radiological resolution.
Methods Fifty patients (42 males; 8 females, 18–65 years) who were diagnosed with amebic liver abscess (>6 cm in size) divided into two groups of 25 patients each, namely single time PNA group (Group A) and the PCD (Group B). Effectiveness of either treatment was measured in terms of duration of hospital stay, days to achieve clinical improvement, 50% reduction in abscess cavity size and total/near total resolution of abscess cavity. The patients were followed up every week for a month and every month for 6 months.
Results Single time PNA was effective in 16 (64%) of the 25 patients while PCD was therapeutic in 23 (92%), without any major complications. Patients in group B showed earlier clinical improvement then group A (7 days vs. 21 days), 50% reduction in volume of abscess cavity (7 days vs. 28 days) and total resolution of abscess cavity was found significantly earlier in group B then group A (35 days vs. 90 days). Average hospital stay in B and A group was (2.3 days and 3.8 days) respectively. Baseline TLC, LFT was comparable in both groups.
Conclusion PCD is better than single time PNA in treatment of larger liver abscesses.
Keywords Percutaneous needle aspiration, Percutaneous catheter drainage
119
To study the prevalence of spontaneous portosystemic shunts in decompensated cirrhosis patients and its relationship with cirrhosis related complications – A prospective study
Deepanshu Khanna, Rishabh Kothari, Premashish Kar
Correspondence – Premashish Kar - [email protected]
Department of Gastroenterology, Max Superspeciality Hospital, Vaishali, Gurgaon 122 001, India
Introduction Spontaneous portosystemic shunts (SPSS) are frequent in liver cirrhosis and their prevalence increases as liver function deteriorates, probably as a consequence of worsening portal hypertension, but without achieving an effective protection against cirrhosis complications. This study is done to detect the prevalence of portosystemic shunts in liver cirrhosis patients and analyze its prognostic role.
Method We conducted a prospective observational study where ninety-two patients with decompensated cirrhosis were evaluated based on history, physical examination, biochemical tests, and abdominal CT angiography findings. Follow-up was done after 6 months for development of cirrhosis-related complications.
Results Out of the 92 cirrhotic patients, 57.6% of patients had SPSS (L-SPSS + S-SPSS) detected by multi-detector computed tomography (MDCT) angiography. Overall, we found L-SPSS in 24 (26.1%) patient, S-SPSS in 29 (31.5%) patients and no shunt identified in 39 (42.4%) patients. Of all patients, splenorenal shunt 25 (27.2%) is the most frequent type followed by paraumbilical shunt (20.7%). Previous decompensating events including hepatic encephalopathy (HE), ascites, SBP and gastrointestinal bleed were experienced more frequently by the L-SPSS group followed by S-SPSS and W-SPSS group. Regarding follow-up, decompensating events episodes of HE developed more frequently in patients with L-SPSS 10 (41.7%) than patients with S-SPSS 7 (24.1%) followed by W-SPSS 5 (12.8%).
Conclusion In summary, all cirrhotic patients should be studied with radiological imaging in order to detect the presence of portosystemic shunt. In several cases, patients with large SPSS had a more impaired liver function and more frequent complications of portal hypertension so these patients would probably benefit from a closer surveillance and more intensive therapy. Moreover, the identification of SPSS became crucial in selected cases, in which the embolization of large SPSS may be associated with improved survival and liver function, as well as preventing the recurrence of HE or variceal bleeding.
Keywords Hepatic encephalopathy, Liver cirrhosis, Portal hypertension, Spontaneous portosystemic shunts, Varices
120
Acute Cytomegalovirus hepatitis in an immunocompetent adult in tertiary care center
Vinay V, M Juned Khan
Correspondence – Vinay V - [email protected]
Department of Medical Gastroenterology, GEM Hospital, 45, Pankaja Mills Road, Palaniappa Nagar, Sowripalayam Pirivu, Ramanathapuram 641 045, India
Objective Challenging differential diagnosis.
Introduction Acute Cytomegalovirus (CMV) virus has an incubation period of about 4 to 6 weeks. Symptoms of CMV infection vary and depend on factors including the age and immune status of the patient. It usually presents as asymptomatic infection in immuno-competent individuals whereas severe disease is usually seen in immunocompromised patients.
Case Report Fifty-three-year-old male patient known case of chronic liver disease. Patient is known alcoholic consumes alcohol occasionally. Presented with history of yellowish discoloration, itching, swelling of abdomen since 3 weeks. History of alternative medication was present. Treatment history was 2 cycles of plasma exchange. Patient was referred to our hospital for liver transplant. Routine etiology was normal, non hepatotrophic viruses work was sent. CMV IgM and IgG was positive. Trans jugular liver biopsy was done which showed inclusion bodies.
Results The patient was treated with valganciclovir that resulted in rapid improvement in clinical status as well as normalization of the liver enzymes. Patient is being followed up on monthly basis now liver function test is normalized. Patient has be delisted form transplant list.
Conclusion This case report presents a rare case; of immunocompetent; male with acute CMV hepatitis who responded favorably to antiviral therapy.
Keywords Cytomegalovirus hepatitis, Immunocompetent, Liver transplant
121
Severe persistent steroid refractory cholestatic viral hepatitis A: Mycophenolate sodium to rescue. A case series
Pathik Parikh
Correspondence - Pathik Parikh - [email protected]
Department of Hepatology and Liver Transplant, Zydus Hospitals, Zydus Hospitals Road, Sarkhej - Gandhinagar Highway, Sola, Ahmedabad 380 054, India
Introduction Hepatitis A is usually a self-limiting illness. However, rarely it leads to persistent jaundice with pruritus. None of the pharmacological agents have been proven to be useful. This leads to significant deterioration in quality of life of the patients. As treating physicians, we need to think out of the box to alleviate their symptoms. We report here a case series of 5 patients who responded to mycophenolate sodium
Case Series Five patients with acute hepatitis A have been included. The median age was 45 years and 3/5 were males. The mean duration of jaundice was 58 days. All patients had jaundice and severe pruritus. The mean bilirubin was 35 mg/dL. The presentation parameters are described in Table 1. The alternate etiological workup, liver ultrasound and liver biopsies were carried out in all. All patients were treated with symptomatic treatment, antihistaminic, cholestyramine, ondansetron, sertraline, ursodeoxycholic acid and multi vitamins. All patients received steroids for minimum 2 weeks before presentation. Two patients underwent therapeutic plasma exchange for 3 cycles without prolonged benefit. All patients were started on Mycophenolate sodium 720 mg per day in two divided doses. All 5 patients showed consistent improvement in symptoms and biochemistry with normalization of liver tests in median 5 weeks duration. None of the patients developed any drug related adverse effects.
Discussion The mechanisms of liver injury in hepatitis A remain incompletely understood. While virus-specific CD8+T cells have long been considered a major cause of HAV-induced liver injury. MMF inhibits de novo purine synthesis, which is indispensable for the proliferation of lymphocytes, induces the apoptosis of activated T cells, suppresses the production of pro-inflammatory cytokines, and augments regulatory T cells thereby halting the ongoing hepatocyte damage. Further studies are warranted to validate our findings.
Keywords Jaundice, MMF, Pruritus, Viral hepatitis
122
A case report of abdominal wall hematoma in a case of decompensated chronic liver disease with ascites and overt gastrointestinal bleeding post diagnostic paracentesis
Suraj Kumar, Bhashyakarla Ramesh Kumar, Malladi Uma Devi, Sahitya Reddy, Venkannagari Vikas Reddy, Zeeshan Ali Mohammed, Rahul Vijay Vargiya
Correspondence - Suraj Kumar - [email protected]
Department of Medical Gastroenterology, Osmania General Hospital, 15-5-104, Begum Bazar, Afzal Gunj, Hyderabad 500 012, India
Introduction Ascites complicating cirrhosis is associated with poor prognosis. Hemorrhagic complications are rare events after paracentesis despite coagulopathy. Performing the procedure under ultrasound guidance can decrease the risk of such complications.
Methods A 60-year-old female with hypertension presented with jaundice since two-months, abdominal distension and swelling of both lower limbs for 10 days, melena for 3 days, decline in urine output for 3 days. No history of alcohol consumption, known liver disease, transfusions, tattooing, family history of liver disease in the past.
Results Hemoglobin 6 g/dL, WBC 6500/mm3, platelet 2.8 L/mm3, serum bilirubin 10.58 mg/dL, direct bilirubin 7 mg/dL, AST 446 U/L, ALT 138 U/L, ALP 378 U/L, albumin 2 g/dL, BUN 9 mg/dL, serum creatinine 1 mg/dL, serum Na 130 meq/L, serum K 3.7 meq/L, serum chloride 102 mEq/L, HIV, HBsAg, HCV - non reactive; prothrombin time 21 sec, ascitic fluid analysis – clear pale yellow colored fluid, 26 WBC/mm3, No RBCs, SAAG 1.66, protein – 0.84 g/dL, ADA – 18 U/L, culture sterile. USG showed cirrhosis of liver with gross ascites; endoscopy showed low-grade esophageal varices, mild portal hypertensive gastropathy; ECG normal, 2D Echo showed concentric LVH. Her CTP - 12, MELD-Na score - 29 points. 8 hours post paracentesis patient had pain and swelling over the site of paracentesis worsening over next 5 hours for which patient underwent non contrast CT scan of abdomen revealed hyperdense collection of 25 cm*5.5 cm*5.4 cm in the intermuscular plane in left anterior abdominal wall extending from left lumbar to left iliac fossa region - abdominal wall hematoma with gross ascites and cirrhosis of liver. Despite best efforts patient succumbed within next 24 hours.
Conclusions Hemorrhagic complications despite being a rare event need to be diagnosed and treated early because it can be rapidly fatal which can be avoided by USG guided procedure. This case also brings up the question whether patients undergoing paracentesis need to undergo tests like thromboelastography for better risk stratification.
Keywords Abdominal paracentesis, Abdominal wall hematoma, Ascites
123
Seroprevalence of hepatitis B virus among pregnant women in India: A systematic review and meta-analysis
Suprabhat Giri 1 , Shradhanjali Sahoo1, Sumaswi Angadi1, Shivaraj Afzalpurkar2, Sridhar Sundaram3, Sukanya Bhrugumalla1
Correspondence - Suprabhat Giri - [email protected]
1Department of Medical Gastroenterology, Nizam's Institute of Medical Sciences, Punjagutta Road, Punjagutta Market, Punjagutta, Hyderabad 500 082, India 2Apollo Multispecialty Hospital, 58, Canal Circular Road, Kadapara, Phool Bagan, Kankurgachi, Kolkata 700 054, India and 3Tata Memorial Hospital, Parel East, Parel, Mumbai 400 012, India
Objectives Hepatitis B virus (HBV) infection during pregnancy is associated with perinatal transmission contributing to the pool of HBV infection in the population. There is a wide variation in the reported data on the seroprevalence of hepatitis B virus in pregnant patients from various parts of India. Hence, a systematic review and meta-analysis was conducted to determine the pooled seroprevalence of HBV and its associated demographic factors.
Methods A comprehensive literature search of Medline, Scopus, and Google Scholar was conducted from January 2000 till April 2022 for studies evaluating the prevalence of HBV in pregnant patients from India.
Results A total of 44 studies with data on 272,595 patients were included in the meta-analysis. The pooled prevalence of hepatitis B surface antigen (HBsAg) in pregnant women was 1.6% (95% confidence interval [CI], 1.4 – 1.8). Among patients with HBsAg positivity, the pooled prevalence of hepatitis B e antigen was 26.0% (95% CI 17.4 – 34.7). There was no significant difference in the odds of HBV seroprevalence based on the age (< 25 years vs. > 25 years) (Odds ratio [OR] 1.07, 95% CI 0.74 – 1.55), parity (primipara vs. multipara) (OR 1.09, 95% CI 0.70 – 1.70) or area of residence (urban vs. rural) (OR 0.88, 95% CI 0.56 – 1.39). However, the odds of HBV seroprevalence in those with no or primary education was higher than in those with secondary level education or higher (OR 2.29, 95% CI 1.24 – 4.23). Prior history of risk factors was present in 13.5% to 22.7% of patients indicating a vertical mode of acquisition.
Conclusion There is a low endemicity of HBV among pregnant women in India. Risk factors are seen in less than 25% of the cases, indicating vertical transmission as the predominant mode of acquisition, which can be reduced by improving vaccination coverage.
Keywords Epidemiology, Hepatitis B, Meta-analysis, Pregnancy
124
Biopsy proven liver injury induced by DPP4 inhibitors: Report of two cases
Naveen Make, B S Ramakrishna, Babu Vinish, Rohan Yewale, Kayalvizhi Jayaraman, Parag Papalkar
Correspondence - Naveen Make - [email protected]
Department of Medical Gastroenterology, SIMS Institute for Medical Sciences, SRM Institutes for Medical Sciences, Metro No.1, Jawaharlal Nehru Road, Landmark, next to Vadapalani, Chennai 600 026, India
Diabetes mellitus is a very common disease and dipeptidyl-peptidase-4 (DPP-4) inhibitors are one of the commonly used oral antihyperglycemic agents for diabetes. DPP-4 inhibitors blocks the degradation of incretin and enhances incretin levels, which stimulate insulin secretion and decreases glucagon production. They are effective in lowering glycosylated hemoglobin (Hb A1c) and improves fasting and postprandial glucose levels DPP-4 inhibitors have a favorable safety profile in clinical trials. Further investigation is needed as rare side effects arise in post-marketing surveillance. Some important but rare side effects of DPP-4 inhibitors are a potential risk for pancreatitis and thyroid cancer. In clinical practice, a drug-induced liver injury is not a common side effect in patients taking DPP-4 inhibitors. We report two cases of drug-induced liver injury caused by sitagliptin and teneligliptin. Our patients developed hepatocellular and cholestatic type of injury. The diagnosis was based upon the temporal relationship of drugs and altered liver enzymes, subsequent improvement of liver enzymes upon discontinuation of the medication and liver biopsy findings suggestive of drug induced liver injury. Clinicians must be aware of the rare but potential consequence of liver injury from DPP4 inhibitors
Keywords Diabetes mellitus, Dipeptidyl peptidase-4 inhibitors, Drug induced liver injury
125
A case of severe alcoholic hepatitis with leukemoid reaction
Vinoth Sermadurai, Kannan Mariappan, Ramani Ratinavel, Vijai Shankar Chidambara Manivasagam, P B Sriram
Correspondence – Vijai Shankar Chidambara - [email protected]
Department of Medical Gastroenterology, Madurai Medical College, Panagal Road, Alwarpuram, Madurai 625 020, India
Alcoholic hepatitis is a pro-inflammatory liver disease associated with short-term morbidity and mortality. The pathophysiology behind alcoholic hepatitis is attributed to oxidative stress, impairment of fatty acid oxidation, and generation of reactive oxygen species. Hematologic abnormalities are rather common in moderate-to-severe alcoholic hepatitis, with moderate leukocytosis (<20,000/uL) a frequent finding in these cases. Leukamoid reaction can occur in patients with severe alcoholic hepatitis and was poor prognositc sign. A 35-year-old male admitted with complaints of jaundice for the past 2 months not associated with prodromes and cholestatic features with moderate ascites, no history of hematemesis and malena, no overt hepatic encephalopathy. On evaluation total count was 50000 cells/mm3, total bilirubin 34.5 mg/dL, direct 20.2 gmg/dL:, AST 80 U/L, ALT 32 U/L, PTINR 2.5, urea 46 mg/dL, serum creatinine 1.2 mg/dL, blood culture, urine culture were negative, CT chest was normal, CT abdomen showed fatty liver, OGD was normal, serum procalcitonin was 0.9. Patient was treated with IV antibiotics and total count was persistently high, Bone marrow was normocellular marrow and no blast or atypical cells. Patient was started on Tab. Prednisolone 40 mg/day and day 7 total bilirubin 30.1 and total count was reduced to 27300 cells/mm3 at day 7. Patient was discharged and on follow-up. Patients with severe alcoholic hepatitis can present with high leukocyte count and after ruling out sepsis, patient can be started on steroids.
Keywords Leukemoid reaction, Severe alcoholic hepatitis, Steroids
126
Prevalence of sarcopenia and its correlation with clinical outcomes in chronic liver disease patients
Padma Lochan Prusty, Shivaram Prasad Singh, Sarthak Swarup, Prajna Anirvan
Correspondence - Padma Prusty - [email protected]
Department of Gastroenterology, Srirama Chandra Bhanja Medical College, Behera Colony, Mangalabag, Cuttack 753 001, India
Background and Objectives Sarcopenia is common in patients with chronic liver disease (CLD) and is characterized by decline in muscle mass, muscle strength, and physical performance and often leads to poor clinical outcomes. We aimed to determine the prevalence of sarcopenia and assess the clinical impact of sarcopenia on CLD patients.
Methods One hundred and one consecutive CLD patients were assessed clinically (hand grip strength, chair stand test, gait speed test) and radiologically (CT scan of abdomen l3 smi, ultrasound of both thigh muscles using mean rectus muscle area) for evaluation of sarcopenia.
Results The prevalence of sarcopenia was found to be 72.3%. Majority of the patients were males (88.1%) with a mean age of 47.91; 9.69 years. There was no difference in the prevalence of sarcopenia with regard to etiology of CLD (alcohol related vs viral etiology). The proportion of p atients with sarcopenia was significantly higher in patients with CTP-B and C cirrhosis (p value;0.005). Serum albumin levels were significantly lower in patients with sarcopenia. CT l3 smi score and mean rectus muscle area were significantly lower in patients with sarcopenia (p value;0.005). CT l3 smi score of 46.65 cm/m2 and mean rectus muscle area of 2.36 cm2 had a sensitivity and specificity of 93% and 94% and 82% and 81% respectively in diagnosing sarcopenia. Aurocs of CT l3 smi and mean rectus muscle area were 0.95 and 0.85 respectively. Mortality and number of hospitalizations were significantly higher in patients with confirmed and severe sarcopenia (p value;0.005). However, on multivariate analysis only male sex and CTP score were independent predictors of mortality.
Conclusion Presence of sarcopenia is significantly associated with greater number of hospitalizations and mortality. CT l3 smi and mean rectus muscle area on USG can be used to assess sarcopenia with considerable accuracy.
Keywords l3 smi, Rectus muscle area, Sarcopenia
127
Platelet-albumin-bilirubin scoring system in predicting outcome of acute variceal bleeding in patients with cirrhosis
Anupama Swarna, Murali R, Aravind A, Caroline Selvi K, Premkumar K, Chezhian A, Muthu Kumaran, Shubha I
Correspondence - Anupama Swarna - [email protected]
Department of Medical Gastroenterology, Madras Medical College, Poonamallee High Road, Park Town, Chennai 600 003, India
Introduction Acute variceal bleeding is a frequent, ominous complication of liver cirrhosis and portal hypertension and is responsible for high morbidity and mortality. There are several scoring systems to predict outcome in variceal bleeds, each with its own limitations. This report, however, evaluates the predictive power of rebleeding of the Platelets-Albumin-Bilirubin (PALBI) score in patients with cirrhosis presenting with acute variceal bleeding.
Methods All the patients who attended to our hospital with acute variceal bleed from 2021-2022 were included in the study. Subjects underwent upper GI endoscopy. Patients were followed for 90 d after the control of acute bleeding for occurrence of rebleeding. PALBI scores were calculated from admission labs, and correlated with control of bleeding, rebleeding. Subjects were divided into PALBI 1, 2 and 3 groups and assessed for 90 d rebleeding rates. Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) scores were calculated for the patients to grade severity of the disease and to correlate with PALBI.
Results Of the 130 patients, mean age was 52.6 years; 80 were male (61.5%), 62 CTP-A (47.7%), 53 CTP-B (40.8%), 15 CTP-C (11.5%); 63 PALBI-1 (48.5%), 23 PALBI-2 (17.7%), and 44 PALBI-3 (33.8%). 1 patient died during hospitalization. The AUROC for predicting rebleeding in acute variceal bleeding was 0.732, 0.710, and 0.818 for CTP, MELD and PALBI scores, respectively.
Conclusion PALBI score on admission is a good prognostic indicator for patients with acute variceal bleeding and predicts rebleeding.
Keywords Acute variceal bleeding, Platelet-albumin-bilirubin score, Rebleeding
128
Platelet indices and neutrophil lymphocyte ratio as a non-invasive diagnostic marker for spontaneous bacterial peritonitis in cirrhotic patients in a tertiary care centre in western Tamil Nadu
Baraneedaran Selvarajan, Arulselvan V, Ravishankar T, Senthil Kumar P, Senthil Vadivu V
Correspondence - Baraneedaran Selvarajan - [email protected]
Department of Medical Gastroenterology, Coimbatore Medical College and Hospital, 2/328 Kamaraj Nagarpethathalapalli Post, Krishnagiri 635 002, India
Introduction Liver cirrhosis is the clinical end stage of different entities of chronic liver disease. Ascites are the most common complication, and around 60% of patients with compensated cirrhosis develop ascites within 10 years of disease onset. Spontaneous bacterial peritonitis (SBP) is a major cause of morbidity and mortality in cirrhotic patients with ascites and the prevalence is about 10$ to 30%. Platelets are considered an important source of pro-thrombotic agents associated with inflammatory markers. The other biomarkers consists of the neutrophil-to-lymphocyte ratio (NLR), which reflects systemic inflammation. The aim of this study was to investigate whether platelet size alterations measured by mean platelet volume (MPV) and platelet distribution width (PDW) along with neutrophil lymphocyte ratio would be useful in predicting SBP.
Methods In this prospective observational study a total of 100 patients with ascites due to cirrhosis were enrolled. The diagnosis of AFI was made on the basis of the presence of at least 250 cells/mL polymorphonuclear leukocyte in the ascitic fluid, with or without positive ascitic fluid culture in the absence of hemorrhagic ascites and secondary peritonitis.
Results Thirty patients out of 100 patients had SBP, and the incidence was high in CHILD C. A statistically significant increase was observed in the SBP group with respect to MPV, PDW and NLR when compared to cirrhotic patients without SBP (p < 0.01).
Conclusion Our study shows that MPV, PDW and NLR is increased in cirrhotic patients with SBP. Platelet indices and NLR measurement can considered to be an accurate diagnostic test in predicting AFI, possibly due to an ongoing systemic inflammatory response.
Keywords Mean platelet volume, Neutrophil lymphocyte ratio, Platelet distribution width
129
A rare case of hepatomegaly and constipation
Jithin John, Avisek Chakravorty, Devika Madhu, Ravindra Pal, Shivabrata Dhal Mohapatra, Aditya Verma, Jacob Raja, Gayathri S, Prasanth T S, Shanid A, Krishnadas Devadas
Correspondence - Jithin John - [email protected]
Department of Medical Gastroenterology, Government Medical College, Ulloor - Akkulam Road, Chalakkuzhi, Thiruvananthapuram 695 011, India
Background Intrahepatic cholestasis can be caused by varied causes. Usually, the first symptom is jaundice which is followed by pruritis. Here we have an interesting case of hepatomegaly with intrahepatic cholestasis, whose symptoms started with constipation.
Case Scenario Fifty-two-year-old, female, with no prior comorbidities, developed constipation, 6 months back and was treated with complementary and alternative medicines (CAMs) for the same with no significant benefits. She also had fatiguability, gradual unintentional weight loss, and a dragging right hypochondrial pain over the last 4 months. Two weeks back, she developed jaundice followed by pruritis and she was referred to us with suspicion of CAMs induced hepatitis. Physical examination revealed icterus, hepatosplenomegaly, and shiny nails. Her baseline investigation showed cholestatic jaundice and an ultrasound abdomen showed hepatosplenomegaly with no extrahepatic obstruction. Etiological evaluations for hepatitis were all negative except for evidence of autoimmune hepatitis (prebiopsy score of 6/6). She was incidentally detected to have hypercalcemia with a serum calcium of 15.1 mg/dL. She was evaluated for the same and found to have suppressed iPTH and elevated serum ACE level. CECT chest and abdomen were done, which showed multiple hypodense hypoenhancing lesions suggestive of granuloma in the liver and spleen. There was also intraabdominal and mediastinal lymphadenopathy. Liver biopsy revealed multiple noncaseating granulomas and periportal fibrosis. All other causes of granulomatous hepatitis were ruled out. A diagnosis of multisystemic sarcoidosis with predominant hepatosplenic involvement was made. She was started on oral prednisolone. With treatment, her calcium normalized and hence constipation resolved. Her LFT also improved over 3 months of treatment.
Conclusions Sarcoidosis can present with constipation secondary to hypercalcemia. Clinicians should be aware of hepatosplenic sarcoidosis as a potential cause of hepatosplenomegaly intrahepatic cholestasis in adults.
Keywords Constipation, Hepatosplenomegaly, Hypercalcemia, Intrahepatic cholestasis, Sarcoidosis
130
A study of portal vein thrombosis: Clinical presentation, management and treatment outcomes in a tertiary care centre
Aakash Shah, Nitesh Bassi, Ishan Mittal, Shishirendu Parihar, V K Dixit, D P Yadav, S K Shukla, Anurag Tiwari, Vinod Kumar Yadav
Correspondence - Aakash Shah - [email protected]
Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221 005, India
Background Portal vein thrombosis (PVT) is defined by complete or partial obstruction of blood flow in the portal vein, due to the presence of a thrombus in the lumen. In general population the lifetime risk of getting PVT is reported to be 1%, in cirrhotics it ranges from 4% to 15%. Frequency of diagnosis of PVT is increasing.
Objective To describe clinical presentation and assess outcomes of PVT.
Methods Fifty-three patients were included from 2021-22 from Department of Gastroenterology. All the details were extracted from the patient records and follow-up was done in this retrospective and prospective observational study.
Results Out of 53 patients, Male: Female ratio was 2:1 mean age being 37 ±6.5 years. Cirrhosis (40%) was the most common etiology, followed by inflammatory states (14%), prothombotic states (11%), infection (10%), carcinoma (6%) (HCC, Ca. GB, papillary Ca of thyroid, adenocarcinoma colon), and surgical intervention (3%). No etiology was identified in 8% of the patients. The most common complaints were abdominal pain (69%), GI bleed (47%), ascites (21%), fever (14%) and hepatic encephalopathy (5%). 17% patients had acute PVT, 83% had chronic PVT. 9.43% patients had coagulation disorders. Most common site was PV (49%), followed by SMV (17%), SV (17%). 64% patients had varices on endoscopy. 83% patients showed PVT on colour doppler ultrasound, and rest were diagnosed with CT abdomen. 51% patients were anticoagulated, 49% patients required beta blockers. Endoscopic interventions were carried out in 37.7% patients. Resolution of varices was noted in 37.7% patients and PV recanalization noted in 24.5% patients with a mean duration of 7±2 months. 19% patients had mortality due to causes like MODS (51%), GI bleed (34%), septic shock (15%).
Conclusion Majority of patients had local or systematic risk factors for PVT. Anticoagulation led to recanalization in more patients and varies regressed with combination of endoscopic and pharmacologic therapies.
Keywords Anticoagulation, Chronic liver disease, Portal vein thrombosis
131
Budd-Chiari syndrome: Clinical, etiological and radiological profile of 35 patients in a tertiary care center
Nitesh Bassi, Aakash Shah, Ishan Mittal, Shishirendu Parihar, V K Dixit, S K Shukla, D P Yadav, Anurag Tiwari, Vinod Kumar Yadav
Correspondence – Nitesh Bassi - [email protected]
Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221 005, India
Background Budd-Chiari syndrome (BCS) consists of disorders causing hepatic venous outflow obstruction (HVOTO) either at the level of the hepatic veins (HV) or at the inferior vena cava (IVC).
Objective To study clinical, etiological and radiological profile of BCS.
Methodology Thirty-five consecutive patients of BCS admitted to Department of Gastroenterology, IMS, BHU between July 2021 and July 2022 were evaluated. The diagnosis was made on the basis of Doppler ultrasonography and CT/MR venography.
Results Twenty-three (65.7%) patients presented with chronic disease, 9 (25.7%) with sub-acute disease and 3 (8.5%) with acute disease. The common presentation findings were: ascites 30 (85%), pedal edema 28 (80%), abdominal pain 25 (71%), dilated veins on abdomen and flanks 22 (63%), tender hepatomegaly 18 (52%) and jaundice in 14 (40%) cases. Twenty-eight (80%) cases were diagnosed with Doppler ultrasonography and 7 (20%) with CT/MR venography. The obstruction was seen in isolated HV in 19 (54.2%), isolated IVC in 5 (14%), and both in 11 (32%) patients. Etiologically 3 (8.5%) cases had idiopathic membranous obstruction in IVC, 2 (5.7%) had lupus anticoagulant positive, malignancy related in 2 (5.7%), protein S deficiency in 2 (5.7%), antithrombin III deficiency in 2 (5.7%) cases and 1 (3.3%) case each of: pregnancy related, chronic myeloid leukemia, hyperhomocystinemia, acute severe ulcerative colitis and 1 patient with celiac disease developed BCS with dysplastic nodules. Nineteen cases (54.2%) were idiopathic. Patients were started on anticoagulants and subjected to percutaneous recanalization, TIPSS or liver transplantation accordingly.
Conclusion BCS usually presents with abdominal distention, pedal edema, tender hepatomegaly, dilated veins and jaundice. Chronic presentation is more frequent. Most commonly obstruction was seen in isolated HV. Idiopathic and inherited/acquired hypercoaguble states were the most common etiology. Majority of patients were detected on Doppler ultrasonography.
Keywords Budd-Chiari syndrome, Hypercoaguable state, IVC membrane, TIPSS
132
Impact of sarcopenia on health-related quality of life impairment in cirrhotic patients in a tertiary care centre in western Tamil Nadu
Ben Xavier, Senthil Vadivu
Correspondence – Senthil Vadivu - [email protected]
Department of Medical Gastroenterology, Coimbatore Medical College, Avinashi Road, Peelamedu, Civil Aerodrome Post, Coimbatore 641 018, India
Introduction Health-related quality of life (HRQOL) is becoming a key component in the evaluation of chronic diseases. Quality of life is variably impaired in cirrhosis, even in uncomplicated patients. Development of sarcopenia is closely related to declined liver function, which also impairs HRQOL. Its prevalence in patients with cirrhosis is estimated to be 40% to 70%. The prevalence of sarcopenia was marginally significantly higher in patients with CTP B or C than in those with CTP A. Chronic liver disease questionnaire (CLDQ) is a frequently used, self-administered, disease specific instrument for measuring the QOL in patients with CLD, regardless of its cause and severity. A study conducted in Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry had translated CLDQ into Tamil (CLDQ-T) and showed good performance characteristics in assessing QOL in Tamil-speaking patients with CLD. The aim of this study is to study the impact of sarcopenia on HRQOL impairment in cirrhotic patients.
Methods A total of 115 cirrhotic patients (mean age, 46 years; range: 35–75 years; 96 male [83.47%]) were analyzed. The CLDQ-T was used to assess HRQOL. The Chi-square and Pearson’s coefficient were used for analysing correlation between sarcopenia and other variables
Results Sixty-five (56.52%) patients had sarcopenia. Sarcopenia was present in 19.1% in CHILD A, 44.8% in CHILD B and 89.3 % in CHILD C cirrhotics. Sarcopenia had a moderate negative correlation with HRQOL as assessed by CLDQ-T particularly in relation with systemic symptoms and activity.
Conclusion The patients with sarcopenia were found to have lower overall HRQOL as per CLDQ-T.
Keywords CLDQ-T, HRQOL, Sarcopenia
133
Evaluating the clinical, laboratory, and management profile in patients of liver abscess from eastern Uttar Pradesh
Shishirendu Parihar , Ishan Mittal, Aakash Shah, Nitesh Bassi, V K Dixit, S K Shukla, D P Yadav, Anurag Tiwari, Vinod Yadav
Correspondence – Shishirendu Parihar - [email protected]
Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221 005, India
Background Since hippocrates, liver abscess has been recognized. Even today, it is a problem with mortality and morbidity rates. A minimally invasive approach to treating this condition has been made possible by recent advances in diagnostic and interventional radiology.
Objective To study patients with liver abscesses for their clinical characteristics, microbial etiologies, and treatment outcomes.
Methods A cross-sectional study was conducted from April 2021 to June 2022 on 100 consecutive liver abscess patients from OPD, Emergency, and IPD at the Department of Gastroenterology, Institute of Medical Sciences, and Banaras Hindu University. History, examination, and laboratory investigations were recorded. Ultrasound-guided aspiration was done, and samples were investigated.
Results The mean age of patients was 42.24±8.24 years. The majority of them were having chronic alcohol abuse (78%). Pain abdomen (100%), fever (95%), anorexia (92%) and nausea/vomiting (56%) were the most common symptoms. Hepatomegaly (90%), pallor (40%) and pleural effusion (32%) were the most common signs. The abscesses were predominantly in the right lobe (73%) and solitary (63%). The abscess etiologies were 65% amebic and 20% pyogenic, 9% were having mixed etiology whereas 6% were culture negative. Percutaneous needle aspiration was done in 64%, catheter drainage in 32%, and surgical intervention for rupture in 4% of patients. Mortality was 3%, all reported in the surgical group. Solitary abscesses were amebic, whereas multiple abscesses were pyogenic (p<0.001).
Conclusions The commonest presentation was a young male alcoholic having a right lobe solitary amebic liver abscess. Most patients of liver abscess can be managed with drugs and minimal radiological intervention.
Keywords Alcohol, Gastroenterology, Liver abscess, Microbial etiologies
134
Diagnostic performance of FIB-4, FIB-5 and APRI in the assessment of advanced fibrosis in non-alcoholic fatty liver disease
Khushboo Madaan, Monika Jain, Gurwant Singh Lamba
Correspondence - Khushboo Madaan - [email protected]
Department of Gastroenterology, Sri Action Balaji Medical Institute, A 4 Block, A 6 Block, Paschim Vihar, New Delhi 110 063, India
Introduction Non-alcoholic fatty liver disease (NAFLD) is one of the most common cause of liver disease worldwide which contributes to the morbidity and mortality of liver disease. Liver stiffness measurement (LSM) is an important prognostic marker and measured most conveniently by transient elastography. However, availability of transient elastography is the limiting factor. Biochemical and clinical scores are indirect methods of measuring liver fibrosis. In this study we evaluate biochemical scores FIB-4, FIB-5 and APRI in distinguishing low grade from advanced fibrosis in NAFLD.
Methods Present study consists of 206 NAFLD patients presenting from September 2020 to May 2022 to Sri Action Balaji Medical Institute. LSM was done using FibroScanâ and clinical and biochemical parameters were recorded. Data were categorised into low and advanced fibrosis depending on LSM. FIB-4, FIB-5 and APRI scores were calculated and their predictive value for advanced fibrosis determined and compared.
Results Our study comprised of 75.24% male patients and 24.76% female patients. Liver stiffness values across all the patients had a median value of 16.15 (IQR 6.33 – 46.23). 37.38% of the patients had low grade fibrosis (≤ 9 kPa) and 62.62% patients high grade (>9 kPa) based on (LSM). Comorbidities of the patients were comparable in either group but liver disease related complications were higher in the advanced fibrosis group. All three scores excellently distinguished low grade from advanced fibrosis. AUC of FIB-4, FIB-5 and APRI were, 0.91, 0.95 and 0.89 respectively, sensitivity 76.74%, 88.31% and 89.14% respectively and specificity 93.51%, 90.70% and 83.12% respectively. The cut-off values of FIB-4, FIB-5 and APRI were 1.16, -8.36 and 1.03 respectively.
Conclusion Non-invasive scoring systems can be used as surrogates for liver stiffness in resource poor centres. FIB-5 could be a optimal trade off considering its high AUC and optimum sensitivity and specificity.
Non-alcoholic fatty liver disease Non-alcoholic fatty liver disease.
Keywords APRI, FIB-4, FIB-5, Liver stiffness measurement, Transient elastography
135
Hepatitis B virus serological screening in an outpatient clinic should include HBsAg, anti-HBs (titre) and anti-HBc (Total): A single centre experience
Jayanthi Venkataramanan
Correspondence - Jayanthi Venkataramanan - [email protected]
Department of Hepatology, Sri Ramachandra Institute of Higher Education and Research, 1, Mount Poonamallee Road, Sri Ramachandra Nagar, Chennai 600 116, India
Background HBsAg screening remains the gold standard for screening hepatitis B virus infection (HBV) in the outpatient clinic.
Aim To determine the profile of HBV infection in an outpatient clinic using HBsAg, anti-HBs (titre) and anti-HBc (total) serological markers.
Methodology Patients attending the outpatient clinic between January 2019 and June 2022 with symptoms pertaining to liver disease were included. Patients already diagnosed as chronic HBV infection/hepatitis irrespective of the “e” antigen status and hepatitis B viral load were also included. Patients were categorized as incidental HBV infection (HBsAg positive; anti -HBc [total] positive), past infection (anti-HBc [total]; anti-HBs positive) and occult HBV infection (HBsAg; anti-HBs negative). To understand the vaccination status, patients were categorized as unprotected if all the 3 markers were negative and as vaccination protected if anti-HBs alone was positive with a titre > 10 IU/L. Patients who did not have details of all the 3 markers were excluded.
Results A total of 931 patients had screening for HBV infection. Table summarises the observation of the viral screening strategy) (No. [%])
Conclusions Apart from managing HBsAg patients, screening for past and occult HBV infection (12%) will support screening other family members. Also, one can enforce the need for regular 6 monthly surveillance for hepatocellular carcinoma. Vaccination protocol can also be imposed.
Keywords Hepatitis B virus, Past and occult HBV, Serology
136
Clinical implications and risk factor analysis of hepatitis B reactivation in patients receiving chemotherapeutic agents
Kondala Yedupati, Vijaishankar Chidambaramanivasagam
Correspondence – Vijaishankar Chidambaramanivasagam - [email protected]
Department of Medical Gastroenterology, Madurai Medical College, Panagal Road, Alwarpuram, Madurai 625 020, India
Background and Aim Hepatitis B virus (HBV) reactivation after chemotheraphy is associated with significant morbidity and mortality and its prevention decreases the risk factor for liver decompensation and mortality. The aim of the study is to know the risk factors for hepatitis B reactivation in a chemotheraphy patients and their clinical profile and follow-up the patients on HBV therapeutic agents.
Materials We included 75 patients who were previously negative for hepatitis B and become positive subsequently during the chemotheraphy. We compared age, sex, past history of blood transfusion, tattooing, surgery, family history of jaundice, tumour type, staging of tumor, liver function test, complete blood count, real time PCR analysis of HBV DNA. All the patients are treated with antivirals and subsequent follow-up done from 2020-2021.
Statistical Analysis It’s a prospective study. Fisher’s exact test was used to compare categorical variables. For non-parametric data Mann–Whitney test was used.
Results Age group > 40 (n=73.3%), female sex (n=75%), past history of surgery (n=65.5%), stage IV tumors (87.3%), combination chemotheraphy drugs76.7%, cycles of chemotheraphy > 6 cycles (66.7%), mean duration from chemotheraphy to onset of jaundice is 4.8 months during the follow-up study 8 patients were developed cirrhosis and portal hypertension, 2 patients were dead, remaining 60 patients showed response to antivirals and follow-up fibroscan value after 6 months mean value is 6.9 kpa.
Conclusion Post chemotheraphy viral reactivation is a preventive disease. Eventhough patients are HBsAg negative we have to screen for anti-HBs, anti-core antibodies, and DNA load. And post chemoreactivation can increase the risk of cirrhosis in population groups at risk for cirrhosis. Post chemo hepatitis B have good outcome if recognized early and treated.
Keywords Chemotheraphy, Cirrhosis, Hepatitis B reactivation
137
Multiple liver SOL in chronic hepatitis C – Not always hepatocellular carcinoma
Moiz Vora, Janardhan Babu
Correspondence - Moiz Vora - [email protected]
Department of Gastroenterology and Hepatology, Asian Institute of Gastroenterology, Mindspace Road, AIG Hospital, Facility Block, Hyderabad 500 032, India
An Indian woman, 57 years of age, presented with chief complaint of mild right upper quadrant discomfort and dull aching pain, easy fatigability and anorexia.
Anti HCV was found to be reactive. Quantitative HCV RNA (PCR) was found to be positive (705302 IU/mL).
Abdominal ultrasound showed hepatomegaly and multiple round target shaped hypoechoic nodules of varying size were noted scattered in both lobes of liver with largest nodules measuring 5.7 × 3.8 cm and spleen was normal in size. Serum AFP was normal and CA19.9 was elevated - 312 U/mL. Serum LDH was 1458 U/L and uric acid was 7.5 gm/dL. Whole body PET CT scan showed enlarged liver, FDG avid (SUV max 14.2), multiple well defined homogenous hypo enhancing, hypodense lesion in both lobes of liver, largest 6.1 × 5.0 cm in segment VIII of liver.
True cut biopsy showed atypical lymphoid infiltrate with mild nuclear atypia, occasional mitosis, sheets of atypical round to pleomorphic cells having medium to large round vesicular, dark stained nucleus with inconspicuous nucleoli and scant cytoplasm. IHC was positive suggestive of non-Holdings lymphoma B cell type.
This patient has been planned for 3 cycles of R-CHOP chemotherapy (combination of rituximab, cyclophosphamide, vincristine, doxorubicin and prednisolone) followed by response assessment.
Primary B-cell lymphoma of the liver is an extremely rare tumor and is thus frequently overlooked diagnosis. An increased incidence of lymphoma has been reported in patients with chronic hepatitis C. Hepatitis C virus is known to be a lymphotropic virus.
Keywords Hepatitis C, Hepatocellular carcinoma, Lymphoma, Response, Space occupying lesions, Therapy
138
Hepatitis C virus genotype and antiviral response to oral direct acting antivirals in patients with chronic hepatitis C at a tertiary care hospital in North India
Rangat Sharma, Vijant Singh Chandail
Correspondence - Rangat Sharma - [email protected]
Department of Internal Medicine, Government Medical College and Hospital, Maheshpura, Chowk, Bakshi Nagar, Jammu 180 001, India
Introduction Hepatitis C virus (HCV) infection is the leading cause of chronic liver related diseases including cirrhosis and hepatocellular carcinoma. Currently, no effective vaccine is available for HCV infection. HCV is most commonly seen in IV drug abusers and CKD patients on maintenance hemodialysis (MHD). The treatment of HCV infection with pegylated interferon alpha and ribavirin leads to a sustained virological response. But a better understanding of HCV lifestyle has resulted in development of several potential directly acting antivirals (DAAs) targeting viral proteins. Directly acting antivirals give high rates of sustained virological response (SVR). Sofosbuvir and Velpatasvir combination is usually recommended in Genotype 1 and 3 in addition to ribavirin in Genotype 3 and Sofosbuvir and Dacletasvir are recommended in Genotype 4.
Aims and Objectives To observe various HCV genotypes and antiviral response to oral directly acting antivirals (DAAs) in patients with chronic hepatitis C.
Methods This study enrolled 440 HCV positive patients in which HCV RNA viral load and genotype was done. Antiviral response was observed after completing 12 weeks of antiviral treatment based on different genotypes by repeating HCV RNA viral load.
Result Among 440 patients, most common genotype found in this hospital was 3 followed by 1, then 4 and among 440 HCV positive patients, 121 completed 12 weeks of DAAs and 100% SVR was observed among these patients illustrating good response of DAAs in HCV infection.
Keywords HCV genotype, Oral antiviral response
139
Validation of non-invasive tests in predicting fibrosis in non-alcoholic fatty liver disease patients in Indians
Samir Hota , Shivaram Prasad Singh, Pallavi Bhuyan
Correspondence - Samir Hota - [email protected]
Department of Gastroenterology, Srirama Chandra Bhanja Medical College, Behera Colony, Mangalabag, Cuttack 753 001, India
Background and Aim Simple non-invasive tests for liver fibrosis like APRI, BARD, NFS, FIB-4 are easy to perform and cheap [1,2]. However, there is paucity of data about these non-invasive tests for prediction of fibrosis in Indian non-alcoholic fatty liver disease (NAFLD) patients since most of the derivation/validation studies have been conducted in western populations. Hence there is a need to assess utility of these non-invasive methods for predicting fibrosis in Indian patients. Aim of this study is to compare various non-invasive scores (APRI, NFS, BARD, FIB -4) with fibro-scan and liver biopsy to predict fibrosis in Indian NAFLD patients.
Methods Patients attending Gastroenterology OPD in SCBMCH, Cuttack were screened for the NAFLD by abdominal USG. Age and sex matched healthy controls were recruited from attendants of patients. Non-invasive scores like NAFLD fibrosis score (NFS), aspartate-aminotransferase (AST)/platelet ratio (APRI), Fib-4, BARD scores were calculated. Measurement of hepatic stiffness was done by transient elastography (TE) and liver-biopsy was performed in patients who gave consent for the procedure.
Results Total number of patients were 136 with mean age and BMI 41.5 ± 9.5 years and 26.64± 3.37 kg/m sq respectively. Twenty patients were diabetic and 16 were hypertensive. The AUROC under APRI, NFS, BARD, FIB-4 and FIBROSCAN were 0.455, 0.479, 0.772, 0.821, 0.834 respectively. At a cut-off of 1.82,1.5,2.26 and 7.95 NFS, BARD, FIB-4 and Fibroscan were 80%, 80%, 60% and 80% sensitive and 32%, 52%, 87%, 90% specific respectively.
Conclusions BARD, FIB-4 and Fibroscan are non-invasive markers of fibrosis that can be utilized as screening tools for Indian NAFLD patients for detection of fibrosis. At a cut-off of 7.95 kpa, the sensitivity and specificity for demarking stage 3/4 fibrosis by Fibroscan was 80% and 90% respectively.
Keywords Indians, NAFLD, Non-invasive tests
140
Hepatitis C and celiac disease a rare association
Mukti Prakash Meher
Correspondence - Mukti Prakash Meher - [email protected]
Department of Gastroenterology and Hepatology, M L N Medical College, Prayagraj, George Town, Prayagraj 211 002, India
Introduction A 70-year-old male presented with loose stool for last 8 weeks and hematemesis last 2 day.
Methods Esophagogastroduodenoscopy revealed 4 column grade 2 varices, for which variceal band ligation done. biopsy taken at the time of endoscopy revealed intraepithelial lymphocytosis, crypt hyperplasia and chronic inflammatory infiltrate in lamina propria along with subtotal villous atrophy. Patient was found positive for anti HCV antibody.
Result USG abdomen showed coarse liver Echotexture along with dilated portal vein (13 mm), moderate ascites IgA anti TTG was highly elevated with a value of 78.82 U/mL. HCV RNA level was 99780 IU/mL. complete blood count revealed, hemoglobin 7 gm/dL, total leukocyte count of 15300, platelet count of 50000. Liver function test revealed serum bilirubin 2.92, SGOT-80, SGPT-70, serum protein-6.81, serum albumin-2.42. patient managed conservatively with gluten-free diet, iron supplementation, antibiotics, human albumin, diuretics, calcium, and discharged with stable vitals. His hemoglobin showed a rise from 7 g/dL to 11g/dL. His diarrhea also settled. Patient was started on sofosbuvir and velpatasvir combination.
Conclusion The prevalence of celiac disease in patient with chronic liver disease is at least 1.5%, which is 15 times higher than that in general population [1]. A case report has shown that cell mediated inflammatory response to HCV may involve T cell restricted to human leukocyte antigen (HLA)-DQ2, the class II HLA allele linked to celiac disease4. HCV has been identified to cause autoimmune processes [2, 3] like development of antinuclear antibodies, lichen planus, Sjogren’s syndrome. Therefore, HCV infection also may have an increased prevalence of celiac disease, which is also an autoimmune disease.
(Histopathology showing intraepithelial lymohocytes and villous atrophy)
Keywords Celiac disease, Crypt hyperplasia, Hematemesis
141
Emergence of carbapenem, colistin resistant bacterial and drug resistant fungal infections in cirrhotic patients
Nikhil Jalori, Deepak Lahoti, Vibhu V Mittal
Correspondence – Nikhil Jalori - [email protected]
Department of Gastroenterology, Max Super Speciality Hospital, 108A, IP Ext, I.P.Extension, Patparganj, Delhi 110 092, India
Background Infection is one of the commonest events leading to hospital admissions in cirrhotic patients. They may trigger decompensation and represent an important cause of increased mortality [1]. We prospectively studied the spectrum of various bacterial and fungal infections along with comorbidities and prognostic factors like and tried to assess their impact on outcome of cirrhotic patients .We attempted to evaluate how outcomes depended on factors like stage of liver disease, microbial resistance, appropriate antibiotics usage and whether outcomes were significantly different from patients who did not have infections.
Methods This prospective observational study was conducted in tertiary care centre of North India. We recruited 220 patients of liver cirrhosis including 127 patients with infections and 93 without infections. Data was collected about demographics, clinical profile and investigations done for management of these patients.
Results Bacterial infections were isolated in 117 (53%) of total patients. 110 out of 152 pathogens isolated were MDR (72.3%). Based on the mode of acquisition of infection, the majority of infections were CA-68 (54%), followed by HC-35 (27%) and nosocomial -24 (19%). Fungal cultures were positive in 24 (15.7%) cases, with Candida sp. being most common-20 (13.1%). ESBL-E (19.7%), CRE (17.7%), CORE (10.5%), Acinetobacter (4.6%) were commonest MDR infections, followed by MDR Candida (8.5%), VRE and others. Patients with multidrug-resistant bacteria had significantly higher mortality-19 (24.68%) vs. 8 (5.59%), duration of stay (8 ± 4.58 vs. 5.51 ± 3.72), the incidence of septic shock-31 (40.26%) vs. 12 (8.39%) and poor response to empiric antibiotics-59 (76.62%) vs. 39 (27.27%) when compared to patients with no infections or infections with the susceptible organism.
Conclusions These findings suggest an increasing prevalence of MDR bacterial and fungal infections in patients with CLD. The presence of infection, especially with MDR, has been associated with poor outcomes.
Keywords Cirrhosis, Drug resistance, Infections
142
Outcome of plasma exchange in rat killer poisoning induced acute liver failure at a tertiary care centre from southern India
Allwin James, Alagammai P L, Srividhya Manjunath, Ramesh Ardhanari
Correspondence - Allwin James - [email protected]
Department of Medical and Surgical Gastroenterology, Meenakshi Mission Hospital and Research Centre, Lake Area, Melur Main Road, Madurai 625 107, India
Introduction Rat killer compound (yellow phosphorus) is a commonly available rodenticide. It is protoplasmic poison causing multiorgan failure. Dose of >1 mg/kg is almost fatal [1, 2]. Here we present clinical profile, observations, and outcome of plasma exchange at our institute.
Methods Study was designed as observational study between July 2021 to July 2022. Any rat killer poison consumption during the study period was included. Demography, clinical presentation, indications, tolerability, and outcome of plasma exchange were analyzed.
Results Forty-eight patients were included. Mean age was 29. All patients were started on N-acetyl cysteine infusion irrespective of dosage. Fifty percent (n=24) had presentation within 24 hours of consumption. Cake formulation of toxin appeared less toxic than paste. Patients who had no decontamination (gastric lavage within 2 hours of consumption), hemodynamic instability (hypotension–not responding to volume challenge), presence of hepatic encephalopathy, high toxin dose, higher lactate levels at admission (> 4), delayed presentation (> 72 hours of consumption), worsening of liver and renal functions despite plasma exchange, had poor outcome (p< 0.05). Indication for therapeutic exchange was based on presence of acute liver failure, bone marrow toxicity. 60% (n=29) underwent plasma exchange for above indications. Three developed hypotension during procedure. Number of sessions was based on LFT and coagulopathy with linear relationship. Nineteen percent (n=9) had bone marrow toxicity at presentation. Neutropenia with increased absolute monocyte count was most common bone marrow toxicity. Leucopenia improved with therapeutic plasma exchange in all patients. Isolated marrow toxicity was seen in 2 patients. New onset diabetes insipidus seen in 4 patients, improved with oral/ nasal desmopressin and fluid management. Despite plasma exchange mortality was seen in of 18% [5].
Conclusion Plasma exchange has emerged as potential therapeutic option for ALF due to rat killer poisoning with favorable outcome in our tertiary care centre.
Keywords Acute liver failure, Plasma exchange, Rat killer poisoning
143
Therapeutic plasma exchange as a bridge therapy in patient with alcohol related acute- on-chronic liver failure
Srividya Manjunath , Alagammai P L, Allwin James D
Correspondence – Alagammai P L - [email protected]
Department of Medical Gastroenterology, Meenakshi Mission Hospital and Research Centre, Lake Area, Melur Road, Madurai 625 107, India
Introduction Acute-on-chronic liver failure (ACLF) is characterized by acute hepatic decompensation, organ failure and high short-term mortality. The ideal treatment for ACLF in the absence of overt organ failure and sepsis is liver transplantation. However, it is feasible only in a subset of patients resulting in high waitlist mortality (67%). Therapeutic plasma exchange (TPE) is now emerging as a bridge therapy in such patients. It is said to help by removal of inflammatory cytokines facilitating native liver regeneration. TPE has shown survival benefit in patient with hepatitis B related ACLF. In this observational study, we aim to look at the benefits of using TPE in patients with alcohol ACLF.
Results A total of 20 male patients were included in the study. TPE was considered for patients with organ failure, Acute kidney injury due to HRS/bile cast nephropathy and those who were not candidates for steroid therapy for severe alcohol hepatitis. Fifteen patients survived at the end of treatment whereas 5 did not. Baseline bilirubin, creatinine, INR were not significantly different between the two groups. Non survivors had higher MELD admission (34.4+/- 6.50) as compared with survivors (32.2+/-5.20), p 0.40. Those with higher grade of encephalopathy (grade III – IV) did not survive even with TPE. Post TPE there was significant reduction in MELD score in survivors by 7 points (25.13+/-3.39, p 0.001) vs. non survivors (29 +/- 5.24, p 0.038). Forty-five percent patients (9) had bile cast nephropathy, 77% of whom had AKI. Twenty percent has AKI with no bile cast nephropathy. AKI however was more severe in patients with bile cast and in these patients, AKI resolved completely after TPE.
Conclusion TPE may be considered as a bridge to survival in patients with alcohol ACLF, who are otherwise poor candidates for steroids or immediate liver transplantation.
Keywords Alcohol ACLF, Bile cast nephropathy, Plasma exchange
144
Survival analysis of patients undergoing plasma exchange for acute liver injury due to rodenticide poisoning at a tertiary care center in Western Tamil Nadu
P S Kirpal, V Arulselvan, T Ravishankar, P Senthilkumar, A Senthilvadivu
Correspondence – P S Kripal - [email protected]
Department of Medical Gastroenterology, Coimbatore Medical College, Avinashi Road, Peelamedu, Civil Aerodrome Post, Coimbatore 641 018, India
Introduction Acute liver failure (ALF) due to rodenticide poisoning is a common indication for emergency liver transplantation in South India [1]. Yellow phosphorus (YP) is the main constituent of commonly available rodenticides in India. Mortality due to YP poisoning has ranged from 20% to 30% in various reports [2, 3].
The only definitive management for acute liver failure following rodenticide poisoning is urgent liver transplantation (LT). The usefulness of plasma exchange (PLEX) in improving survival in acute liver failure due to rodenticide poisoning in settings where there is poor accessibility to liver transplant is being increasingly recognized [3, 4]. This study examined the 28-day transplant free survival rates among patients with acute liver failure due to rodenticide poisoning who underwent PLEX at a tertiary care hospital in Western Tamil Nadu.
Methods Consecutive patients who underwent PLEX for acute liver failure due to rodenticide poisoning during the study period, who met Tamil Nadu chapter of Indian Society of Gastroenterology (TN-ISG) guidelines [5] criteria for PLEX were observed during treatment period and followed up untill 28 days. Baseline characteristics of patients, type of PLEX administered and survival rates at 28 days were observed.
Results Twenty patients underwent PLEX for acute liver failure due to rodenticide poisoning during the study period of 6 months. Mean age of the study population was 32.5 years (range 17-68) and 12 (60%) were males. The median INR at time of first PLEX was 4.8 6 (30%) had grade 2 or higher hepatic at the time of initiation of PLEX. All Patients received low volume response guided PLEX using ultrafiltration technique. Survival rate at 28 days was 90% (18),10 patients (50%) responded to single cycle of PLEX.
Conclusion PLEX is likely to significantly improve liver transplant free survival in acute liver failure due to rodenticide poisoning.
Keywords Acute liver failure, Plasma exchange (PLEX), Rodenticide poisoning
145
Hepatic hematoma – A rare postoperative complication of endoscopic retrograde cholangiopancreatography
Dandi Kranthi, Amol Dahale, Girish Muppa
Correspondence - Amol Dahale - [email protected]
Department of Medical Gastroenterology, Dr D Y Patil Medical College and Research Centre, Sant Tukaram Nagar, Pimpri Colony, Pimpri-Chinchwad, Pune 411 018, India
Introduction Nowadays, endoscopic retrograde cholangiopancreatography (ERCP) is the most minimally invasive procedure used to treat biliary and pancreatic disease. ERCP has the highest incidence of complications ranging from 2.5% to 8% with mortality rate ranging from 0.5% to 1%. An exception ERCP complication is represented by subcapsular hematoma. Since 2000, world literature has no not reported more than 20 cases. In this case report, we described a further rare case of subcapsular hepatic hematoma manifested only with abdominal pain and drop in hemoglobin.
Case Presentation A 26-year-old postpartum female with no comorbidities presented with complaints of jaundice and right upper quadrant pain. Magnetic resonance cholangiopancreatography (MRCP) was suggestive of cholelithiasis with choledocholithiasis. ERCP was suggestive of choledocholithiasis. Common bile duct (CBD) clearance with stenting was done. Four to six hours post ERCP, patient developed abdominal pain in right upper quadrant. On examination pulse rate was 120/min, blood pressure – 80/40 mmHg and patient had severe tenderness in right hypochondrium with no signs of peritonitis. Bed side ultrasonography showed subcapsular hematoma (14 × 14 × 11 cm) in right lobe of liver which was confirmed by cross sectional imaging. patient was further deteriorated, hemogram showed fall in hemoglobin to 6 mg/dL following day. Patient was resusciated started on ionotropes, multiple packed cell volume transfusion were given. She was managed conservatively and was discharged. on three months of follow-up, repeat scan showed decrease in size of liver hematoma.
Conclusion Hepatic injury and hematoma of the liver are rare and dreaded complication of ERCP and in most needs intervention in the form of surgery or pigtel drainage (if infected). Treatment is decided on case-to-case basis.
Keywords ERCP complications, ERCP, Hepatic hematoma
146
Influence of esophageal flap valve on esophageal variceal bleeding
Jay Chudasama, Harsh Gandhi
Correspondence - Jay Chudasama - [email protected]
Department of Gastroenterology, Topiwala National Medical College and B Y L Nair Hospital, Mumbai Central, Mumbai 400 008, India
Introduction Increased exposure to gastric acid in patients with abnormal gastroesophageal flap valve (GEFV) may lead to increase esophageal variceal bleeding.
Aim To investigate the relationship between GEFV and esophageal variceal bleeding episodes.
Methods It is an interim analysis of a cross-sectional study involving 109 patients with esophageal varices and flap valve of any grade. Patients are divided into two groups on basis of Hill’s grade of flap valve (Hill‘grade 1, 2-normal and Hill’s grade 3, 4-abnormal). They are assessed with esophagogastroduodenoscopy and incidence of variceal bleeding and size of varices (Two groups: largeb[>5mm] and small [<5 mm] varices) are compared with Hill’s Grade of flap valve.
Results This study included 109 patients out of which 72 had normal and 37 had abnormal flap valve. Number of bleeding episodes was significantly higher in patients with esophageal varices who had abnormal flap valve compared to whom having normal flap valve (Mean number of bleeding episodes- 2.5 vs. 1.1, p<0.001). Predominantly, patients with abnormal flap valve had larger varices while patients with normal flap valve had smaller varices (94.6% vs. 73.6%, p<0.001).
Conclusion Abnormal GEFV is independent risk factor for esophageal variceal bleeding.
Keywords Esophageal varices, Hill'grade
147
To assess response to steroids in patients with Autoimmune hepatitis and validate SURFASA score
Harsh Gandhi, Shubham Jain
Correspondence - Harsh Gandhi - [email protected]
Department of Medical Gastroenterology, Topiwala National Medical College and B Y L Nair Charitable Hospital, Mumbai Central, Mumbai 400 008, India
Introduction In autoimmune hepatitis (AIH) patients, response to steroids and optimal timing of liver transplantation (LT) always remains controversial. Aim of study is to assess response to steroids at day 3 and to validate SURFASA score in our population group. SURFASA score can identify patients who are non-responders to steroids. LT-free survival is higher in patients with a SURFASA score <-0.9.
Methods It is interim analysis of observational retrospective and prospective study involving 27 patients of AIH divided into acute AIH, acute severe (AS) AIH and acute on chronic liver failure. Response to steroids was assessed in these 3 groups of patients.
Results Out of 27 patients, 14 patients (51.9%) presented as acute AIH, 10 (37%) as acute-on-chronic liver failure (ACLF), 3 (11.1%) as AS AIH. Mean age of the patients was 47.7 (SD – 13.9) years, 66.7 % (18) of which were women. All patients who died (6) belonged to ACLF group. Patients who died have SURFASA score in range of -1.18 to -3.14 and patients who survived have SURFASA score in range of -4 to -5.1 (p<0.001). While traditional scores such as Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) at D0 and D3 of starting steroids were also accurate (p<0.001).
Conclusion SURFASA score is useful in predicting steroid response and patient survival. But the thresholds of the SURFASA score may differ in different populations depending on various factors.
Keywords Autoimmune hepatitis, Steroids, SURFASA score
148
Comparative study of proportion of cardiac disease in patients of non-alcoholic fatty liver disease with or without metabolic syndrome
Majid Khan, B. Vishwanath Tantry, Sandeep Gopal, Anurag Shetty, Suresh Shenoy
Correspondence - B. Vishwanath Tantry - [email protected]
Kasturba Medical College Hospital, Ambedkar Circle Mangalore, Manipal Academy Of Higher Education, Manipal 575 001, India
Introduction Non-alcoholic fatty liver disease (NAFLD) is a worldwide public-health problem affecting up to 1/3rd of adults, Prevalence of NAFLD in India is 9% to 32%, it is frequently associated with metabolic syndrome. Cardiovascular disease (CVD) is the leading cause of mortality among patients with NAFLD (accounting for about 40% of total deaths). This study was undertaken to evaluate the risk of CVD in NAFLD patient with or without metabolic syndrome.
Methods This is a analytical cross-sectional study conducted on 40 patients having NAFLD (diagnosed by ultrasonogram [USG] abdomen and liver stiffness by Fibroscan), and these patients were screened for the presence or absence of metabolic syndrome and divided into two groups (NAFLD with or without metabolic syndrome). Subsequently these group of patients underwent cardiovascular screening by ECG, 2D Echocardiography and TMT.
Results Among the 40 NAFLD patients, 25 (62.5%) patient had NALFD without metabolic syndrome and 15 (37.5%) patients were with metabolic syndrome. Among 40 NAFLD patients, 7 (17.5%) patients had cardiovascular disease. In NAFLD patients without metabolic syndrome 4 (16%) patients had CVD (3 patient had concentric LVH and 1 patient had concentric LVH with ventricular ectopics). Among NAFLD patients with metabolic syndrome 3 (20%) patients had CVD (2 patients had coronary artery disease - TMT positive and 1 patient had concentric LVH).
Conclusion NAFLD patients with metabolic syndrome had significant coronary artery disease as compared to none in NAFLD patients without metabolic syndrome, all individuals with NAFLD should be screened for features of metabolic syndrome and cardiovascular disease.
Keywords Cardiovascular disease, Metabolic syndrome, NAFLD
149
Acanthosis nigricans-A rare cutaneous association in progressive familial intrahepatic cholestasis type 3
Rahul Vijayvargiya , Bhashyakarla Ramesh Kumar, Uma Devi, Sahitya L, M D Zeeshan, Ch. Suraj, Vikas Reddy
Correspondence - Rahul Vijayvargiya - [email protected]
Department of Medical Gastroenterology, Liver Care Unit, Osmania General Hospital, Afzal Gunj, Hydearabad 500 012, India
Introduction Progressive familial intrahepatic cholestasis (PFIC) refers to heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin [1]. Defects in ABCB4, encoding the multi-drug resistant 3 protein (MDR3), impair biliary phospholipid secretion resulting in PFIC type 32. Acanthosis nigricans is a cutaneous manifestation of an underlying condition. It usually develops in in skin folds, such as the back of the neck, axilla, and groin, where it presents as velvety hyper-pigmented patches with poorly defined borders [3].
Case Report A 12-year-old female who is known case of PFIC type 3 came for follow-up with chief complaints of pruritus and increased pigmentation over neck region and forehead. Dermatology opinion took for that and Skin biopsy done which suggestive of acanthosis nigricans.
Discussion Acanthosis nigricans is most commonly associated with diabetes, insulin resistance, internal malignancy, hormone disorders or with the use of certain medications like systemic glucocorticoids and oral contraceptives [4]. The pathophysiological process behind acanthosis nigricans appears to be related to the proliferation of fibroblasts and the enhanced stimulation of epidermal keratinocytes [5]. In literature association with PFIC is not mentioned. Here, we reporting a case of Acanthosis nigricans in PFIC type 3 patients.
References
1. Jacquemin E. Progressive familial intrahepatic cholestasis: genetic basis and treatment. In: Pediatric liver. Clin Liver Dis. 2000; 4:753-63.
2. Jacquemin E. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases. Semin Liv Dis. 2001; 21:551-62.
3. Burke JP, Hale DE, Hazuda HP, Stern MP. A quantitative scale of acanthosis nigricans. Diabetes Care. 1999; 22:1655-9.
4. Habif, Thomas P. (2009). Clinical dermatology (5th ed.). Edinburgh: Mosby. ISBN 978-0-7234-3541-9.
5. Jeong KH, Oh SJ, Chon S, Lee MH. Generalized acanthosis nigricans related to type B insulin resistance syndrome: A case report. Cutis. 2010; 86:299-302.
Keywords Acanthosis nigricans, PFIC
150
Role of serum phosphate levels in acute-on-chronic liver failure patients to predict short-term mortality
Rohit Wagh, Meghraj Ingle, Vikas Pandey, Shamshersingh Chauhan, Vipul Choudhari
Correspondence - Meghraj Ingle - [email protected]
Department of Medical Gastroenterology, Lokmanya Tilak Municipal Medical College and Hospital, Lokmanya Tilak Medical College and Hospital, Sion, Mumbai 400 022, India
Introduction Acute-on-chronic liver failure (ACLF) is an acute hepatic insult manifesting as jaundice and coagulopathy complicated within 4 weeks by clinical ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease/cirrhosis and is associated with a high 28-day mortality. Given the property of rapid regeneration power of the liver, the metabolic and synthetic demands increase adenosine triphosphate (ATP) production by rapidly dividing liver cells. Increase in ATP synthesis requires inorganic phosphate, increasing the flux of phosphate into the liver causing hypophosphatemia in patients with a healthy functioning liver. Therefore, hyperphosphatemia could identify a group of ACLF patients with insufficient functional liver mass and help in predicting adverse outcomes.
Methods It is an observational study in a tertiary care centre. We took 92 diagnosed patients of ACLF and followed them over a period of 28 days. All baseline demographic details, routine blood workup, viral markers, serum phosphate, serum lactate, autoimmune profile (wherever necessary) were done. All the patients were followed up prospectively and 28-day mortality was compared with baseline serum phosphate levels and other parameters.
Results Most common acute insult included alcoholic hepatitis-47.82% (44), alcoholic hepatitis with drug induced liver injury- 10.86% (10), infections-9.78% (9), etc. while chronic insult included alcohol only-75% (69), autoimmune hepatitis-7.6% (7), chronic hepatitis B only-6.5% (6), cause unknown- 6.5% (6), etc. 28-day mortality was seen in 11.9% (11) ACLF patients. Hyperphosphatemia (≥ 4.5 g/dL) was seen in all 11 (100%) patients who died within 28 days and only in 5 (6%) out remaining 81 remaining survivors (p value >0.05).
Conclusion Higher serum phosphate level was associated with increased 28-day mortality and can be used as a predictor of short-term mortality in ACLF patients.
Keywords ACLF, Mortality, Serum phosphate
151
Liver mass presenting as acute cardiorespiratory failure
Raya Venkatesh Reddy, Rishi Raman, Shiran Shetty, Balaji Musunuri
Correspondence - Raya Venkatesh Reddy - [email protected]
Department of Gastroenterology and Hepatology, New OPD Building, Kasturba Medical College, MAHE, Tiger Circle Road, Madhav Nagar, Manipal 576 104, India
Introduction Sarcomatoid carcinoma (SC), also known as spindle cell carcinoma, is a malignant tumor type of unclear pathogenesis. Usually presents as abdomen pain. We reporting a rare presentation of liver mass. Case: A 58-year-old male nil morbidities presented with history of exertional dyspnea, fatigue and right upper quadrant pain since 1 month. On examination patient is having tachypnoea, tachycardia, and hypoxia. Investigations showed hypoxia and primary respiratory acidosis on ABG. 2D echo showed EF–36%, restrictive filling pattern in left ventricle with some extracardiac structure compressing right atrium. Serology is negative, AFP – 10 ng/mL, NT PRO -BNP – 20926 pg/mL. Triphasic contrast-enhanced computed tomography (CECT) abdomen showed 17*16*15cms large exophytic lesion with peripheral enhancement and central necrosis, lesion is noted to compress the right atrium. Ultrasound-guided biopsy of the lesion showed pleomorphic spindle cells with extensive area of necrosis. Immunohistochemistry (IHC) showed positive for Cytokeratins (CK), epithelial membrane antigen (EMA) and vimentin, negative for C – kit and PDGFR oncogene suggestive of primary hepatic sarcoid carcinoma. Patient is planned for emergency surgical decompression, but patient succumbed and died due to cardiac failure.
Discussion HSC has been reported in 1.8% of all surgically resected HCCs and in 3.9% to 9.4% of the autopsied cases. Primary hepatic sarcoid carcinoma (PHSC) typically presents as a mass with peripheral enhancement, central necrosis. Using immunohistochemical staining, the detection of CK, EMA and vimentin may be useful for the diagnosis of PHSC. The preferred treatment for PHSC is surgical resection. The prognosis of PHSC is particularly poor due to its high malignancy and local recurrence rates, venous invasion and intrahepatic, distant and lymph node metastasis.
Conclusion In conclusion, PHSC is an aggressive tumour type, which is characterized by a rapid clinical course. Early detection and radical resection may improve patient prognosis.
Keywords Cardiac failure, Primary hepatic sarcoid carcinoma
152
Association of liver dysfunction in corona virus disease-19 patients
Santosh Kumar, Santosh Kumar Nayan
Correspondence - Santosh Kumar - [email protected]
Department of Emergency Medicine, Indira Gandhi Institute of Medical Sciences, Bailey Road, Sheikhpura, Patna 800 014, India
Background Many of the pioneer studies from China in the context of corona virus disease-19 (COVID-19) have reported liver involvement as high as 60% among patients with COVID-19 infection. The presence of ACE2 receptors in the liver and systemic inflammation along with drug induced damage are the possible mechanisms. The current study was aimed to assess the liver function abnormalities among patients infected with COVID-19 and to find any association with respect to other patient characteristics.
Methods An observational study with cross-sectional design was done by Department of Emergency Medicine, Indira Gandhi Institute of Medical Sciences, Patna. Three hundred adult patients with confirmed SARS-CoV-2 infection on real-time reverse transcription–polymerase chain reaction (RT-PCR) who were admitted in the hospital between -------------- and -------------- were considered for inclusion in the study. Prior ethical approval was obtained from the Institutional Ethics Committee.
Results The mean age was 45.7 years with male dominance. Male to female ratio was 2.4. Study participants were divided in 4 groups based on the grade of symptoms of COVID-19. Majority (69.3%) had mild symptoms. Overall abnormal liver function tests (LFTs) was observed in 55.7% patients. Alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) were elevated in 50.3%, 53.3% and 53.3% cases respectively. The levels of AST, ALT and ALP between different groups based on severity of disease symptoms was also statistically significant.
Conclusion Liver dysfunction is not very uncommon in COVID-19 patients. Available literature suggests that gastrointestinal involvement with deranged liver enzymes are noted among a significant number of patients.
Keywords COVID-19, Liver dysfunction, Liver enzymes
153
Diabetic with emphysematous liver abscess: A case report
Subburathinam Gopalan , Vijai Shankar C, Kannan M, Ramani R
Correspondence - Vijai Shankar C - [email protected]
Department of Medical Gastroenterology, Madurai Medical College. Panagal Road, Alwarpuram, Madurai 625 020, India
Gas forming organisms can affect a variety of organs with liver being involved very rarely. Emphyseatous liver abscess is a condition where the abscess cavity contains air with an incidence of 6% to 24%, more prevalent in southeast Asian populations. The usual culprit is Klebsiella pneumoniae in 80% cases, while E. coli, salmonella, and clostridium perfrigens are seen in 20% cases [1, 2]. Patients usually present only with fever and malaise attributable to poorly controlled hyperglycemia in most of the cases as it masks the severity of the underlying pathology. Due to a high mortality rate ranging from 27% to 30%, this condition warrants timely diagnosis, intensive care, and prompt intervention [3].
We herein present a case of 54-year-old diabetic and hypertensive female, who had a poor glycemic control, with previous history of laparoscopic cholecystectomy and total abdominal hysterectomy with bilateral salphinoopherectomy. She was brought with fever, abdominal pain, jaundice, and oliguria. Basic investigations revealed leucocytosis, prerenal azotemia, direct hyperbilurubinemia with 4-fold rise of liver enzymes. Computed tomography of the abdomen showed a cystic necrotic mass with multiple air fluid levels involving the segments 5 and 6 of liver, suggestive of emphysematous liver abscess. The patient underwent an emergency ultrasound guided percutaneous drainage of the abscess. Klebsiella pneumoniae was grown in both pus and blood cultures and the patient was treated with intravenous antibiotics according to sensitivity reports. During the course of treatment, patient showed clinical improvement and recovered from renal failure. The drain was removed after 18 days and discharged. This case emphasises the need for suspecting emphysematous liver abscess in a patient with poorly controlled hyperglycemia as prompt intervention can prevent mortality.
Keywords Emphysematous liver abscess, Gas forming organism, Klebsiella
154
Non HFE hemochromatosis - The uncommon variant
Mohammed Zeeshan Ali , Ramesh Kumar B, Uma Devi M, Sahitya L, Rahul Vijayvargiya, Suraj Kumar Ch., Vikas Reddy V
Correspondence - Mohammed Zeeshan Ali - [email protected]
Department of Gastroenterology, Osmania Medical College, Osmania General Hospital, Afzalgunj, Hyderabad 500 012, India
Hemochromatosis is a rare multisystem disorder due to defect in the regulation of gastrointestinal iron absorption leading to abnormal deposition of inorganic iron in parenchymal tissues. These defects are commonly due to abnormal regulation of Hepcidin. More than 90% of the cases of hereditary hemochromatosis are HFE gene related, and minority are non HFE related hemochromatosis. The four common non HFE hereditary hemochromatosis are caused by mutation in hemojuvelin, hepcidin, transferrin receptor 2 and ferroportin genes. Commonly these mutations are associated with more severe course of disease compared to HFE hemochromatosis. Awareness and high degree of suspicion is needed to not misdiagnose this non HFE mutation disease as end stage liver disease with iron overload or due to secondary hemochromatosis. Early diagnosis of these mutations in the patient and their family members and initiation of treatment before organ failures develop will help the patient lead a normal life.
Keywords Hereditary hemochromatosis, HFE gene mutation, Iron overload, Non HFE hemochromatosis
155
Granulomatous disease with hepatic involvement in a south Indian female
Kishwanth Rayappan , Kannan M, Ramani R, Vijai Shankar C, Sriram P B
Correspondence – Kannan M - [email protected]
Department of Medical Gastroenterology, Madurai Medical College, Panagal Road, Alwarpuram, Madurai 625 020, India
Granulomatous diseases involving the liver may present as a primary process or as a manifestation of a systemic disease. Sarcoidosis, a multi systemic granulomatous disease of unknown etiology usually manifests with lung and skin lesions. Liver is involved in about 50% to 80 % of the cases without abdominal symptoms while 5% to 25% of the cases present with clinically significant liver involvement in the form of hepatomegaly and raised alkaline phosphatase [1, 2]. It has been extensively studied in African American population, while in India, it is still in its early stages of evaluation and it can be assumed that it is being under reported [3]. We herein present a case of sarcoidosis in a middle aged south Indian female with symptomatic liver involvement. She presented with right upper quadrant abdominal pain and non-productive cough for 6 months. There was no jaundice or cholestatic symptoms. Clinical examination revealed hepatomegaly with the liver spanning up to 22 cm and a mild splenomegaly. Her basic lab investigations showed an elevation of ESR, globulin levels and a predominant cholestatic pattern of liver function derangement with a fourfold increase in alkaline phosphatase. Computed tomography of the chest showed bilateral hilar lymphadenopathy with reticulonodular infiltrates. After ruling out infections and autoimmune causes by serological tests, Sarcoidosis was suspected and was supported by elevated serum angiotensin converting enzyme levels and liver biopsy findings of non-caseating granuloma. She responded symptomatically well to steroids and is being followed up. This case illustrates a clinical entity rare in Indian population and reiterates the need for consideration of sarcoidosis as a potential diagnosis in a population where the disease is less studied.
Keywords Hepatic, Indian, Sarcoidosis
156
Epidemiological profile of acute hepatitis patients hospitalized in a tertiary care center in Western India
Pankaj Nawghare, Shubham Jain, Vishal M, Saurabh Bansal, Sanjay Chandnani, Pravin Rathi
Correspondence - Pankaj Nawghare - [email protected]
Department of Gastroenterology, Topiwala National Medical College and B Y L Nair Hospital, Mumbai Central, Mumbai 400 008, India
Introduction Acute hepatitis is major global burden in India. However, an epidemiological study depicting situation of acute hepatitis in Western India is missing. We conducted this study to elucidates the epidemiology, risk factor, clinical features, and outcome among clinically suspected AVH cases.
Methods This was a single center, retrospective study conducted at tertiary care center. We recruited data retrospectively from discharge/death file. Patients with history compatible with acute hepatitis with a deranged liver function test were enrolled for analysis.
Result Total 14,236 patients admitted from 1st January 2018 to 31st December 2019 were analyzed. 1840 patients with acute hepatitis were included in study. Mean age of population was 30.92±24.2 years with majority being males (62.7%). Most common symptom was nausea (72%). Other common symptoms were abdominal pain (54%), fever (48%) and generalized weakness (45%). Icterus was seen in 80%, while hepatomegaly seen in 32% cases. One hundred and eight (5.9%) patients were having underlying cirrhosis. 2% and 1.1% of patients presented with acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). Hepatitis E (63.7%) was predominant etiology followed by hepatitis A (17.5%) and hepatitis B (9.3 %). Drug-induced liver injury (DILI) constitute for 4.8 % of cases. Among patients with DILI, majorities were taking herbal and complementary medication (86%). Autoimmune hepatitis and Wilson disease constitute 3% and 0.3% of cases respectively. Coinfection was seen in 3% cases. Case fatality rate in our study was 2.3%, with all patients were having either ALF or ACLF at presentation. Only shortcoming of our study was it include only patients who were admitted to hospital and not from community.
Conclusion Acute hepatitis is continued to be major health problem in India. Majority of cases still attributed to hepatitis E due to poor sanitary condition. ALF and ACLF is associated with poor outcome.
Keywords Acute hepatitis, Hepatitis E, Male
157
A prospective randomized comparative four arm intervention study of efficacy and safety of saroglitazar and vitamin E in patients with non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis-An interim analysis
Bilal Mir, Brij Sharma, Rajesh Sharma, Vishal Bodh, Ashish Chauhan
Correspondence - Bilal Mir - [email protected]
Department of Gastroenterology, Indira Gandhi Medical College, Ridge Sanjauli Road, Lakkar Bazar, Shimla 171 001, India
Background and Aim Among available pharmacotherapies, vitamin E and Saroglitazar are used in India for non-alcoholic fatty liver disease (NAFLD). However, no head-to-head comparative study for these drugs is available. In this prospective intervention trial, we studied the efficacy and safety of saroglitazar and vitamin E for patients of NAFLD/non-alcoholic steatohepatitis (NASH).
Methods We prospectively analyzed 104 patients of NAFLD grouped into four study arms as, saroglitazar 4 mg daily alone (n=28) vs. vitamin E 800IU daily (n=22) alone vs vitamin E and saroglitazar combination(n=24) vs. placebo (n=30). All the demographic variables, anthropometric data and biochemical parameters including liver function tests were noted. All patients underwent fibro elastography to determine the severity of steatosis as controlled attenuation parameter (CAP) and fibrosis as liver stiffness measurement (LSM). Reassessment with repeat blood testing and fibro elastography was done after 24 weeks of treatment and results were recorded.
Results The mean age of study population was 45±12 years with mean body mass index (BMI) 29±11, among which 60% were males. Compared to placebo, saroglitazar alone, vitamin E alone and combination therapy significantly improved serum alanine transaminase (ALT) (43% vs. 22% ,47% vs. 25% and 55% vs. 20% respectively; p=<0.03, p=<0.04 and p=<0.02).The reduction in CAP was seen more with combination therapy compared to individual drug alone (p=<0.04) and the reduction in LSM was greater with saroglitazar limb compared to vitamin E and combination therapy (p=<0.05). Improvement in glycemic and lipidomic parameters were comparable between saroglitazar alone and combination therapy but less pronounced with vitamin E, with respect to placebo. The rates of adverse events were comparable between groups except for body aches that were more common in saroglitazar group.
Conclusions Both saroglitazar and vitamin E significantly improved liver biochemistry, CAP and LSM. However, the combination therapy showed better efficacy in LSM and CAP reduction along with biochemical, glycemic and lipidomic parameters.
Keywords Fibroelastography, Non-alcoholic fatty liver disease, Saroglitazar
158
Prevalence of frailty in cirrhotic- A observational study
Yogesh Bairwa , Meghraj Ingle, Saiprasad Lad
Correspondence - Meghraj Ingle - [email protected]
Department of Gastroenterology, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai 400 022, India
Background Frailty is increasingly recognized as a major prognostic factor in cirrhosis Its assessment and intervention towards performance improvement is an important step in the management of liver cirrhosis. In this study, we aimed to assess the prevalence of frailty in patients of liver cirrhosis in a tertiary care center.
Methods Ninety-three patients were enrolled in this observational cohort study. Frailty assessment was done using compares fried frailty index (FFI), clinical frailty index (CFI), short physical performance battery (SPPB), Edmonton frail scale (EFS), LFI, Eastern Cooperative Oncology Group (ECOG), Karnofsky performance scale (KPS); Instrumental activity of daily living. The primary outcome was a prevalence of frailty in cirrhotic patients, then its prevalence in different subgroups according to etiology, Child-Turcotte-Pugh (CTP) score; model for end-stage liver disease (MELD) score.
Results Seventy-three (81.1%) males and 13 (18.9%) females with a mean age of 43.89; 9.67 years were included. The most common cause of cirrhosis was alcoholic liver disease (47.7%) followed by hepatitis B (14.1%) and hepatitis C (7.8 %). The prevalence of frailty based on LFI (46.67%), KPS (35.55%), FFI (38.9%), CFI (38.90%), SPPB (47.80%), EFI (31.20%), IDAL (31.10%), ECOG (36.70%). There was no significant difference of prevalence among different indexes (p value; 0.05).
Conclusions The prevalence of frailty based on LFI is 46.67 %. LFI, KPS, FFI, CFI, SPPB, EFI, IDAL, and ECOG are comparable in frailty assessment in patients with cirrhosis.
Keywords Child-Turcotte-Pugh (CTP), Frailty, Liver frailty index, Model for end-stage liver disease
159
Prevalence of chronic hepatitis B, hepatitis C and human immunodeficiency virus infection in people who inject drugs, and barriers to care for antiviral therapy: A prospective integrated deaddiction and microelimination cohort study
Anchal Sandhu, Madhumita Premkumar, Abhishek Ghosh, Debashish Basu, Ajay Kumar Duseja, Sunil Taneja, Arka De, Vishesh Kumar, Surender Sehrawat, Shikha Guleria, Jasvinder Nain
Correspondence - Madhumita Premkumar - [email protected]
Department of Hepatology, Post Graduate Institute of Medical Education and Research, Nehru Hospital Extension Block, Sector-12, Chandigarh 160 012, India
People who inject drugs (PWID) are at a high risk of developing chronic viral hepatitis B (HBV) and HCV infections as well as human immunodeficiency virus (HIV) infection due to unsafe injection practices. PWID report high social stigma, and often fail to seek treatment or complete direct-acting antivirals (DAAs) therapy. In addition, they are at risk of other substance use disorders (SUD).
Methods We screened 760 consecutive PWID reporting to the Drug De-addiction and Treatment Centre (DDTC) of Postgraduate Institute of Medical Education and Research, Chandigarh for chronic viral hepatitis using enzyme linked immunosorbent assay (ELISA) assays for HBsAg and anti-HCV and human immunodeficiency virus (HIV) rapid antigen test. Those testing positive on the screening test underwent confirmative testing and viral load estimation, and were then provided integrated free-of-charge DAAs+DDTC therapy under the National Viral Hepatitis Control Programme (NVHCP).
Results We screened 760 PWID (all male, mean age 25.5±3.72, rural 18.6%). Of them, 1.3% were HIV positive, 50.1% were anti-HCV reactive and 13.2% were HBsAg positive. Despite the fact that 381 individuals tested positive for an anti-HCV antibody, only 36 (9.4 %) agreed to go for HCV viral load testing. 9.4 % were found to be viremic and treated with Sofosbuvir-Daclatasvir for 12 weeks, with adherence 86.1% SVR-12 rate. Use of heroin (28.3%), alcohol (13.1%), smoking (16.2%), chewing tobacco (4.1%), and marijuana (3.9%), pain medication (0.5%) were the predominant SUD, alone or in combination Barriers to care were that 60.1% were unaware about the free DAAs under NVHCP, 32.0% reported social stigma and 7.8% claimed lack of access to specialized care.
Conclusion We report a high prevalence of undiagnosed HCV, HBV and HIV infection in PWID at our centre, who are at risk of transmitting to others as well as getting reinfected despite treatment. So integrated viral therapy and deaddiction is essential to encourage therapy acceptance with high cure rates.
Keywords DDTC, HBsAg, Hepatitis C, HIV, PWID
160
Low skeletal muscle strength parallels the nutrient deficit among Indian patients with cirrhosis
Pallavi Gindodia , Roopam Negi, Roopam Madan, Richa Bhargava, Pankaj Singh, Vikas Singla, Ayushi Singh, Dhairya Madan *
Correspondence - Kaushal Madan - [email protected]
Centre for Gastroenterology, Hepatology and Endoscopy, Max Institute of Liver and GI Sciences, 1 2, Press Enclave Marg, Saket Institutional Area, Saket, New Delhi 110 017, India, and *Himalayan Institute of Medical Sciences, Joly Grant, Bhania Wala, Dehradun 248 140, India
Introduction Malnutrition as assessed by low muscle mass and/or low muscle strength is prevalent in patients with cirrhosis. One of the factors leading to sarcopenia, is poor nutrient intake.
Aim To determine the association of skeletal muscle strength with nutrient intake among Indian cirrhotics.
Methods Consecutive patients with cirrhosis attending the OPD or admitted to Max Centre for Gastroenterology, Hepatology and Endoscopy were included. Patients with history of or current presentation with ascites, hepatic encephalopathy or variceal bleeding were labeled as decompensated cirrhotics. Skeletal muscle strength was measured using Jamar type hand grip dynamometer using the average of 3 measurements from the dominant hand. Nutrient intake was assessed using 24-hour recall to calculate the calories and proteins taken by the patients.
Results Between December 2021 and July 2022, 56 patients with cirrhosis (44 compensated and 12 decompensated; 80.7% males; median age 56 (29-81) years) were included. The HGS was lower among patients with decompensated cirrhosis, but it did not reach statistical significance (17.5 [9.33-29.60] vs. 19.3 [9.66-29.60] kgs; p=0.550), probably because of lower number of decompensated cases. Low HGS was significantly correlated with low calorie intake (Spearman’s correlation coefficient 0.305; p=0.010) but not with low protein intake (Spearman’s correlation coefficient 0.027; p=0.823).
Conclusions Low calorie intake may be the driving factor for low muscle strength among Indian cirrhotics, so replenishment of calories may help in improving their nutritional parameters.
Keywords Calorie intake, Cirrhosis, HGS, Muscle strength
161
A study of prevalence, precipitating factors and predictors of acute kidney injury in patients with cirrhosis of liver and its impact on in-hospital mortality
Nikhil Gandhi, B N Choudhury, Mallika Bhattacharyya, Utpal Jyoti Deka, Jayanta Nanda, Preeti Sarma, Pallab Medhi, Antara Sen
Correspondence - Nikhil Gandhi - [email protected]
Department of Gastroenterology, Gauhati Medical College, Narakasur Hilltop, Bhangagarh, Guwahati 781 032, India
Introduction Patients with cirrhosis are prone to develop acute kidney injury and is one of the common complications occurring in 20% to 50% of hospitalized patients. Development of acute kidney injury (AKI) has a dismal prognosis with an estimated mortality of about 50% in 30 days. Thus, aim of our study is to determine the prevalence, precipitating factors and predictors of AKI in cirrhotic patients and its impact on in-hospital mortality.
Methods A prospective observational study was conducted in 252 consecutive cirrhotic patients hospitalized in our department from January 2021 to July 2022. Patient’s demographic data and clinical profile was collected using a standardized proforma. Biochemical, hematological and abdominal imaging was done in all patients. All patients were then followed up until discharge or death.
Results Out of 252 patients, 215 (85.3%) were males with a mean age of 48.49 and 46.82 years for those with and without AKI respectively. The prevalence of AKI was 28.57% (72/252). Out of 72 patients with AKI, 35 patients died (48.6%), accounting for 39.8% of all in-patient mortality. Most patients who died had stage-3 AKI (37.1%). There was a significant association between AKI and mortality (p≤0.05). The major precipitating factors of AKI were infections (66.67%), refractory ascites (13.8%), gastrointestinal bleeding (12.5%) and herbal medications (6.9%). On multivariate analysis, MELD-Na score, sodium levels, presence of ascites and infections were independent predictors of development of AKI.
Conclusion AKI is common in patients with cirrhosis of liver with high in-hospital mortality. Early identification and recognition of these precipitants and independent predictors of AKI may help in prompt treatment with reduction in patient mortality and treatment cost.
Keywords Acute kidney injury, Cirrhosis of liver
162
Anthropometric and metabolic profiles and their association with advanced fibrosis in patients with non-alcoholic fatty liver disease
J ithin John, Prasanth Sudheendran, Jijo Varghese, Shanid Abdul Sathar, Krishnadas Devadas
Correspondence - Jithin John - [email protected]
Department of Medical Gastroenterology, Government Medical College, Ulloor - Akkulam Road, Chalakkuzhi, Thiruvananthapuram 695 011, India
Background and Aims Advanced fibrosis is the most important predictor of overall mortality in patients with non-alcoholic fatty liver disease (NAFLD). Identifying people at high risk of fibrosis and referring them for fibrosis assessment is of paramount importance. We tried to assess various anthropometric as well as metabolic factors and their association with advanced fibrosis.
Methods Cross-sectional observational study including 1617 patients of NAFLD. Baseline clinic-demographic, anthropometric and metabolic profiles were noted. Liver fibrosis was assessed using Vibration Controlled Transient Elastography (VCTE) with VCTE ≥ 9.9 kPa is taken as advanced fibrosis. Univariate as well as multivariate logistic regression was used to identify the independent predictors of advanced fibrosis.
Results The mean age was 43.3 years with a mean body mass index (BMI) of 26.28. Among 1617 NAFLD patients, 225 (16.2%) had advanced fibrosis. The mean age was higher in the advanced fibrosis group (50.8 vs. 42.1 p<0.001). Gender was not significantly different between the two groups. Even though high-density lipoprotein (HDL) and triglyceride were significant in the univariate analysis, multivariate analysis did not show the same. Binary logistic regression analysis showed that BMI, waist circumference, hip circumference, and waist-hip ratio (WHR) were significantly higher in the advanced fibrosis group. Diabetes mellitus as well as the increasing trend of metabolic components significantly contributed to advanced fibrosis.
Conclusions NAFLD subjects having higher BMI, higher waist circumference, higher hip circumference, and higher WHR should be referred for fibrosis assessment at the earliest. Mid-arm circumference and triceps skin fold thickness have no relationship with advanced fibrosis. Advancing age (more than 50 years) and the presence of diabetes mellitus are useful predictors of advanced fibrosis. Gender, lipid profile, and systemic hypertension are not good predictors for advanced fibrosis.
Keywords Advanced fibrosis, Anthropometry, Metabolic profiles, Non-alcoholic fatty liver disease
163
Role of C-reactive protein and neutrophil-to-lymphocyte ratio for predicting the outcome in patients with cirrhosis and decompensation
Banwari Yadav, M Manimaran
Correspondence - M Manimaran - [email protected]
Department of Medical Gastroenterology, Stanley Medical College, No.1, Old Jail Road, George Town, Chennai 600 001, India
Background and Aim The role of clinical parameters such as systemic inflammatory response syndrome (SIRS) in predicting the infection remains unclear in cirrhosis patients. The aim was to evaluate the usefulness of inflammatory markers namely C-reactive protein (CRP) and the neutrophil-to-lymphocyte ratio (NLR) for diagnosis of infection and predicting the outcomes in hospitalized cirrhotic patients.
Methods A prospective study was carried out in Department of Medical Gastroenterology. The study included 67 cirrhotic patients consecutively hospitalized from November 2021 to May 2022. The presence of overt infection and survival was evaluated. CRP concentration, NLR, model for end-stage liver disease (MELD) score and the presence of SIRS were assessed.
Results Sixty-seven patients were included, 46 were male, 21 female. Out of them SBP 32 (47.7%), UTI 14 (20.8%), cellulitis 3 (4.47%), while 18 were without any infection at admission. Mean CRP in SBP (42±21.2 mg/L), UTI (28±19.67 mg/L), cellulitis (36±23.90 mg/L), without infection (04±2.1 mg/L), p-value 0.006). Elevated NLR was seen in patients with infections as compared to patients without infections. SIRS in infections group was 89%, while in non-infection group was 12.09%. Odds ratio for CRP and NLR in predicting HRS-AKI was 8.66. AUROC for CRP in mortality at 5 months (0.64 p-value 0.002) and NLR 0.32 (p-value 0.08).
Conclusions Both CRP and NLR helps in assessing infections at admissions, however CRP predict mortality at 5 months more than NLR.
Keywords C-reactive protein, Infection, Liver cirrhosis, Neutrophil-to-lymphocyte ratio
164
A rare case of cholestatic jaundice
Prafulla Singh, Harish Kulkarni, Sumit Kumar, Sai Krishna Katepally, P Shravan Kumar
Correspondence - Prafulla Singh - [email protected]
Department of Gastroenterology, Gandhi Medical College, Musheerabad, Padmarao Nagar, Secunderabad 500 003, India
Idiopathic adulthood ductopenia (IAD) is a rare chronic cholestatic liver disease of unknown cause characterized by loss of the interlobular bile ducts. Since the symptoms and presentation of IAD can be nonspecific, it continues to be a diagnosis of exclusion. There are two types of IAD, In Type 1, ductopenia is <50% of portal tracts and has benign course while in type 2 ductopenia is >50% leading to cirrhosis and liver failure.
Here we report a case of 30 years old male presented with jaundice and pruiritus. On evaluation, bilirubin and serum alkaline phosphatase were found to be elevated. Viral markers, autoimmune profile and chronic liver disease work-up was unremarkable. Ultrasonography (USG) and magnetic resonance cholangiopancreatography (MRCP) were normal. Liver biopsy showed absence of interlobular bile ducts in 40% of portal triad suggestive of IAD (Type 1). Type 1 has benign course that responds to ursodeoxycholic acid (UDCA). We advised UDCA to the patient and his symptoms, serum bilirubin and alkaline phosphatase (ALP) levels improved. Till now, less than 100 cases was reported in medical literature [1,2,3].
References
1. Kaung A, Sundaram V, Dhall D, Tran TT. A case of mild idiopathic adulthood ductopenia and brief review of literature. Gastroenterol Rep (Oxf). 2015;3:167-9.
2. Moreno A, Carreño V, Cano A, González C. Idiopathic biliary ductopenia in adults without symptoms of liver disease. N Engl J Med. 1997;336:835-8.
3. Park BC, Park SM, Choi EY, et al. A case of idiopathic adulthood ductopenia. Korean J Intern Med. 2009; 24: 270–3.
Keywords Cholestatic jaundice, Idiopathic adult ductopenia
165
Prevalence of prolonged QTc and its impact on liver transplantation outcomes in a cohort of patients with liver cirrhosis. A single centre experience
Saranya Sankar, Fathimathu Zahra, Mathew Jacob, Mohammed Fawas. Biju Chandran, Sudheer Mohammed, Charles Panackel
Correspondence - Charles Panackel - [email protected]
Integrated Liver Care, Aster Medcity, Kuttisahib Road Cheranelloor, South Chittoor, Kochi 682 027, India
Introduction Prolonged QTc is an early marker of cirrhotic cardiomyopathy. It is correlated with ventricular arrhythmias and sudden cardiac death in etiologies other than liver cirrhosis.
Aim To evaluate the prevalence of prolonged QTc in a cohort of patients with cirrhosis liver evaluated for liver transplantation. To analyze the correlation of prolonged QTc with the severity of the liver disease.To look at the impact of prolonged QTc on peri-transplant cardiac morbidity and mortality.
Methods A single centre retrospective analytical observational study. All patients with complete data to evaluate the etiology and severity of the liver disease. Patients with an electrolyte imbalance, drug intake or cardiac conditions that could account for prolonged QTc were excluded. Patients were divided into three groups based on the severity of liver disease (Group-1 MELD-Na £20, Group-2 MELD-Na 21-29, Group-3 MELD-Na ³30). Statistical analysis was done using Statistical Package for the Social Sciences (SPSS) 21.0 software.
Results During the study period, 139 patients fulfilled the inclusion criteria. The mean age was 51.65±8.86. The study population was predominantly males, 116 (83.45%). The mean MELD-Na was 23.32±6.15. The etiology of liver disease was predominantly non-alcoholic steatohepatitis (NASH) in 78 patients (56.1%), ALD in 46 patients (33.09%), AIH in 12 (8.6%) and others 3 (2.1%). The mean QTc in the study cohort was 454.11±41.12 (Group -1 451.29±40.84, Group-2 457.99±40.50, Group -3 453.74±31.85). Prolonged QTc was seen in 85 patients (61.15%) Group 1 - 59.18%, Group 2 - 64.79%, Group 3 – 52.63%. All patients with prolonged QTc underwent uneventful liver transplantation.
Conclusion Prolonged QTc is common in patients with liver cirrhosis. In the current study, prolonged QTc did not correlate with the severity of liver disease, probably because of the low number of patients in group 3. Prolonged QTc was not associated with increased cardiovascular morbidity or mortality peri-transplant.
Keywords Cirrhotic cardiomyopathy, Liver cirrhosis, Prolonged QTc
166
Performance of Baveno VI and expanded Baveno VI criteria for avoiding endoscopy in Indian patient with compensated advanced chronic liver disease
Pallavi Gindodia, Kaushal Madan, Richa Bhargava, Sawan Boppana, Vikas Singla, Ayushi Singh, Jatin Aggarwal, Abhaya Indrayan
Correspondence - Kaushal Madan - [email protected]
Centre for Gastroenterology, Hepatology and Endoscopy, Max Institute of Liver and GI Sciences, 1 2, Press Enclave Marg, Saket Institutional Area, Saket, New Delhi 110 017, India
Introduction More and more cirrhotics are being diagnosed at an early stage, known as compensated advanced chronic liver disease (cACLD). It is impractical to subject this population to screening endoscopy. There is a need to validate the Baveno VI and expanded Baveno VI criteria to avoid doing a screening endoscopy in Indian setting.
Aim To assess the performance of Baveno VI and expanded Baveno VI criteria among Indian patients with cACLD.
Methods Consecutive patients with cACLD (liver stiffness >15) of any etiology, were included. Patients without a recent (within last 6 months) upper GI endoscopy report, and those with any history of decompensation in the past were excluded. Patients with a liver stiffness value, (LSM) >20 kPa and with platelet counts >1.5 lacs/mm3 were said to be meeting the Baveno VI criterion. Patients with LSM >25 kPa and platelet counts >1.1 lacs/mm3 were said to be meeting the expanded Baveno VI criterion for avoiding doing an endoscopy. The presence of low-risk esophageal varices on endoscopy was considered as confirming the findings of the non-invasive criteria and presence of high risk varices or h/o variceal bleed were considered as negative confirmation.
Results Of 69 cACLD, 31 were excluded. Of the 38, 22 (57.9%) were males and the median age was 56.5 (30-76) years). The sensitivity, specificity, positive predictive value and negative predictive value of Baveno VI criterion for avoiding screening endoscopy were 14.8%, 83.3%, 80% and 17.8% respectively. The corresponding values for expanded Baveno VI criterion were 30.8%, 83.3%, 88.8% and 21.7% respectively.
Conclusions More data is needed to assess the performance of both Baveno VI and expanded Baveno VI criteria in Indian patient with cACLD.
Keywords Baveno VI criteria, Fibroscan, Platelet counts
167
Emerging trends of bacterial infections in patients with liver cirrhosis - A clinical audit from a tertiary centre in western India
Jaseem Ansari, Harshal Gadhikar, Sanjana Bhagwat, Amol Bapaye, Nisarg Patel, Sachin Palnitkar, Mangesh Borkar, Ajay B R
Correspondence – Harsha Gadhikar - [email protected]
Department of Gastroenterology, Shivanand Desai Center for Digestive Disorders, Deenanath Mangeshkar Hospital, Kothrud, Deenanath Mangeshkar Hospital Road, Erandwane, Pune 411 004, India
Introduction Bacterial infections in liver cirrhosis (LC) patients cause acute-on-chronic liver failure (ACLF), multi-organ dysfunction (MODS) and is a leading cause of mortality. Antibiotic resistance is fast emerging, reemphasizing judicious utilization of antibiotics. The aim was to study the clinical and microbiological profile of LC patients with bacterial infections.
Methods Retrospective analysis of prospectively maintained database of LC patients. Three hundred and seventy-eight patients with LC admitted from January 2019 to December 2021. One hundred and eleven patients with infections included. Clinical, laboratory, microbiological data and sensitivity patterns analyzed.
Results Total admissions = 131, out of these, readmissions = 20, same infection = 12. Child-Turcotte-Pugh (CTP) score C 90/131 (68.7%). MELD Na < 15- 9/131 (6.8%); MELD Na >15- 122/131 (93.1%). 63/131 (48%) – AKI.
Culture positive (urine, ascites, sputum/endotracheal aspirate, skin, abscess, urethral discharge, blood) = 116, urine 45/116 (38.7%) > bacteremia 22/116 (18.9%). Gram negative infections - 90/116 (77.5%), gram positive infections – 26/116 (22.4%). Nosocomial infections 14/116 (12%). 30/116 (25.8%) - MDR; E. coli most common. 26/116 (22.4%) – XDR; K. Pneumonia most common.
SBP incidence 52/131 (39.6%); CTP C 42/52 (80.7%), CTP B 10/52 (19.2%); 36 typical and 16 atypical presentation (hepatic encephalopathy 12, breathlessness 3, hematemesis 1). Nosocomial SBP 3/20 culture positive SBP (15%). Commonest microorganism - E. coli 8/20 (40%) for SBP. 14/20 (70%) and 7/20 (35%) culture positive SBP resistant to 3rd-4th gen cephalosporins and piperacillin-tazobactam (PT). 3/8 (37.5%) on norfloxacin primary prophylaxis-developed culture positive SBP; 2/3(66%) resistant to quinolones. 46/81 (56.7%) and 41/86 (47%) culture sensitivity pattern resistant to PT and carbapenems.
49/131(37.4%) – ACLF. Mortality 42/111 (37.8%); CTP C 27/42 (64.2%), CTP B 13/42 (30.9%), CTP A 2/42 (4.7%); 23/42 (54.7%)-ACLF; 33 (29.7%) deaths during same admission.
Conclusion Emerging incidence of quinolone resistance emphasises the need to improvise antibiotic prophylaxis against SBP. Empirical antibiotic strategy needs to be revised in view of the high MDR/XDR rates especially in recurrent infections.
Keywords Acute on chronic liver failure, Bacterial infections, Liver cirrhosis
168
Prognostication of survival following pharmacologic treatment in decompensated cirrhosis with hepatorenal syndrome-Acute kidney injury
Vijay Narayanan, Antony George, Jesse Jacob, Krishnadas Devadas, Srijaya Sreesh
Correspondence - Vijay Narayanan - [email protected]
Department of Medical Gastroenterology, Government Medical College, Ulloor - Akkulam Road, Chalakkuzhi, Thiruvananthapuram 695 011, India
Background and Aims Hepatorenal syndrome-acute kidney injury (HRS-AKI) is one of the most challenging complications of advanced liver disease and is associated with extremely high mortality. The early identification of factors that predict short-term mortality in HRS-AKI is crucial to fast-track patients for liver transplantation. We assessed the outcomes of pharmacologic treatment and predictors of mortality in patients with HRS-AKI
Methods Eighty-four patients diagnosed to have HRS-AKI (based on the new ICA definition) who were treated with terlipressin and albumin were included. The response to pharmacologic therapy was assessed. Patients were then followed up for a duration of six months and factors which predict six-month survival were analyzed. Survival analysis was performed using the Kaplan–Meier method with log-rank test for comparison between the groups. Cox regression models were used to assess the association of clinical characteristics with overall survival.
Results Eighty-four patients with HRS-AKI were included. A complete response to therapy was seen in 54.8%, partial response in 14.3%, and no response in 31%. The factors associated with six-month mortality were the presence of hepatic encephalopathy, baseline stage of AKI, model for end-stage liver disease sodium score (MELD Na), and non-response to pharmacologic treatment. Treatment non-responders had higher mortality as compared to complete responders at one month (27% vs. 9%) and six months (74% vs. 45%). Mean transplant-free survival at six months was significantly longer in the treatment responders (148 days vs. 90 days, log-rank p<0.001). Cox regression analysis revealed that the independent predictors of six-month mortality were response to treatment (HR=0.527, p- 0.004) and MELD Na > 23 (HR=1.071, p-0.018).
Conclusion Response to pharmacologic treatment and MELD-sodium score are independent predictors of six-month mortality in HRS-AKI. Treatment non-responders have higher mortality and should be identified early to expedite liver transplantation
Keywords Acute kidney injury, Hepatorenal syndrome, Mortality
169
Knowledge, behavior and patterns of substance use disorder in people who inject drugs with chronic hepatitis C virus infection
Shikha Guleria, Anchal Sandhu, Madhumita Premkumar, Abhishek Ghosh, Debashis Basu, Ajay Duseja, Sunil Taneja, Arka De, Jasvinder Nain, Surender Sehrawat, Vishesh Kumar
Correspondence – Madhumita Premkumar - [email protected]
Department of Hepatology, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh 160 012, India
Background As previously reported, the National Viral Hepatitis Control Programme of India in the state of Punjab has a cure rate of 90.1% for people who inject drugs (PWID) with hepatitis C virus (HCV) infection, but a dropout rate of 15.6%. However, due to perceived stigma, PWID and patients with ongoing substance use disorders or injection drug use avoid general clinics, delaying referral until drug abstinence is confirmed. This leads to additional infections, breaks in treatment, and risk of drug-resistant HCV variants spreading among PWID.
Methods An integrated care team used a combination of directed acting antiviral agents (DAAs) to provide combined deaddiction therapy and management for HCV infection. We examined the knowledge, behavior; patterns of substance use disorder in PWID and assessed the risk factors for treatment failure and reinfection in patients who had been sent for specialized treatment for drug addiction.
Results We enrolled 300 PWID with viremic HCV infection (99.6% men; mean age 28 years; 91% literate and 33.3% married). Of them, 252 (84%) underwent deaddiction at Postgraduate Institute of Medical Education and Research, Chandigarh, and were given DAAs based treatment. Patients with active IDU had a cure rate of 90.4% and had 89.6% adherence. The cure rate in those with interruptions was reduced at 57.1%. Although 81.6% of PWID had accurate knowledge of the spread of HBV and HCV infection, only 39.6% of people had family members tested for HBV/HCV. Approximately 1% of people received herbal treatment, and 42% received hepatitis B vaccinations. Use of heroin (12.6%), alcohol (29.3%), nicotine (26.3%), chewing tobacco (1.6%), intravenous drugs (5%), marijuana (7.33%), opium (3.33%) and pain medications (2.33%) were reported, alone or in combination. Buprenorphine (246, 82%), nicotine patch (22,7.3%), ketorolac (20,6.6%) and nicotine gum (14,4.6%) were used as deaddiction therapy with counseling.
Conclusion DAAs based treatment ensures cure rate >90% in PWID who adhere to therapy.
Keywords Direct-acting antiviral agents, Drug resistant, Hepatitis C, PWID, Treatment
170
KGHeBTA (King George’s Medical University Hepatitis B Therapeutic Algorithm): A new cocktail, ready to be sipped and clinico-epidemiological spectrum of hepatitis B
Ajay Patwa 1 , Amar Deep2, Pratishtha Mishra1, Sumit Rungta2, Anil Gangwar2, Ankur Yadav2, Virendra Atam1, Kamlesh Kumar Gupta1, Bhaskar Agrawal3, Sanjeev Kumar Verma4
Correspondence - Ajay Patwa - [email protected]
Departments of 1Medicine, 2 Medical Gastroenterology, 3Prosthodontics, and 4Pediatrics, King George's Medical University, Chowk, Lucknow 226 003, India
Background There is lack of a simplified and comprehensive, diagnostic, and therapeutic algorithm for hepatitis B for day-to-day practice. There is lack of large-scale data on prevalence of different clinical stages, testing circumstances and risk factors for hepatitis B from our region. We tried to fulfil these gaps by our study.
Methods KGHeBTA (King George’s Medical University hepatitis B therapeutic algorithm), a new simplified and practical version of diagnostic and therapeutic algorithm for hepatitis B, was developed, primarily based on standard existing guidelines. Prevalence of different clinical stages of HBsAg positive patients, attending our hepatobiliary clinic, was estimated and their treatment records reviewed retrospectively. Testing circumstances and risk factors were noted.
Results Among 1508 data record sheets, 421 were complete. 221 had detectable hepatitis B virus DNA. 21% were cirrhotic and 79% non-cirrhotic. 72% were incidentally detected asymptomatic hepatitis B (IDAHB), 7% hepatitis B with acute symptoms (HBWAS), 0.7% acute hepatitis B (AHB) and 22% chronic hepatitis B (CHB). 20% patients were eligible for antivirals and 80% patients were not eligible. 32% patients were actually treated with antivirals due to inclusion of some special indications as pregnancy and family history. Screening during various medical illnesses (40%) was the most common and during health camps (0.2%) the least common testing approach. Road-side shaving (52%) was the most common and intravenous drug abuse (0.2%) the least common risk factor for detection of hepatitis B in our data pool.
Conclusions HBsAg positive patients can be easily worked up and treated based on the proposed algorithm (KGHeBTA). According to the algorithm, about one fourth to one fifth of all HBsAg positive patients were eligible and treated with oral antivirals. Most of the patients were IDAHB screened during medical illnesses. Roadside shaving and intravenous drug abuse were the most and the least common risk factors.
Keywords Chronic hepatitis B, HBV-DNA, Natural history, Risk factors, Testing approaches
171
Carotid intima-media thickness as a non-invasive tool to assess the risk of atherosclerotic cardiovascular disease in lean and non-lean non-alcoholic fatty liver disease patients
Jithin John, Avisek Chakravorty, Rushil Solanki, Devika Madhu, Ravindra Pal, Vijay Narayanan, Shivabrata Dhal Mohapatra, Yamuna R Pillai, Krishnadas Devadas
Correspondence - Jithin John - [email protected]
Department of Medical Gastroenterology, Government Medical College, Ulloor - Akkulam Road, Chalakkuzhi, Thiruvananthapuram 695 011, India
Background and Aims Non-alcoholic fatty liver disease (NAFLD) is now identified in normal body weight individuals also, termed lean NAFLD. Cardiovascular disease (CVD) is the major cause of mortality in NAFLD patients. We tried to assess the risk of atherosclerotic CVD in lean NAFLD individuals, by measuring the carotid intima media thickness (CIMT).
Methods Cross-sectional observational study including 120 patients of lean NAFLD (BMI<23 kg/m2) and 120 non-lean NAFLD (BMI≥23 kg/m2). Baseline demographic and clinical data was noted, including measurement of hemogram, liver biochemistry, lipid profile and homeostasis model assessment-estimated insulin resistance (HOMA-IR). Liver fibrosis was assessed using vibration controlled transient elastography (VCTE). CIMT was measured using standard software in carotid doppler ultrasound. Data was compared between the 2 groups, and factors independently predicting CIMT were determined using multivariate linear regression.
Results Lean NAFLD patients had significantly lesser mean waist circumference, total and visceral body fat percentage compared to non-lean patients (p<0.001 for all). Both groups had comparable waist-hip ratio (p=0.639). Non-lean NAFLD group had significantly higher H0MA-IR and serum triglycerides (p<0.001 for both). Other parameters of lipid profile and liver biochemistry were comparable. 55.8% of lean NAFLD population had metabolic syndrome, compared to 80.8% of the non-lean (p<0.001), by NCEP ATPIII criteria. At least one component of MetS was present in 92.5% of the lean population. Liver fibrosis by VCTE was similar in both the groups (p=0.162). When the groups were taken as a whole, CIMT was comparable (p=0.626), but in the 18-40 years age group, lean NAFLD subjects had significantly higher CIMT (p=0.034). Serum ALT, serum LDL and VCTE were found to independently predict the CIMT. Serum alanine transaminase (ALT) >75 IU/mL, serum low-density lipoprotein (LDL) >134 mg/dL and VCTE >9.4 kPa were the optimum cut-offs for predicting a high CIMT.
Conclusions Lean NAFLD subjects tend to have an equal risk of atherosclerotic CVD when compared to their overweight/ obese counterparts. Serum ALT, LDL and liver elastography values independently predict CIMT in NAFLD patients.
Keywords Carotid atherosclerosis, Carotid intima-media thickness, Lean NAFLD
172
A rare cause of hepatitis with multiorgan dysfunction
Prasanna Gore , Gaurav Mehta, Vatsal Kothari, Tanu Singhal, Sameer Tulpule
Correspondence – Gaurav Mehta - [email protected]
Department of Gastroenterology, Kokilaben Dhirubhai Ambani Hospital, Rao Saheb, Achutrao Patwardhan Marg, Four Bungalows, Andheri West, Mumbai 400 053, India
Case History A 58-year-old male came with complaints of fever, abdominal pain, vomiting, burning micturition, abdominal distension since 4-5 days. Preliminary blood test revealed Crp:29.182, PCT:8.05, AST:422, ALT:235, creatinine:3.23, bicarbonates:18.36, total bilirubin :9.49, direct bilirubin:8.52, indirect bilirubin:1.37, sodium :128, potassium:4.32, anti-HEV IgM: positive, scrub typhus IgM positive, leptospira and varicella IgM was positive. CPK:40.9, Hb:13.5, WBC:13440, platelets:165000. Patient had vesicles all over his trunk biopsy from ruptured vesicle: herpes infection, HSV1 and HSV 2 IgM and IgG antibodies positive. Patient was started on antibiotics and antifungals. ANA positive and speckled pattern and ASMA positive, autoimmune profile negative, C3,C4 levels were normal, In view of persistent deranged LFT trangjugular liver biopsy was done suggestive of foci of geographic hemorrhagic necrosis correlating with herpes hepatitis. In view of persistent hyperbilirubinemia, rising creatinine, breathlessness, disorientation, HSV hepatitis. Patient was started on Inj.Acyclovir. Patient became increasingly hypoxic and desaturated to 82% patient was intubated and mechanically ventilated CSF was positive for HSV, In view of thrombocytopenia and high counts and hypergammglobinemia SPEP was sent suggestive of polyclonal B cell activation suspected. Patient was on regular hemodialysis in ch w of worsening creatinine and creatinine improved, Inj.Methylprednisolone started in view of worsening parameters under antibiotics cover and steroids tapered gradually, patient improved well and recovered well.
Final diagnosis: Disseminated HSV 1 and 2 Infection (hepatitis and encephalitis) With MODS (AKI, LRTI) and polyclonal B cell activation syndrome with hypergamma globulinemia.
Keywords Hepatitis, HSV, Hypergammglobinemia, MODS
173
Vanishing bile duct syndrome due to dapsone toxicity
Nitin Pai, Chaitanya Lodha, Sahil Rasane
Correspondence - Chaitanya Lodha - [email protected]
Department of Gastroenterology, Ruby Hall Clinics, Rajeev Gandhi Infotech Park, MIDC Phase No 1, Plot No, P-33, Hinjawadi, Pune 411 057, India
Introduction Many dermatologic and non-dermatologic conditions need daspone therapy. Obligatory (dose-dependent) adverse drug reactions include hemolytic anemia, methemoglobinemia and hypersensitivity reactions to dapsone called the dapsone hypersensitivity syndrome.
Case Report A 23-year-old male, teacher by occupation, presented with insidious onset jaundice for 1 month which was progressively increasing associated with pale stools associated with dull aching low intensity right upper quadrant abdominal pain, low grade intermittent fever for 1 month, He also complaint of recent onset difficulty in opening mouth, lip swelling. He gave no history of gastrointestinal bleed, ascites, altered sensorium. He gave history of recurrent pustular nodular swelling in bilateral axilla, groin for 4 years. He took herbal/allopathy medications on and off for 4 years for the same. The patient was started on dapsone in December 2020 suspecting leprosy in view of multiple lesions. Dapsone stopped on 10/2/2021. On examination, he had scarring over the mandibles, bilateral tender axillary lymphadenopathy, thick velvety plaques over the axilla, groins, lower abdomen and neck with skin tags and multiple discharging sinuses with pus. On evaluation, serum IgG level was 20 mg/dL, contrast-enhanced computed tomography (CECT) showed hepatomegaly with mild diffuse fatty infiltration, splenomegaly, and multiple splenic infarcts. Gastroscopy (RHC) Kodsi grade I esophageal candidiasis, no other abnormality. Gastroscopy (RHC) Kodsi grade I esophageal candidiasis, no other abnormality. Transabdominal liver biopsy was suggestive of chronic intrahepatic cholestatic liver injury with mild hepatitis and marked ductopenia favoring vanishing bile duct syndrome. Drainage of the infected hidradenitis suppurativa was done and patient was started on antibiotics per the sensitivity report. Steroids were started 7 days later with a normal procalcitonin.
Conclusion High index of suspicion for early diagnosis of dapson hypersensitivity. Monitor patients for development of dapsone hypersensitivity syndrome. If drug is not withdrawn, it could have deleterious and potentially fatal effects due to major organ dysfunction
Keywords Dapsone hypersensitivity syndrome, Dapsone toxicity, Vanishing bile duct disease
174
Ciprofloxacin induced vanishing bile duct syndrome - A case report
Kishore Kumar Rajaram, Kandasamy Alias Kumar E, Poppy Rejoice R, Shafique A
Correspondence - Kishore Kumar Rajaram - [email protected]
Department of Medical Gastroenterology, Tirunelveli Medical College, 3, High Ground Road, Palayamkottai, Tirunelveli 627 011, India
Introduction Vanishing bile duct syndrome (VBDS) refers to a group of acquired disorders associated with progressive destruction and disappearance of the intrahepatic bile ducts leading to cholestasis. It has been described in different pathologic conditions including infection, ischemia, adverse drug reactions, autoimmune diseases, allograft rejection, and humoral factors associated with malignancy. Prognosis is variable and partially dependent upon the etiology of bile duct injury. We report a case of a 52-year-old male who developed vanishing bile duct syndrome a month later after using ciprofloxacin.
Methods Case Report - A 52-year-old male patient presented to us with jaundice, pruritus and easy fatiguability associated with weight loss. He had a history of diarrhea for which he has been treated with ciprofloxacin. Personal history was unremarkable. Physical examination revealed scratch marks and his conjunctivae were icteric. Laboratory investigations showed 17.6 mg/dL total bilirubin, 11.5 mg/dL conjugated bilirubin, 35 IU/L alanine transaminase, 320 IU/L gammaglutamyl-transpeptidase, 358 IU/L alkaline phosphatase, and 10 mm/h erythrocyte sedimentation rate (ESR). Serologic tests were negative for viral hepatitis A, B, C and E. Abdominal ultrasound showed that liver had homogeneous texture with normal bile ducts and gallbladder.
Result After ruling out the common causes such obstruction, infection by magnetic resonance cholangiopancreatography (MRCP), hepatitis panel then he was screened for autoimmune hepatitis and Wilson disease also. Finally, patient was subjected for percutaneous liver biopsy with Cytokeratin 7 staining, which showed >50% duct loss.
Conclusion VBDS should be considered when liver injury and cholestasis develop after antibiotics commencement. The level of suspicion must be further heightened when more common causes of cholestasis, such as biliary obstruction, are excluded. Early recognition of this association and cessation of the causative agent are paramount to achieving a successful outcome.
Keywords Cholestasis, Ciprofloxacin, Vanishing bile duct syndrome
175
Clinical implications and risk factor analysis of hepatitis B and C reactivation in patients receiving chemotherapeutic agents
Kondala Yedupati, Vijaishankar Chidambaramanivasagam, Kannan Mariappan, Ramani Ratinavel, Sriram P
Correspondence – Vijaishankar Chidambaramanivasagam - [email protected]
Department of Medical Gastroenterology, Madurai Medical College. Panagal Road, Alwarpuram, Madurai 625 020, India
Aim Aim of the study is to assess the risk factors for post chemotherapy hepatitis B and C reactivation and their clinical profile.
Materials Study group included 87 post chemotherapy viral reactivation patients of Government Rajaji Hospital, Madurai of which 75 patients had hepatitis B and 12 patients had hepatitis C reactivation. Demographic profile of individuals, history of blood transfusion, tattooing, surgery, family history of jaundice, tumour type, staging of tumor, duration of onset of jaundice after starting therapy, radiotherapy, liver function test, complete blood count, real time PCR analysis of HBV DNA and HCV RNA were analyzed. All deserving patients were treated, and subsequent follow-up done from 2020-2021.
Statistical Analysis It’s a prospective study. Fishers’ exact test was used to compare categorical variables. For non-parametric data Mann –Whitney test was used.
Results Post chemotherapy reactivation seen predominantly in age > 40 years (n=73.3%), female (n=75%), past history of surgery (n=65.5%). Majority of patients were on chemotherapy for carcinoma breast stage IV (87.3%), 68.6% individuals have silent reactivation, HBV associated icteric hepatitis 28.4%. Alkylating agent and antimetabolite combination therapy causing major reactivation in our study population (76.7%). Patients presented with reactivation after 6 cycles of chemotheraphy (66.7%) and mean duration from chemotheraphy to onset of jaundice is 4.8 months. Majority of the patients (67+12 patients) showed response to antivirals and follow up fibroscan value after 6 months mean value is 6.9 kpa. HCV reactivation is seen < 40 years more with hematological malignancy.
Conclusion Hepatitis B reactivation is more common than hepatitis C reactivation, elder age, female, usage of combination chemotheraphy agents, stage IV breast tumors, duration of chemotherapy and radiotheraphy are risk factors. Hepatitis C reactivation more in younger age and associated with hematological malignancies.
Keywords Chemotheraphy, Cirrhosis, Hepatitis B reactivation, Hepatitis C reactivation
176
A case of hepatic visceral larva migrans
Saurabh Gaur, Komal Kalla, Mukesh Kalla, Ramesh Roop Rai, Pankaj Shrimal, Aman Manocha, Alok Verma, Sumit Patter, Shreyans Jain, Suresh Kumawat
Correspondence – Saurabh Gaur - [email protected]
Department of Gastroenterology, S R Kalla Memorial Gastro and General Hospital, 78-79, Dhuleshwar Garden, C Scheme, Jaipur 302 001, India
Introduction Visceral larva migrans (VLM) is a systemic manifestation of migration of second stage larvae of nematodes through the tissue of human viscera. The liver is the most common organ to be involved due to its portal venous blood supply. Presenting a case of 16-year-old boy from a rural background presented with intermittent abdominal pain, malaise, loss of appetite and restlessness for 3 months.
Method Blood investigation revealed microcytic hypochromic anemia and eosinophilia (blood eosinophil count being 27%, AEC-1610 cu/mm). Serum alkaline phosphatase raised (885 IU/L), other liver function parameters normal. Coagulation profiles were normal. Serum α-fetoprotein came normal (<0.5 IU/mL). Ultrasound abdomen showed ill-defined hypoechoic lesions in right lobe of liver. Contrast-enhanced computed tomography (CECT) scan of the abdomen showed large hypodense SOL with multiloculated cystic areas (5.7 × 6.4 × 7.2 cms) in segment 6/7 of liver. A provisional diagnosis of hepatic lesions associated with parasitic infestation was made. The stool examination for entamoeba histolytica, giardia and ascaris ova and cyst were negative along with their serology. The values of serum IgE levels were also high (1860 IU/L).
USG guided fine needle aspiration cytology (FNAC) of the lesion with Giemsa stains showed cellular smears comprising mixed inflammatory cells predominantly consisting of eosinophils with few degenerated cells were also seen. No parasites were identified in the smears. The findings were suggestive of eosinophilic abscess, thus with correlating radiological findings, a final diagnosis of visceral larva migrans was made.
Results The patient was empirically given 400 MG twice daily albendazole for 5 days. The patient was totally relieved of his symptoms and complete resolution of hepatic sol seen.
Conclusion We can say in developing countries peripheral eosinophilia with hepatic Sol, one must keep the differential diagnosis of parasite infestation.
Keywords Hepatic SOL, Visceral larva migrans
177
Prevalence and predictors of significant liver fibrosis among Type II diabetes mellitus patients attending primary healthcare facilities
Aayushi Rastogi, Archana Ramalingam, Manya Prasad, Umesh Kapil, Guresh Kumar, Shiv Kumar Sarin
Correspondence – Aayushi Rastogi - [email protected]
Department of Clinical Epidemiology, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi 110 070, India
Background Patients with type 2 diabetes mellitus (T2DM) are at high risk for significant liver fibrosis, and have accelerated progression to advanced liver fibrosis and cirrhosis. Despite the high burden of T2DM prevalence estimates for significant liver fibrosis among T2DM are limited, from a country like India, which is recognized as the diabetic capital of the world. The present study aimed at assessing the prevalence of significant liver fibrosis among T2DM in primary healthcare settings using transient elastography as a screening tool.
Methods A cross-sectional study was undertaken between 2021-22 in previously diagnosed patients with diabetes seeking medical care in primary healthcare clinics of Delhi, India. A mobile screening unit with trained research staff administered a brief questionnaire to assess the personal and family medical history and behavioral risk factors. They also measured the anthropometric parameters and drew a venous blood sample for biochemical testing. Transient elastography was performed and significant liver fibrosis was defined as liver stiffness measurement of ≥7.9 kPa. Univariable and multivariable analysis was done to find out the factors associated with significant liver fibrosis using STATA v-14 with statistical significance considered at p-value <0.05.
Results: A total of 1674 participants with diabetes were included in the study with a mean age of 52±11.4 years and 55% were males. Prevalence of significant liver fibrosis was 24% (95% CI:21.9%-26.1%) among patients with diabetes. Older age, use of insulin, uncontrolled glycemic levels, morbid obesity, raised waist circumference, history of hypothyroid disease dyslipidemia, viral hepatitis, harmful use of alcohol, high socioeconomic status and occupation classified based on physical activity, were important predictors of significant liver fibrosis among diabetes patients (Table 1).
Conclusions The study highlights the high prevalence of significant liver fibrosis among T2DM in primary healthcare settings.
Keywords Diabetes mellitus, Liver fibrosis, NAFLD, Obesity, Screening
178
A rare cause of prolonged cholestatic hepatitis – Hepatic sarcoidosis
Siddharth Shukla 1 , Shreya Shruti2, Kim Vaiphei3, Anupam Lal4, Jayanta Samanta1, Saroj Kant Sinha1
Correspondence –Saroj Kant Sinha - [email protected]
Departments of 1Gastroenterology, 3Histopathology, and 4Radiodiagnosis, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India, 2Government Medical College and Hospital, Sector 32, Chandigarh 160 030, India
A 46-year-old diabetic female presented with jaundice and pruritus for four weeks. She had cholecystectomy five years back. Physical examination revealed deep icterus and mild hepatomegaly. Investigations showed total bilirubin 16 mg%, 4-6-fold elevated transaminases and 6-8-fold elevated alkaline phosphatase. Ultrasonography showed mild hepatomegaly and normal biliary system. Viral markers (hepatitis A–E), ANA, SMA, AMA and tissue transglutaminase antibody were all negative. Magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound showed normal biliary system. These investigations were repeated after 4-5 weeks, and results were similar. Due to intense pruritus despite medical treatment, endoscopic retrograde cholangiopancreatography (ERCP) and external biliary drainage was done. Jaundice and pruritus improved partially within 2 weeks, but mild jaundice persisted and alkaline phosphatase remained elevated. computerized tomography (CT) scan of chest/abdomen and positron emission tomography (PET) scan showed evidence of hilar and mediastinal lymph node enlargement with changes of interstitial lung disease. angiotensin converting enzyme level was elevated, Mantoux test was negative and liver biopsy showed granulomatous inflammation consistent with sarcoidosis. Her symptoms improved with oral prednisolone, but she relapsed twice on tapering dose of prednisolone. Azathioprine was added (1.5 mg/kg) which she continued for two years and tapered off. There was no relapse over next one year.
Discussion and Conclusion Sarcoidosis is systemic granulomatous disease characterized by non-caseating granulomas which most commonly occur in lungs. Hepatic involvement is not uncommon but prolonged cholestatic hepatitis is rare and is generally not considered in differential diagnosis of such syndrome. Here we are reporting rare manifestation of sarcoidosis in the form of prolonged cholestatic hepatitis.
Keywords Cholestasis, Hepatic Sarcoidosis
179
Clinical profile and treatment of hepatocellular carcinoma in a tertiary care hospital
Swaapnika Vemulapalli, Venkatakrishnan Leela, Mukundan S, Thirumal P, Karthikeyan R K, Arun P, Ravindra K
Correspondence – Swaapnika Vemulapalli - [email protected]
Department of Medical Gastroenterology, P S G Institute of Medical Sciences and Research, Avinashi Road, Peelamedu, Coimbatore 641 004, India
Background Hepatocellular carcinoma (HCC) is the sixth most common malignancy reported worldwide accounting for significant mortality and morbidity, especially in chronic liver disease patients. The incidence of HCC is 2.8 per 100,000 population per year in 2015. Hepatitis B remains the main etiology of HCC accounting for about 50 percent of cases followed by hepatitis-C. There is increasing incidence of HCC which is mainly due to incr
easing incidence of non-alcoholic steatohepatitis (NASH) and better surveillance of HCC among high risk groups. Hence this study is aimed to assess the clinical profile and treatment of HCC in a tertiary care hospital.
Methods A cohort (retrospective and prospective) study of 150 patients of HCC patients from January 2012 till August 2022 who presented to Gastroenterology and Hepatology Clinic at PSG Hospital, Coimbatore were included in the study.
Results Total patients analyzed were 150. Of those males were 83% (n=124) and females were 17% (n=26) with majority belonging to low socioeconomic status 30% (n=45). Mean age at diagnosis was 57.3±10.1 yrs.13% (n=20) were incidentally detected where 77% (n=115) had symptoms. 60% (n=90) presented with chief complaint of pain abdomen followed by weight loss in 40% (n=60). In 30.4% (n=46) etiology was identified as hepatitis B followed by 20.2% (n=30) with NASH and 10.4% (n=16) were alcoholic. Mean model for end-stage liver disease (MELD) score was 12.14±8.2.40.8% (n=60) had alpha-fetoprotein (AFP) more than 400 ng/mL at presentation. 42% (n=63) presented with Barcelona Clinic Liver Cancer (BCLC) stage C followed by 29% (n=44) with stage B. Distant metastasis were noted in 20% (n=30) with most common site being lung which is involved in 8% (n=12). 40% (n=60) had invasion in to portal vein leading to tumoral thrombosis. Treatment options were given to 83% (n=124), among which systemic chemotherapy was given in 42% (n=52) and trans arterial chemoembolization (TACE) in 31% (n=47).
Conclusion Emphasis to be made on earlier detection of HCC by adherence to screening protocols which will provide varied therapeutic options leading to better quality of life.
Keywords Alcohol, Hepatitis B, Hepatocellularcarcinoma
180
Incidence of hepatocellular carcinoma in patients of hepatitis C following treatment with directly acting antivirals: Study from tertiary care center in Tamil Nadu
Dhanush Thomas, Venkatakrishnan Leelakrishnan, Mukundan Swaminathan, Thirumal Perumal, Kartikayan S, Arun P
Correspondence – Dhanush Thomas - [email protected]
Department of Gastroenterology, P S G Institute of Medical Sciences, Off, Avinashi Road, Peelamedu, Coimbatore 641 004, India
Introduction Chronic hepatitis C the leading risk factor for hepatocellular carcinoma (HCC) among cirrhotics. In patients with cirrhosis de novo HCC occurs at rate of 3-7%. With recent advent of highly effective DAA, irrespective of the stage of liver disease, 90% of patients achieved SVR. Recent studies reported an increased incidence of denovo and recurrent HCC in patients treated with DAA.
Aim and Objective To assess the incidence of HCC in HCV cirrhotic patients who achieved SV
R after treatment with DAA.
Methods Type of study: Retrospective study. Place of study: PSG Hospitals, Coimbatore. Inclusion criteria - chronic HCV patients with cirrhosis. (1) Age > 18 years, treated with DAA. (2) Patient should achieve SVR after treatment with DAA. Exclusion criteria were non cirrhotics, who do not achieve SVR 12 after treatment with DAA and HCC before DAA treatment.
Results One hundred patients with chronic HCV infection treated with DAAs were included. HCV RNA viral load was rechecked at 4 weeks, end of treatment, 12 and 24 weeks. 66/100 have cirrhosis of liver. These patients were followed up for 6+/- 22 months. This report includes a series of 9 patients who developed HCC after achieving SVR. The patients were 3 males and 6 females of age around 55-76. There was no evidence of HCC pre-treatment. The predominant genotype was genotype 4. Sofosbuvir + ribavirin was prescribed to 2 (22.2%), sofosbuvir+ribavirin+daclatasvir to 2 patients (22.2%). Ledipasvir+Sofosbuvir to 5 patients (55.5%). sVR at week 12 was achieved in 9 cases (100%). Most of these new lesions were small; <3 cm in 5 patients (55.5%), 3-5 cm in 3 cases (33.3%), while 1 patient had a lesion > 5 cm. All patients developed HCC after an average of 8 months after achieving SVR.
Conclusion Rigourous screening of HCC during and post DAA should be done.
Keywords Cirrhosis, Direct acting antivirals, Hepatitis C, Hepatocellular carcinoma
181
Two different entities or the same?
Kishore Kumar Rajaram , Kandasamy Alias Kumar E, Poppy Rejoice R, Shafique A
Correspondence – Kishore Kumar Rajaram - [email protected]
Department of Medical Gastroenterology, Tirunelveli Medical College, 3, High Ground Road, Palayamkottai, Tirunelveli 627 011, India
Introduction Non-cirrhotic portal fibrosis (NCPF) clinically characterized by features of portal hypertension-moderate to massive splenomegaly, with or without hypersplenism, preserved liver functions, and patent hepatic and portal veins. According to the consensus statement of the Asia Pacific Association for the Study of the Liver (APASL) on NCPF, the disease accounts for approximately 10% to 30% of all cases of variceal bleed in several parts of the world including India.
Methods: Case Report A 20-year-old female with 2 months of gestation presented with complaints of easy fatiguability. Routine blood investigations revealed bicytopenia. USG shows massive splenomegaly with collaterals, but portal vein doppler study shows normal portal vein diameter and portal velocity. Then she was treated blood transfusion. After transfusion patient developed hemolytic jaundice, which resulted in spontaneous abortion with expulsion of dead fetus. Direct and indirect Coombs test also negative. Peripheral smear study shows dimorphic anemia with thrombocytopenia. Patient underwent endoscopy to rule out varix and GI cause of blood loss. Esophagogastroduodenoscopy (EGD) showed Grade 1 esophageal varix. Then ceruloplasmin and ophthalmology examination was done, which turns out to be normal. Autoimmune hepatitis panel was negative except ANA which was positive. As per rheumatologist opinion, she was screened for connective tissue diseases. Finally, she had Low C3 and C4 levels with Ro52 positivity alone (dsDNA and anti-histone was negative).
Result Liver biopsy shows normal lobular architecture with portal vein sclerosis with possibility of non-cirrhotic portal fibrosis. Patient was started on treatment with steroid (? connective tissue disease) and beta blockers.
Conclusion NCPH, which is a rare under-recognized condition both clinically and pathologically, should be considered in persons who have clinical manifestations of portal hypertension in the absence of cirrhosis. In case of middle-aged women, we have to think in terms of connective tissue diseases like SLE, APLA.
Keywords Non cirrhosis, Portal hypertension, SLE
182
Downregulation of TLR7 and status of HbsAg and HbeAg may act as predictive marker for HBV mother to child transmission
Simanta Kalita, Subhash Medhi, Panchanan Das, Sangitanjan Dutta
Correspondence – Subhash Medhi - [email protected]
Department of Bioengineering and Technology, Gauhati University, Gopinath Bordoloi Nagar, Jalukbari, Guwahati 781 014, India
Background and Purpose Hepatitis B virus (HBV) infection is one of the major contributor of global disease burden and its vertical transmission is a major concern to health care. The intriguing role of toll-like receptors have not been yet extensively studied in HBV mother to child transmission (MTCT). In this study the expression pattern of TLR 7mRNA were analyzed in venous blood samples collected from 25 HBsAg+ve mother during delivery from Gauhati Medical College and Hospital, Guwahati, Assam and it is correlated with HbsAg, HbeAg and HbeAb.
Methodology HbsAg, HbeAg and HbeAb were detected using ELISA and TLR7 mRNA expression is performed by real-time polymerase chain reaction (RT-PCR).
Results and Discussions Downregulation of TLR-7 was found to be statistically significant among mother HbeAg positive samples with the majority of the n=12 samples showing downregulation with mean fold change value of 0.55±0.24 (p=0.00, <0.05). A similar down-regulation of TLR7 mRNA pattern was observed for cord blood HbsAg positive samples (p=0.002) and HBV DNA positive venous blood (n=11) and cord blood (n=13).
Conclusions The study concludes that the downregulation of TLR7 along with HBsAg and HbeAg status may be an indication of vertical transmission of HBV.
Acknowledgments: The authors acknowledges the Department of Science and Technology, Govt. of India, Ministry of Science and Technology, New Delhi 110 016, for providing DST INSPIRE Fellowship for doctoral program.
Keywords HBV, mRNA, MTCT, TLR7
183
A rare presentation of massive hepatomegaly secondary to amyloidosis
Chhagan Birda, Yadav Suresh Chand, Isha Stutee, Rengarajan Rajagopal, Jyotsna Naresh Bharti, Ashish Agarwal
Correspondence – Ashish Agarwal - [email protected]
Department of Gastroenterology, All India Institute of Medical Sciences, Marudhar Industrial Area, 2nd Phase, M.I.A. 1st Phase, Basni, Basni, Jodhpur 342 005, India
Background Hepatomegaly is a common sign and can result from multiple inflammatory, infiltrative, and congestive disorders. We here report a case of patient with massive hepatomegaly that uncovered a diagnosis of systemic amyloidosis.
Case Report A 46-year-old female, presented with complaints of continuous pain and perception of lump in right upper abdomen for 8 months. She also had constitutional symptoms including easy fatigability, anorexia, and significant weight loss. On examination she had massive, firm hepatomegaly. Her lab investigations revealed elevated alkaline phosphatase (ALP), hypergammaglobulinemia and dyslipidemia. Contrast enhanced computed tomography (CECT) scan of chest and abdomen showed cardiomegaly and massive hepatomegaly. Further evaluation including echocardiogram, cardiac and abdominal magnetic resonance imaging (MRI) were suggestive of systemic infiltrative disorder. Abdominal fat pad, rectal and bone marrow biopsies were negative for amyloid but liver biopsy showed characteristic apple-green birefringence on Congo red staining. For characterization of misfolded protein, myeloma work up was done which was suggestive of light chain disease for which patient is being planned for hematopoietic stem cell transplantation (HSCT).
Conclusion Amyloidosis should be considered in patients presenting with hepatomegaly, raised ALP and other organ system involvement.
Keywords Systemic amyloidosis hepatomegaly multiple myeloma
184
Platelet to lymphocyte ratio as a non-invasive biomarker in assessing fibrosis in hepatitis C related liver disease
Uma Devi Malladi, Dinesh Kumar Dugganapalli, Jagveer Singh, Tony Pious, Bhaavan Paladugu
Correspondence – Dinesh Kumar Dugganapalli - [email protected]
Department of Medical Gastroenterology, Osmania Medical College, 5-1-876, Turrebaz Khan Road, Troop Bazaar, Koti, Hyderabad 500 095, India
Background Liver fibrosis is common problem in hepatitis C virus infection. Its evaluation is important for prognosis
Aim Evaluate the platelet to lymphocyte ratio (PLR) as non-invasive predictive marker of liver fibrosis in HCV patients and to compare PLR to transient elastography in assessing liver fibrosis.
Methods Thirty-five patients were recruited underwent physical examination and various clinical examination for assessing fibrosis. Transient elastography measurement using echosens fibroscan was performed. Patients were classified in to those with mild fibrosis (F1-F3) and significant fibrosis (F4) and compared with platelet to lymphocyte ratio. data analyzed using independent t test and International Business Machines (IBM) Statistical Package for Social Sciences (SPSS) software method.
Results The average age of the patients was 46±9.57 years, mainly men (n=18;51.4%) and 37.15% (n=13) had significant fibrosis (F4). PLR was lower in patients with significant fibrosis F4 vs. non F4 (81.13±38.55 vs 133.35±80.08; p = 0.035). APRI and FIB-4 were also calculated comparable with PLR (p <0.05). Age, platelet count, total serum bilirubin, liver stiffness, APRI, FIB-4 and PLR were predictors of significant fibrosis (p<0.05).
Conclusion Platelet to lymphocyte ratio (PLR) can be used as predictive marker for assessing significant fibrosis and is comparable to transient elastography and other non-invasive markers like APRI and FIB-4.
Keywords APRI, Hepatitis C, Platelet to lymphocyte ratio, Transient elastography
185
Fibroscan as a non-invasive tool in the study of liver fibrosis in non-alcoholic fatty liver disease
Sharathchandra Khanappanavar , Nandeesh H P, Deepak Suvarna, Aradya H V, Vijaykumar T R, Ganesh Koppad, Hitesh M R
Correspondence – Sharathchandra Khanappanavar - [email protected]
Department of Gastroenterology, J S S Hospital, Mahatma Gandhi Road, Fort Mohalla, Mysuru 570 004, India
Introduction The prevalence of non-alcoholic fatty liver disease (NAFLD) in India is reported to be between 9% to 32%. Simple and non-invasive, quantitative laboratory tests and radiological testing for the assessment of liver fibrosis in NAFLD have evolved to estimate the presence of steatohepatitis.
Inclusion Criteria Patients with fatty liver on ultrasonogram (USG). Patients 18 to 80 years of age of either sex. Exclusion criteria Alcohol intake >20 gm per day, HBsAg reactive, positive for anti-HCV, HIV, tuberculosis, Study design: Prospective study, duration: January 2021 to August 2022, Sample size:100.
Method of collection of data Patients will be selected for study according to all inclusion and exclusion criteria. A detailed history, clinical and laboratory data of these patients was recorded as per the questionnaiore. The Fibroscan scores will be then correlated with NAFLD, fibrosis score and fibrosis- 4 score.
Results In our study, 58 males 42 were female. prevalence of NAFLD in men was higher of 100 NAFLD patients, 43 showed no fibrosis (F0), 42 showed mild to moderate fibrosis (F1-F2), 15 severe fibrosis (F3-F4). Among the NAFLD patients with advanced fibrosis (n =15), 60 were male and 40 female. In our study 76% patients had Grade 1 fatty liver, 14% had Grade 2 and 10% had Grade 3. The mean stiffness scores for these grades was 5.66, 8.51 and 15.92 kpa respectively.
Conclusion Age cannot be used as a predictor of hepatic fibrosis in NAFLD. Male patients are more likely to suffer from advanced fibrosis than female patients. Diabetes, hypertension, obesity and hypertg are important risk factors for causing NAFLD. Therefore, NAFLD can be regarded as a hepatic manifestation of metabolic syndrome. FIB 4 score can diagnose likelihood of having advanced fibrosis or no fibrosis but cannot exclude minimal fibrosis. Statistically significant strong positive correlation was observed between Fibroscan and FIB4.
Keywords Diabetes, Fatty liver, Fibroscan
186
Neuroinflammation and its role in the pathogenicity of hepatic encephalopathy in patients with acute liver failure (Type A), in patients with cirrhosis (Type C) with hepatic encephalopathy
Madhu Chopra, Madhumita Premkumar, Anuradha Rakesh Kumar, Vashista Chakraborti, Ajay Duseja, Yogesh Kumar Chawla, Radha Krishan Dhiman*
Correspondence – Radha Krishan Dhiman - [email protected]
Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India, and *Department of Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raibareli Road, Lucknow 226 014, India
Background Hepatic encephalopathy (HE) is a neuropsychological condition, caused by ammonia, cerebral edema, and inflammation in patients with hepatic impairment, such as acute liver failure (ALF) or cirrhosis. Using the postmortem necropsies, we investigated the role of neuroinflammation, oxidative stress and cerebral edema in the pathogenesis of HE in ALF and cirrhosis patients.
Methods Brain tissues from 26 patients, including disease control (DC) without any liver/neurological disorder (n=10), liver cirrhosis with HE (n=10), and ALF (n=6) were collected at the time of autopsy. Wet and dry weight technique was used to determine the percentage of brain water (BW) content. The qRT-PCR and immunohistochemistry (IHC) were used to evaluate the expression of microglial markers (Iba-1, OX-42), proinflammatory cytokines (IL6,TNF-α,IL-1β), oxidative/nitrosative marker (Hsp-27, iNOS). The markers of blood brain barrier (BBB) (MMP-9, Occludin-1, Claudin-5) was demonstrated by IHC. Further, we also used ELISA technique to investigate the expression of IL-6 and IL-1β
Results The BW% was increased in patients with ALF and cirrhosis with HE in comparison with DC. In ALF patients, mRNA expression of Iba-1(p=0.009), OX-42 (p<0.001), IL-6 (p<0.001), TNFα (p=0.018), IL-1β (p=0.021) and iNOS (p=0.029) was upregulated as compared to DC. In patients with cirrhosis with HE the mRNA expression of OX-42, IL-6, TNF-α, IL-1β, Hsp-27, was found to be upregulated, but only Iba-1 expression level was significantly elevated (p=0.024). IHC analysis demonstrated the increased expression of Iba-1 (p<0.001), IL-1β (p=0.001), Hsp-27 (p=0.029), and iNOS (p=0.002) in patients with ALF, whereas in cirrhosis with HE patients, only Iba-1 (p=0.004) expression was statistically significant. Expression of MMP9, Occludin-1, and Claudin-5 markers showed the increased intensity through IHC in endothelial cells in patients with ALF compared to DC. The quantitative analysis performed through ELISA showed the increased concentration for IL-1β and IL-6 in ALF patients in comparison to cirrhosis with HE and DC.
Conclusion We demonstrated a substantial activation of the microglia through the expression of proinflammatory cytokines and oxidative/nitrosative markers in the cortical region of patients with ALF, as well as in patients with cirrhosis and HE, but with lower expression. Neuroinflammation due to excessive microglia activation might led to cerebral edema in patients with ALF and liver cirrhosis with HE
Keywords ALF, Cirrhosis, HE, Neuroinflammation
187
Role of cardiac scintigraphy-Myocardial perfusion imaging in diagnosis of cirrhotic cardiomyopathy
Vishesh Kumar, Madhumita Premkumar, Bhupendra Kumar Sihag, Ankur Gupta, Ashwani Sood, Ajay K. Duseja, Sunil Taneja, Arka De, Sahaj R, Nipun Verma, Surender Sehrawat, Jasvinder Nain, Anchal Sandhu, Shikha Guleria
Correspondence – Madhumita Premkumar - [email protected]
Department of Hepatology, Zydus Hospitals, Zydus Hospitals Road, Near Sola Bridge, Sarkhej – Gandhinagar Highway, Ahmedabad 380 054, India
Background Cirrhotic cardiomyopathy (CCM), defined as chronic cardiac dysfunction (LV systolic or diastolic dysfunction) in patients with cirrhosis, may be improved by therapy. The Echocardiographic E/e’ ratio is a predictor of survival in left ventricle diastolic dysfunction (LVDD) independent of the severity of the liver disease.
Methods In this study we evaluated objective imaging modalities like stress myocardial perfusion imaging (MPI) and multigated acquisition (MUGA) scan in cirrhotic cardiomyopathy and compared it with standard transthoracic echocardiography (TTE) with tissue doppler imaging (TDI) and speckle-tracking. We determined if these patients had underlying myocardial perfusion defects and also if diastolic dysfunction could be assessed using nuclear scintigraphy.
Result A total of 30 patients diagnosed with CCM (mean age 50±9.8 yrs, 70% male, 60%-ethanol-related, 16% NASH) were recruited the mean MELD Na was 13.7±4.2, of whom 73.3% were on beta blocker therapy. Mean E/e’ was 8.25±3.9 and cardiac output was 4.7± 2.7 L/min. On MPI scan, only 2% had reduced ejection fraction and 3.3% had evidence of myocardial perfusion defects. MPI scan showed 10% had evidence of reduced cardiac contractility. All 30 patients showed changes on electrocardiography including QTc prolongation (>403 ms). The Global longitudinal strain (GLS) score showed a good correlation with E/e’ ratio.
Conclusion Use of MPI/MUGA scans are a useful adjunct to TTE and TDI in patients with CCM as it provides information on undiagnosed coronary artery disease and left ventricle (LV) and right ventricle (RV) function separately.
Keywords Cirrhotic Cardiomyopathy, Echocardiography, Left ventricle dystolic dysfunction, Stress thallium
188
Prolonged steroid refractory cholestatic viral hepatitis A: Mycophenolate sodium to rescue. A case series
Pathik Parikh
Correspondence – Pathik Parikh - [email protected]
Department of Hepatology and Liver Transplant, Zydus Hospitals, Zydus Hospitals Road, Near Sola Bridge, Sarkhej – Gandhinagar Highway, Ahmedabad 380 054, India
Introduction Hepatitis A is usually a self-limiting illness. However, rarely it leads to persistent jaundice with pruritus. None of the pharmacological agents have been proven to be useful. This leads to significant deterioration in quality of life of the patients. As treating physicians, we need to think out of the box to alleviate their symptoms. We report here a case series of 5 patients who responded to mycophenolate sodium.
Case Series Five patients with acute hepatitis A have been included. The median age was 45 years and 3/5 were males. The mean duration of jaundice was 58 days. All patients had jaundice and severe pruritus. The mean bilirubin was 35 mg/dL. The presentation parameters are described in Table 1. The alternate etiological workup, liver ultrasound and liver biopsies were carried out in all. All patients were treated with symptomatic treatment, antihistaminic, cholestyramine, ondansetron, sertraline, ursodeoxycholic acid and multi vitamins. All patients received steroids for minimum 2 weeks before presentation. Two patients underwent therapeutic plasma exchange for 3 cycles without prolonged benefit. All patients were started on Mycophenolate sodium 720 mg per day in two divided doses. All 5 patients showed consistent improvement in symptoms and biochemistry with normalization of liver tests in median 5 weeks duration. None of the patients developed any drug related adverse effects
Discussion The mechanisms of liver injury in hepatitis A remain incompletely understood. While virus-specific CD8+T cells have long been considered a major cause of HAV-induced liver injury. MMF inhibits de novo purine synthesis, which is indispensable for the proliferation of lymphocytes, induces the apoptosis of activated T cells, suppresses the production of pro-inflammatory cytokines, and augments regulatory T cells thereby halting the ongoing hepatocyte damage. Further studies are warranted to validate our findings.
Keywords Jaundice, MMF, Pruritus, Viral hepatitis
189
Lenvatinib induced tumor lysis syndrome in hepatocellular carcinoma
Manjeet Goyal , Arshdeep Singh, Shivam Kalra, Ajit Sood
Correspondence – Manjeet Goyal - [email protected]
Department of Medical Gastroenterology, Dayanand Medical College and Hospital Tagore Nagar Civil Lines, Ludhiana 141 001, India
Hepatocellular carcinoma (HCC) constitutes more than 90% of primary tumors of the liver. Its incidence is on the rise and varied paraneoplastic manifestations have been reported. One such entity is the tumor lysis syndrome (TLS). TLS is a metabolic emergency resulting from the lysis of tumor cells leading to acute kidney injury (AKI), dyselectrolemia and, if left untreated, can lead to mortality. Lenvatinib, an oral multi-tyrosine kinase inhibitor is currently the first-line therapy for unresectable HCC. Though TLS is extremely rare in patients with HCC, we hereby report a case of TLS in a patient of HCC treated with Lenvatinib.
Keywords Hepatocellular carcinoma, Lenvatinib, Tumor lysis syndrome
190
Restrictive transfusion strategy was safe and reduced prophylactic use of blood products for plasma exchange port insertions in patients with liver disease
Vijesh V S 1 , Santhosh E Kumar 2 , Dolly Daniel 3 , Tulasi Geever 3 , Sukesh C Nair 3 , Joy Mammen 3 , Vinoi G David 4 , Santosh Varughese 4 , Kunwar Ashish Singh 2 , Ashish Goel 2 , C E Eapen 2 , Uday George Zachariah 1
Correspondence – Uday George Zachariah - [email protected]
Departments of 1Clinical Gastroenterology and Hepatology, 2Department of Hepatology, 3Department of Transfusion Medicine and Immunohematology, 4Nephrology, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Background Liver disease patients have deranged conventional coagulation parameters, which are not indicative of the rebalanced coagulation status.
Methods Retrospective study of consecutive patients undergoing plasma exchange (PLEX) for liver disease from October 2016 to February 2022. Early study period (2016-2019), patients with abnormal conventional coagulation parameters, were transfused prior to port insertion. Subsequently, during late study period (2020-2022), a restrictive transfusion policy was used, which coincided with the expanding use of ROTEM.
We aimed to measure the difference in prophylactic blood product usage and procedure related bleeding between the liberal vs. restrictive transfusion groups. All PLEX port were placed under USG guidance by trained personnel.
Results We studied 263 patients (age 35 [23-48] years) with MELD of 31 [25-38], acute on chronic liver failure [41.8%], acute liver failure [28.5%]). 117 patients received liberal prophylactic blood products transfusion compared to 146 where a restrictive transfusion strategy (ROTEM guidance followed). Thrombocytopenia (<50000/cumm) and coagulopathy (INR >1.5) were similar in early and late study periods (9.4% vs. 6.8%, p value 0.45 and 88.9% vs. 84.9%, p value 0.35).
For PLEX port insertion, prophylactic transfusion (FFP [35.4%], cryoprecipitate [2.7%], platelets [2.3%]) was given to 98 (37.2%) patients. 67.5% (79/117) patients in liberal transfusion received prophylactic products compared to 13% (19/146) in restrictive transfusion group; p value < 0.001. The number of FFP units received among patients in the liberal transfusion group was higher than restrictive transfusion group (4 vs. 0; p value< 0.001). Local bleeding during insertion was noted in 3 (1.1%) patients (2 in liberal and 1 in restrictive transfusion group) with major bleed in one.
Conclusion Restrictive transfusion strategy helped to reduce prophylactic blood product use for PLEX port insertion without increasing bleeding risk among liver disease patients.
Keywords Bleeding, Plasma exchange, Restrictive transfusion
191
A study of the prevalence of acute and chronic liver diseases among newly detected HBsAg positive subjects: A single centre experience
Chitta Ranjan Khatua 1 , Shivaram Prasad Singh2
Correspondence – Chitta Ranjan Khatua - [email protected]
1Department of Gastroenterology, MKCG Medical College, Berhampur, Odisha, and 2Kalinga Gastroenterology Foundation, Bajrakabati Road, Cuttack 753 001, India
Background Hepatitis B surface antigen (HBsAg) positive individuals are frequently encountered during routine health check-ups, blood donation, antenatal check-up, family screening, evaluation of liver related illness and other health related conditions. Many of them have various forms of serious liver diseases which goes undetected.
Aims We performed a prospective study to study the spectrum of liver diseases including chronic liver disease (CLD) and hepatocellular carcinoma (HCC) in newly detected HBsAg positive subjects.
Methods This study was conducted in consecutive patients with newly detected hepatitis B virus (HBV) infection attending the Gastroenterology OPD of MKCG Medical College, Berhampur between July 2020 and July 2022. Serological, biochemical, radiological and endoscopic evaluation was performed to study the type and severity of liver diseases.
Results Five hundred and eight HBV positive subjects were enrolled. Three hundred and ninety (76.8%) of them were males. While 71.2% (362) did not have significant liver disease, 28.8% (146) had various liver diseases like acute viral hepatitis (5.9%), chronic liver disease (CLD) (20.5%), and HCC (2.4%). Patients without liver related illness (71.2%) were younger than the patients with liver related illness (39.3±14.2:44.9±13.7; p<0.001). Among the patients with liver related illnesses, unfortunately only 18 (12.3%) HBsAg positive subjects were aware of the consequences of HBV infection. Besides, 9 (6.2%) had history of discontinuation of antiviral treatment, while 9 (6.2%) had HBV infection among family members.
Conclusion About one fourth of HBV infected patients had significant liver related disorders; of them a tenth had HCC at the time of evaluation. Patients with liver related illness were older in comparison to other HBsAg positive subjects, and most of the patients presented during fifth decade. Among HBV infected subjects, the awareness about the consequences of HBV infection was very poor.
Keywords Chronic liver disease, Hepatitis B surface antigen, Hepatitis B virus
192
To evaluate the prevalence of spontaneous portosystemic shunts in decompensated cirrhosis patients and its prognostic significance
Rishabh Kothari, Deepanshu Khanna, Premashis Kar
Correspondence – Premashis Kar - [email protected]
Department of Gastroenterology, Max Superspeciality Hospital, Sector 1, Vaishali, Ghaziabad 201 010, India
Introduction Spontaneous portosystemic shunts (SPSS) are frequent in liver cirrhosis and their prevalence increases as liver function deteriorates, probably as a consequence of worsening portal hypertension, but without achieving an effective protection against cirrhosis complications. This study is done to detect the prevalence of portosystemic shunts in liver cirrhosis patients and analyze its prognostic role.
Method We conducted a prospective observational study where ninety two patients with decompensated cirrhosis were evaluated based on history, physical examination, biochemical tests, and abdominal CT angiography findings. Follow-up was done after 6 months for development of cirrhosis-related complications.
Results Out of the 92 cirrhotic patients, 57.6% of patients had SPSS (L-SPSS + S-SPSS) detected by MDCT angiography. Overall, we found L-SPSS in 24 (26.1%) patient, S-SPSS in 29 (31.5%) patients and no shunt identified in 39 (42.4%) patients. Of all patients, splenorenal shunt 25 (27.2%) is the most frequent type followed by paraumbilical shunt (20.7%). Previous decompensating events including hepatic encephalopathy, ascites, SBP and GI bleed were experienced more frequently by the L-SPSS group followed by S-SPSS and W-SPSS group. Regarding follow-up, decompensating events episodes of HE developed more frequently in patients with L-SPSS 10 (41.7%) than patients with S-SPSS 7 (24.1%) followed by W-SPSS 5 (12.8%).
Conclusion In summary, all cirrhotic patients should be studied with radiological imaging in order to detect the presence of portosystemic shunt. In several cases, patients with large SPSS had a more impaired liver function and more frequent complications of portal hypertension so these patients would probably benefit from a closer surveillance and more intensive therapy. Moreover, the identification of SPSS became crucial in selected cases, in which the embolization of large SPSS may be associated with improved survival and liver function, as well as preventing the recurrence of HE or variceal bleeding.
Keywords Hepatic encephalopathy, Liver cirrhosis, Portal hypertension, Spontaneous Portosystemic shunts, Varices
193
An interim proteomics analysis of the longitudinal study reveals biological pathways and predictive proteins in acute kidney injury with decompensated cirrhosis
Inder Bhan Singh , Arka De, Vivek Kumar, Ashok Kumar Yadav, Virendra Singh
Correspondence – Virendra Singh - [email protected]
Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India
Introduction The development of acute kidney injury (AKI) in decompensated cirrhosis (DC) adversely impacts pre- and post-transplant outcomes. The prognosis of AKI in DC is difficult to study non-invasively. We hypothesized that urine proteomics could provide insight into the various pathways involved in the development of AKI in DC.
Method In this ongoing prospective longitudinal study we are enrolling patients with DC in the outpatient setting and following them up for the development of AKI. So far out of 78 patients, 11 developed AKI on following. We compared the baseline urinary protein of these 11 AKI patients with 11 propensity matched patients who did not develop AKI. AKI was defined according to International Club of Ascites criteria. Urine protein profiling was done using liquid chromatography-mass spectrometry (LC-MS) and was inferred using proteome discoverer 2.5. Pathways involved in the genesis of AKI were identified using various bioinformatic tools (gprofiler for gene ontology (GO), string and cytoscape for networking, reactome for pathway analysis). Hypergeometric distribution test was used to determine whether specific pathways are enriched. Probability score obtained was corrected for false discovery rate (FDR) using the Benjamani-Hochberg method.
Results LC-MS reveals several pathways that were putatively involved in the development of AKI. One hundred and ninety-two 261 identifiers in the sample were found in Reactome. Proteomic analysis revealed that 231 out of 2000 proteins were significantly increased in AKI group and 168 had ≥log2 difference in comparison to patients without AKI. Significant pathways identified included neutrophil degranulation, Extracellular matrix organization and degradation, innate immune system, FCERI mediated MAPK activation, FCERI mediated NF-kB activation, classical antibody-mediated complement activation and scavenging of heme from plasma (Fig. 1).
Conclusions Urinary proteomics suggests that pathways involved in immunity and inflammation play an important role in the development of AKI in patients with DC in the outpatient setting.
Keywords Acute kidney injury, Cirrhosis, Proteomics
194
10% fall in serum bilirubin predicts survival in patients with hepatitis B related liver failure undergoing low volume therapeutic plasma exchange
Vijay Balaji Muthukumaran 1 , Kunwar Ashish Singh 2 , Santhosh Kumar E 2 , Santosh Varughese 3 , Vinoi David 3 , Dolly Daniel 4 , Gayathiri K C 4 , Subramani K 5 , Kishore Pichamuthu 5 , Ashish Goel 2 , Uday George Zachariah 2 , Eapen C E 2
Correspondence – Vijay Balaji Muthukumaran - [email protected]
Departments of 1Gastroenterology, 2Hepatology, 3Nephrology, 4Transfusion Medicine and Immunohaematology, and 5Critical Care, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Background and Aims Plasma exchange (PLEX) is a promising novel therapy improving survival in patients with liver failure syndromes. The aim of the study was to estimate the 30-day transplant free survival in patients undergoing PLEX-LV (low-volume PLEX) for acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) due to hepatitis B virus (HBV) infection.
Methods We retrospectively analyzed patients who underwent PLEX-LV for ALF and ACLF due to viral infections between January 2018 and June 2022. Baseline parameters and dynamic change (Delta: Pre-PLEX-Post-PLEX %) in severity parameters after PLEX-LV were noted. 30-day outcome was assessed.
Results Of the 358 patients who underwent PLEX-LV for liver disease, 34 had viral infection (HBV=21, HAV=4, HEV=3, EBV=3, dengue=2, HSV=1). Twenty-one patients with HBV related liver failure (ALF:9, ACLF:12; M:57, age:50, 22-67years; median, range; MELD score:31, 21-49; plasma VWF antigen:428, 148-1063 IU/mL) underwent PLEX-LV (sessions: 3,1-5; volume per session:1400,875-1600 mL). 14/21 (67%) patients survived at 1-month (ALF:6/9; ACLF:8/12). Of the 5 (56%) patients with ALF who met Kings College criteria for emergency liver transplantation, 3 (60%) survived with PLEX-LV at 1-month.
None of the baseline severity parameters (MELD score, plasma VWF antigen etc.) predicted 1-month survival in these patients who underwent PLEX-LV. On analyzing the dynamic change after PLEX-LV, delta bilirubin (p=0.0001; AUROC:1), delta MELD (p=0.020) and delta VWF (p=0.033; AUROC: 0.8,0.6-1) were statistically significant predictors of 1-month survival. All 14 patients with serum bilirubin decrease >10% survived at the end of 30 days whereas all 7 patients who did not achieve the 10% decrease in serum bilirubin died within 30 days. In the study patients, one (4.76%) had transfusion related circulatory overload.
Conclusion Low volume PLEX (PLEX-LV) appears to improve outcome in patients with HBV related ALF and ACLF. In patients with HBV related liver failure who undergo PLEX-LV, a decrease in serum bilirubin of >10% with plasma exchange predicts 1-month survival.
Keywords Acute liver failure, Acute-on-chronic liver failure, Hepatitis B virus, PLEX-LV
195
A case of hepatic amyloidosis presenting as rapidly progressive hepatic failure
Adarsh C K , Pooja Krishnappa, Bhuvan Shetty, Vamshi A
Correspondence – Adarsh C K - [email protected]
Department of Medical Gastroenterology, BGS G1leangles Global Hospital, 67, Uttarahalli Main Road, Sunkalpalya, Bengaluru 560 060, India
Introduction Hepatomegaly (57% to 83%) and elevated ALP (86%) are the most common presentations in hepatic amyloidosis. Patient may have associated ascites, most likely due to concurrent heart failure or hypoalbuminemia. Rarely ascites may result from peritoneal amyloidosis. CLD, rapidly progressive hepatic failure and portal hypertension are rare.
Case Report An elderly male aged 67-year-old presented with complaints of abdominal distension of 2 months duration (requiring recurrent LVP), pedal edema and progressive jaundice of one month duration, no pruritus. Investigation done outside showed Hb-14.4, TC-11490, Plt-205000, INR-2.17, TB/DB-5.2/3.6, AST-135, ALT-63, ALP-226, albumin-2.2, creatinine-1.2, Na-129 and ANA -positive. Ascitic fluid analysis showed High SAAG, low protein ascites. CT abdomen showed hepatomegaly with nodular margins with gross ascites. UGI endoscopy showed small esophageal varices, mild PHG. Patient was referred to us for TIPS/liver transplant in view of refractory ascites. Patient underwent TJLB in view of hepatomegaly, rapid progression, normal platelets and ANA positivity. Biopsy showed dense deposition of pale eosionophilic acellular material-amyloid. BM biopsy showed moderately hypercellular marrow and plasmacytosis (25%). Immunofixation EP positive for lambda band. PET CT showed hepatomegaly with diffuse homogenous enhancement with no FDG avid lesion. Patient developed bleed PR, sigmoidoscopy showed rectal ulcers. Rectal biopsy showed focal ulceration with amyloid deposits. He was diagnosed to have IgG lambda myeloma with liver and GIT involvement, hepatic amyloidosis with PHTN with ascites, esophageal-varices, rectal-ulcer with amyloid deposits. Hematology opinion taken and was started on chemotherapy. Patient had altered sensorium, GI bleed, AKI and MODS within one week. He was admitted at nearby hospital, dialyzed, was on ventilator and passed away.
Conclusion Hepatic amyloidosis presenting as rapidly progressive liver failure is a rare entity. Diagnosis of hepatic amyloidosis needs to be considered in presence of atypical features of CLD/portal hypertension.
Keywords Hepatic amyloidosis, Liver failure, Trans jugular liver biopsy
196
Prevalence of lean and non-obese non-alcoholic fatty liver disease in India: Systematic review and meta-analysis
Arka De, Naveen Bhagat, Akash Roy*, Manu Mehta, Priya Singh, Aamir Bashir, Ajay Duseja
Correspondence – Arka De - [email protected]
Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India, and *Institute of Gastrosciences and Liver Transplantation, Apollo Multispecialty Hospital, 58, Canal Circular Road, Kadapara, Phool Bagan, Kankurgachi, Kolkata 700 054, India
Introduction Non-alcoholic fatty liver disease (NAFLD) has emerged as a major cause of chronic liver disease. Although most patients with NAFLD are obese, it is being increasingly recognised in non-obese and lean individuals. We performed a systematic review and meta-analysis to assess the prevalence of lean and non-obese NAFLD in India.
Methods Systematic search of PubMed, Embase, Scopus, and Google Scholar was done to retrieve studies from India (published in any form till 10th August 2022) which reported the proportion of lean or non-obese individuals among patients with NAFLD, or the burden of lean or non-obese NAFLD among the general population. Lean and non-obese were defined as BMI <23 kg/m2 and <25 kg/m2, respectively. Quality of included studies was graded as poor, average or high-quality using Hoy’s checklist. Heterogeneity was assessed using Cochran’s Q (p<0.1) and I2 ≥50%. Both fixed and random effects model were used depending upon heterogeneity. Publication bias was assessed using Begg’s test.
Results Sixteen studies meeting the eligibility criteria were included in the meta-analysis. All the studies were of average quality. Among patients with NAFLD, the proportion of those who were lean or non-obese were 17.5% (95% CI: 13.8-21.5%) and 34.2% (95% CI: 29.7-38.9%). Among the general population, the prevalence of lean and non-obese NAFLD were 6.4% (95% CI: 4.7-8.2%) and 10.9% (95% CI: 6.6-16.3%). There was significant heterogeneity for all analyses and random effects models have been reported. However, there was no publication bias.
Conclusion Although uncommon the burden of lean or non-obese NAFLD is not trivial in the Indian subcontinent.
Keywords fatty liver, Lean, NAFLD
197
The clinical profile of non-tumoral portal vein thrombosis in 463 patients with decompensated liver disease from a tertiary care centre in south India
Shivabrata Dhal Mohapatra , Jacob Raja, Srijaya Sreesh
Correspondence – Srijaya Sreesh - [email protected]
Department of Medical Gastroenterology, Government Medical College, Ulloor - Akkulam Road, Chalakkuzhi, Thiruvananthapuram 695 011, India
Backgrounds and Aims Portal vein thrombosis (PVT) is defined as thrombosis of the portal vein and branches of splenoportal axis. Incidence of PVT in compensated liver disease is between 0.6% to 5% and up to 25% in advanced disease. Presence of PVT in decompensated chronic liver disease (DCLD) is associated with significant morbidity and mortality. We evaluated the proportion and risk factors associated with non-malignant PVT in DCLD patients.
Methods Five hundred and two patients with DCLD were enrolled over a period of 1.5 years. Patients underwent detailed clinical history and evaluation, baseline investigation and ultrasonography. Contrast-enhanced computed tomography (CECT) abdomen was performed in patients with USG evidence of PVT or alteration in portal flow dynamics.
Results Thirty-nine patients were excluded. Fifty-one of the 463 patients included had PVT (11.0%). Duration of cirrhosis >4 years (p<0.01), non-alcoholic steatohepatitis (NASH) related etiology (p<0.01), prior history of obesity (p<0.01), dyslipidemia with high serum cholesterol and low-density lipoprotein (LDL) (p<0.01), clinically evident sarcopenia (p<0.01), first initial decompensation of cirrhosis as upper gastrointestinal bleed (UGIB), ≥2 prior UGIB (p=0.002), poorly controlled ascites (p<0.01), ≥2 history of episodes of SBP (p<0.01), platelet count <66.5 × 109/L (p=0.002), leukocyte count <5350/cu mm (p<0.01) were significantly associated with PVT group. There was no difference between CHILD B and C status, among the 2 groups. On multiple logistic regression analysis, ≥2 prior endoscopic variceal ligation, SAAG >1.95 were found as independent risk factors for development of PVT in DCLD patients.
Conclusions Proportion of non-malignant PVT in decompensated cirrhosis was 11%. Presence of poorly controlled ascites, prior history of UGIB, high SAAG, low platelet count as markers of severity of portal hypertension in cirrhosis are significantly associated with non-malignant PVT in DCLD. Patients with prior history of obesity and dyslipdemia, with NASH related cirrhosis are at high risk for the development of PVT.
Keywords Decompensated chronic liver disease, Hepatocellular carcinoma, Non-malignant portal vein thrombosis
198
Full dose sofosbuvir-velpatasvir in chronic hepatitis C in end-stage renal disease patients
Aadil Ashraf, Altaf Shah1, Muzaffar Wani
Correspondence – Aadil Ashraf - [email protected]
Department of Medical Gastroenterology, Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500 082, India, and 1Sher-i-Kashmir Institute of Medical Sciences, (SKIMS), SKIMS Main Road, Soura, Srinagar 190 011, India
Background India is witnessing high hepatitis C virus (HCV) infection burden in patients of chronic kidney disease. Due to nonavailability of costly recommended directly acting antiviral drugs in ESRD, pan-genotypic combination of Sofosbuvir-Velpatasvir can become an economical option. Data regarding treatment with this combination is scarce. Ours is the largest study from Indian subcontinent.
Objectives The study was undertaken to assess the efficacy, safety and side effect profile of Sofosbuvir-Velpatasvir in ESRD and patients on hemodialysis.
Participants Included both in and outpatient treatment naïve anti-HCV positive ESRD patients after proper informed consent.
Methodology The study was conducted from 1st September 2018 till February 2021. All the patients were evaluated for liver disease. All the patients received open label combination of sofosbuvir and velpatasvir (400 mg/100 mg). The primary and secondary endpoint was to assess sustained virological response (SVR12) and safety profile respectively. Institutional Ethical Clearance (IEC) was sought before starting the study.
Results One hundred and sixty-two patients were included in the study. Mean age in our study population was 43.08±12.08 years. Mean creatinine in our study population was 7.01± 2.61 mg/dL. One hundred forty-two (87.6 %) achieved viral clearance at 4 weeks of therapy. One hundred and sixty (98.7%) of the patients achieved end of treatment viral clearance and same number of patients maintained viral clearance 12 weeks after stopping the treatment (SVR12). Significant difference was seen in pre and post treatment serum bilirubin and ALT levels. No significant difference was found in pre and post treatment Sr albumin, creatinine and other parameters. The adverse effects noticed were nausea (20%), vomiting (18%), headache (10%), weakness (7%).
Conclusion Our study showed excellent efficacy with the safety profile of this drug combination in the studied population.
Keywords HCV in ESRD, HCV in hemodialysis, Sofosbuivir
199
Sarcopenia is associated with hepatic encephalopathy in patients with cirrhosis
Jayanta Nanda , Bikash Narayan Choudhury, Mallika Bhattacharyya, Utpal Jyoti Deka, Bhaskar Jyoti Baruah, Nikhil Gandhi, Preeti Sarma, Antara Sen, Pallab Medhi, Juchidananda Bhuyan, Suranjana Hazarika
Correspondence – Jayanta Nanda - [email protected]
Department of Gastroenterology, Gauhati Medical College, Narakasur Hilltop, G M C Hospital Road, Bhangagarh, Guwahati 781 032, India
Introduction Sarcopenia is an important burden in liver cirrhosis patients representing a negative prognostic factor. We investigated whether a decrease in muscle mass and muscle strength was associated independently with the occurrence of hepatic encephalopathy (HE).
Methods Patients diagnosed with chronic liver disease were enrolled from February 2022 to July 2022. Mid arm muscle circumference (MAMC) was used to assess sarcopenia. For the present study sarcopenia is defined as MAMC less than 5 th percentile for age. Handheld dynamometer was used to assess muscle grip strength. Cut off for decreased muscle strength is defined according to BMI. Multivariate logistic regression was performed keeping HE as the standard reference. Statistical analysis done using Statistical Package for Social Sciences (SPSS) version 25.
Results Total of 146 patients were analyzed. Of the total patients 116 (79.5%) and 102 (69%) patients had sarcopenia and decreased grip strength respectively. Mean MAMC in sarcopenic group was 19.13 cm (SD,1.78) as compared to 22.73 cm (SD, 1.68) in patients having normal muscle mass. Patients having normal and decreased grip strength have a mean dynamometer score of 28.26 kg (SD, 5.3) and 20.48 kg (SD, 5.5) respectively. Sarcopenic patients had higher prevalence of HE as compared with patients having normal MAMC (34% vs. 10%, p = .007). Also patients having decreased grip strength had more frequency of HE as compared to patients having normal grip strength (35% vs. 13%, P=.009). By multivariate regression analysis, sarcopenia (p=0.004), hypokalemia (p=0.019) and total bilirubin (p=.005) were independently associated with occurrence of HE. Decreased grip strength was not associated independently with HE (p=.465).
Conclusion Sarcopenia and hypokalemia but not decreased grip strength were independently associated with occurance of HE in patients with cirrhosis.
Keywords Cirrhosis, Grip strength, Hepatic encephalopathy, Hepatology, Nutrition, Sarcopenia
200
Safety and efficacy of Saroglitazar in improving FIB4 index in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis population - A 52-week, real world experience
Mayank Mehrotra
Correspondence – Mayank Mehrotra - [email protected]
Department of Gastroenterology, Regency Hospital Ltd., 112/335 A, Swaroop Nagar, Near Madhuraj Hospital, Kanpur, India
Background and Aims Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease worldwide and affects around 30% of the adult population in Asia. The fibrosis scores are reasonable options for diagnosis and assessing treatment progression in routine practice. The Fibrosis-4 index (FIB-4) has been shown to be a prognostic marker of liver-related outcomes in patients with NAFLD. We evaluated the efficacy and safety of Saroglitazar 4 mg OD in NAFLD/NASH in routine clinical practice.
Methods A total 94 documented NAFLD patients (90.4% males and 64.5% non-diabetics) with elevated LFT (mean AST 60.4+21.3 and ALT 90.2+39.5) and baseline mean fibrosis scores (FIB4 1.37+0.6, NFS-1.47+1.11, APRI 0.84+0.33), were prescribed on Saroglitazar 4 mg OD, and the effectiveness was analyzed based on changes in LFT, FIB4 Index and triglycerides level at 12 and 24 weeks. Out of 94 patients, 44 were followed up and also analyzed at 52 weeks. The study population was of mean age 38.1±11.2 years and mean BMI 26.5+3.6 kg/m2. 90.4 % patients (n=85), (severe fibrosis n=8, indeterminate fibrosis n=77) at baseline have elevated one or more fibrosis score. The data was analyzed to find out improvements at 12, 24 and 52 weeks from baseline and statistical significance was established using paired sample T- test.
Results The study shows statistically significant improvements in the measured parameters from baseline. Also, there was significant improvement in overall FIB 4 score by 12.7%, 27.9% and 39.9% at 12, 24 and 52 weeks respectively, with 80.9% patients (n=76) in low FIB4 range after 24 week and 97.7% after week 52, compared to 51.1% (n=48) patients at baseline.
Conclusions The study shows Saroglitazar 4 mg OD as a safe and effective treatment option for NAFLD/NASH, with significant improvement in all liver related parameters.
Keywords FIB-4 index, NAFLD, Saroglitazar
201
Therapeutic plasma exchange helps in management of pregnancy associated liver failure
Sushovan Baidya, Ashish Goel, Santosh Varughese, Dolly Daniel, Subramani Kandasamy, Santosh Kumar E, Asish Singh, Uday George Zachariah, C E Eapen
Correspondence – Sushovan Baidya - [email protected]
Department of Hepatology, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Introduction We present an unusual case of peri-partum acute-on-chronic liver failure complicated by thrombotic microangiopathy managed successfully with therapeutic plasma exchange.
Case A 21-year-old female (G1P1), with no history of gestational diabetes mellitus or hypertension, delivered a 3.5 kg healthy girl baby at 39 weeks by caesarean section. She was noted to have ascites during surgery and postoperatively developed decrease in urine output, worsening ascites, along with abdominal pain and jaundice. She became hypotensive with deterioration in sensorium. On presentation she had ascites, splenomegaly, lactic acidosis, thrombocytopenia (platelet count-15000/cmm), hyperbilirubinemia (S. bilirubin-18 mg/dL), coagulopathy (INR-3.5) and acute kidney injury (S. creatinine- 2.5 mg/dL). On imaging there was ascites, splenomegaly, attenuated portal vein replaced by collaterals and no retained products of conception. Gastroscopy showed small esophageal varices. Presence of thrombocytopenia, kidney injury, high schistocytes (9.88%) on peripheral smear, raised LDH and low ADAMTS 13 (24%) suggested thrombotic microangiopathy, thus a probable post-partum HELLP syndrome.
Etiological evaluation was negative for alternate aetiology of thrombotic microangiopathy (e.g. tropical fever syndromes, Wilsonian crisis, sepsis etc.). Besides supportive management, which included mechanical ventilation and renal replacement, the patient underwent five sessions of therapeutic plasma exchange (PLEX). A plasma volume of 7300 mL was replaced with an equal volume of fresh frozen plasma over 7 days. The patient was also given broad spectrum antibiotics with low dose steroids. The patient showed gradual improvement in general condition and renal function and discharged in a stable state after an in-hospital stayof 51 days, which included 25 days on ventilator and 40 days in intensive care unit. The patient remains well after 10 months of follow-up.
Conclusion Thrombotic microangiopathy is not uncommon in the peri-partum period and often associated with HELLP syndrome. The case highlights the role of therapeutic plasma exchange in managing these patients.
Keywords Plasma exchange, PLEX, HELLP syndrome
202
Predictors of response to standard medical therapy in hepatorenal syndrome (HRS-AKI) patients
Ajay Kumar, Roshan George, Bhawna Mahajan, Ujjwal Sonika, Ashok Dalal, Sanjeev Sachdeva
Correspondence – Roshan George - [email protected]
Department of Gastroenterology, Govind Ballabh Pant Institute of Post Graduate Medical Education and Research, 1, Jawaharlal Nehru Marg, New Delhi 110 002, India
Introduction The HRS-AKI is managed with vasoconstrictor drugs and albumin (SMT) however overall resolution occurs in about 30% to 40% patients; also treatment is associated with significant adverse effects. The present study was done to find the predictors of response in HRS-AKI patients managed with SMT.
Methods The consecutive decompensated cirrhosis (DC) patients who were diagnosed as HRS-AKI (International Club of Ascites [ICA] 2015) seen between March 2020 and February 2021 were enrolled. The patients were treated with vasoconstrictor (terlipressin or noradrenaline) and 20% human albumin. HRS-AKI response to treatment was defined as per ICA 2015 criterion, those who had complete response of HRS-AKI were classified as ‘responders’ and patients with partial response and no response of HRS-AKI were classified as ‘non-responders’.
Results Overall 25 HRS-AKI patients (mean age 49.52±13.7 years and 21 [84%] males) were enrolled. The 9 (36%) patients had infections (spontaneous bacterial peritonitis n=6, pneumonia n=2 and bacteremia n=1), mean arterial pressure was 80.04±9.35 mmHg, mean Child score was 10.9±2.3 and mean MELD score was 29.84±6.87 respectively. The vasoconstrictor therapy used was terlipressin (n=24) and noradrenaline (n=1), 14 patients were responders and 11 were non-responders. On multivariate analysis higher platelet count (p=0.04) and high Interleukin-6 (IL-6) (p=0.02) were predictors of response to SMT.
Conclusion Platelet count and IL-6 levels are predictors of response to SMT in HRS-AKI patients however further studies need to be done to evaluate their role.
Keywords Decompensated cirrhosis, HRS-AKI, Vasoconstrictor
203
Acute cytomegalovirus hepatitis in immunocompetent patient
Vinay V
Correspondence – Vinay V - [email protected]
Department of Medical Gastroenterology, GEM Hospital, Pankaj Mill Road, Ramanathapuram, Coimbatore 641 045, India
Objective Challenging differential diagnosis.
Introduction Cytomegalovirus (CMV) has an incubation period of about 4 to 6 weeks. Symptoms of CMV infection vary and depend on factors including the age and immune status of the patient. It usually presents as asymptomatic infection in immuno-competent individuals whereas severe disease is usually seen in immunocompromised patients.
Case Report A 53-year-old male patient known case of chronic liver disease. Patient is known alcoholic consumes alcohol occasionally. Presented with history of yellowish discoloration, itching, swelling of abdomen since 3 weeks. History of alternative medication was present. Treatment history was 2 cycles of plasma exchange. Patient was referred to our hospital for liver transplant. Routine etiology was normal, non hepatotrophic viruses work was sent. CMV IgM and IgG was positive. Trans jugular liver biopsy was done which showed inclusion bodies.
Results The patient was treated with valganciclovir that resulted in rapid improvement in clinical status as well as normalization of the liver enzymes. Patient is being followed up on monthly basis now liver function test is normalized. Patient has be delisted form transplant list.
Conclusion This case report presents a rare case of immunocompetent male with acute CMV hepatitis who responded favorably to antiviral therapy.
Keywords Cytomegalovirus hepatitis, Immunocompetent, Liver transplant
204
Cardiac dysfunction in chronic liver disease: 2 D echo cardiograph and tissue doppler study
Devarakonda-Madhusudhana
Correspondence – Devarakonda Madhusudhana - [email protected]
Department of Medical Gastroenterology, Narayana Medical College and Hospital, Chinthareddipalem, Nellore 524 002, India
Echocardiography is a non-invasive method to find cirrhotic cardiomyopathy in chronic liver disease. Important to evaluate cardiovascular function and filling dynamics in every patient with cirrhosis, especially if the patient is a candidate for any intervention that may affect hemodynamics or diseases that place stress on the heart.
The aim of this study was to find out the prevalence of cardiac changes in patient with chronic liver disease using conventional echocardiography and a tissue Doppler study to correlate the clinical profile and echocardiographic changes in patients with chronic liver disease.
Methodology We identified 100 patients at Department of Medical Gastroenterology, Narayana Medical College and Hospital as part of cross-sectional observational study in chronic liver disease of any cause was made on the basis of clinical history and examination, biochemical and serological evaluation, and ultrasonographic imaging, and selected case, subjected for conventional echocardiographic study and tissue Doppler imaging to assess the cardiac status.
Results In the study, majority of patients were males (n=60, 60%) in the age group of > 40 yr. Over all prevalence of cardiac abnormalities were found in 53%. The prevalence of cardiac abnormalities 57.9% in Child class C, 45.7% in Child class B, 50% in Child class A, increased with severity of chronic liver disease. As per Chi-square test (62.2% vs. 37.8%; p> 0.05). Increased prevalence of cardiac abnormalities found in ethanol related chronic liver disease as per Chi-square test (66% vs. 34; p>0.05). Among cardiac abnormalities, prevalence of diastolic dysfunction was 88%, Systolic dysfunction was 16%, and pulmonary arterial hypertension was 41%. High prevalence of subclinical cardiac abnormalities in chronic liver disease patients, advising an echocardiogram for patients with cirrhosis (CTPS - B and C) will be beneficial in early screening.
Keywords Chronic liver disease, Conventional echo, CTPS, (Child-Turcott-Pugh score), Diastolic, Systolic,Tissue doppler
205
Alcohol drinking patterns among patients of liver disease admitted to a tertiary care hospital in Gujarat
Aakash Sethi , Jaya Pathak, Kalpita Shringarpure, Kaatyayani Choudhary, Gayatri Laha
Correspondence – Aakash Sethi - [email protected]
Government Medical College, Vinoba Bhave Road, Anandpura, Vadodara 390 001, India
Introduction The amount, duration and type of alcohol consumption is related to the occurrence of alcoholic liver disease (ALD). Consumption more than 160 grams (men) and 90 grams (female) puts a patient at risk for developing ALD. However, this data is unavailable for the Indian scenario; given the genetic differences among Asians and Western population, this data would be useful. We aim to estimate the duration, amount and the drinking pattern which leads to development of ALD
Methods One hundred and twenty admitted adult patients and consuming alcohol were included and divided into two groups - ALD group- patients having no other cause for liver disease and consuming hazardous levels of alcohol based on alcohol use disorder identification test (AUDIT-C) scores. Non-ALD group- Rest all patients. The amount of alcohol consumed was first recorded in ml and then converted to grams using Nayak et al's. study. The groups were compared using the Mann-Whitney test. Quantitative data was expressed using mean±SD or median with IQR.
Results Seventy-three ALD and 47 non-ALD patients were included. The median duration of alcohol intake was eight years (IQR= 5 years). Commonly patient drank country made liquor (82.6%). The mean amount of alcohol consumed (absolute alcohol*duration*frequency) in ALD group was 3557.14 year alcohol (SD=1658.03) and in the non-ALD group was 1654.29 (SD=610.08) (p=0.010).The hazardous drinkers consumed 360.14 (SD=170.92) gm of absolute alcohol per day while the non-hazardous drinkers consumed 126.67 gm (SD=44.22) (p=0.007).
Limitations Recall bias could be present as patients were chronic drinkers. Patients could be reluctant to fully and accurately disclose their alcohol intake.
Conclusion We found that drinking about 360 gm/day of absolute alcohol conferred statistically significantly higher chances of developing alcoholic liver cirrhosis and hepatitis. However, less than 1/3rd patients developed alcoholic liver cirrhosis due to alcoholism.
Keywords Alcohol drinking pattern, Alcoholic liver disease, Hazardous alcohol consumption
206
Zinc deficiency as a marker of severity of chronic liver disease
Rahul Sangwan, Ritesh Kumar Gupta, Lokesh Kumar Sharma
Correspondence – Rahul Sangwan - [email protected]
Department of Internal Medicine, Atal Bihari Vajpayee Institute of Medical Sciences (ABVIMS) and Dr. Ram Manohar Lohia Hospital, Baba Kharak Singh Road, Type III, Connaught Place, New Delhi 110 001, India
Introduction Chronic liver disease is a common health problem in the developing world. Zinc is an essential trace element playing a pivotal role in liver functioning. The aim of the study is to compare the S. zinc levels in patients with the severity of chronic liver disease on basis of Child-Turcotte-Pugh (CTP) scoring and to compare S. zinc levels in patients with compensated and decompensated chronic liver disease.
Methods The cross-sectional observational study was conducted for a period of 1 year and 6 months on 105 patients of the 18-65 years age group, who presented with chronic liver disease irrespective of severity and underlying etiology. Patients were classified into three groups on the basis of CTP scoring (CTP-A, B, C). All patients’ serum zinc was collected and its value was compared with the other groups.
Results 1. Zinc deficiency is more profound with increasing severity of chronic liver disease. There is a strong negative correlation between CTP score and S. zinc (rho = -0.8) and was statistically significant (p<0.001). 2. Zinc values are much lower in the decompensated chronic liver as compared to compensated liver disease. The mean values of serum zinc in CTP-A was 67.1 μg/dL, in CTP-B was 48.2 μg/dL, and in CTP-C was 31.6 μg/dL.
Conclusion Zinc deficiency is commonly encountered in chronic liver disease. Zinc deficiency is aggravated with the severity of chronic liver disease. Hence, zinc shall be measured routinely in patients of chronic liver disease and can be regarded as a marker of its severity.
Keywords Chronic liver disease, Cirrhosis, Zinc
207
A study on prevalence of adrenal insufficiency in patients with acute and chronic liver failure with short Synacthen test
Chevigoni Saidulu , Sukanya Bhrugumalla
Correspondence – Sukanya Bhrugumalla - [email protected]
Department of Medical Gastroenterology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad 500 082, India
Introduction Adrenal reserve depletion and overstimulation of the hypothalamus-pituitary-adrenal (HPA) axis are causes for adrenal insufficiency (AI) in critically ill individuals. Cirrhosis is a predisposing condition for AI as well. Both stable cirrhotics and liver transplant patients have been reported to have AI. Presence of AI in liver disease increases the risk of cardio circulatory compromise, infections, and mortality. Hence, we aimed to study the prevalence of AI in patients with acute and chronic liver failure which can help in prognostication.
Methods This prospective observation study was conducted in at a tertiary care center in South India. Adrenal insufficiency assessed by low dose short Synacthen test giving 1μg of synthetic ACTH (Syntropac) intravenously followed by measuring serum cortisol level at baseline (>5 μg/dL) and 60 min later. A level >500 nmol/L (18 μg/dlL) denoted normal response.
Results Twenty-five patients (23 males, mean age) were recruited. The commonest etiology was ethanol (76%). Among these, 80% and 20% of the patients were CTP C and CTP B, respectively. Adrenal insufficiency before SST was seen in 16%, and after SST seen in 40%. Adrenal insufficiency significantly correlating with short Synacthen test (SST) test (p< 0.031) and total bilirubin (p<0.042) levels. No correlation was observed with hepatic encephalopathy, AKI, SBP, variceal status, CTP score, and MELD-Na.
Conclusion Measurement of serum cortisol level after SST increases the probability of diagnosis of adrenal insufficiency compared to basal serum cortisol levels.
Keywords Addrenal insufficiency, Cirrhosis, Short synacthen test
208
Non-cirrhotic portal hypertension: Clinical profile and progression to liver cirrhosis
Santosh Hajare, Aditi Rao
Correspondence –Aditi Rao - [email protected]
Department of Gastroenterology, J. N. Medical College, JNMC KLE University Campus, Nehru Nagar, Belagavi 590 010, India
Background and Aim Non-cirrhotic portal hypertension (NCPH) is a heterogenous group of liver disorders of vascular origin, leading to portal hypertension [1]. NCPH is a common cause of portal hypertension in Japan and Indian subcontinent, constituting up to 30% and 40% of the cases respectively, while only 3% to 5% of portal hypertension in Western countries is attributed to NCPH [2]. The mean age of NCPH patients varies from 25-35 years [3]. The present study was undertaken up in a tertiary care centre in North Karnataka to determine the epidemiology and clinical profile of patients presenting with NCPH and the incidence of patients progressing from non-cirrhotic stage to cirrhotic stage.
Methods A retrospective clinical study, with 136 presenting with NCPH patients, was conducted. Patients with variceal bleed and other abdominal complaints were included for the study. All the patients were subjected to the upper/lower GI endoscopy (EUS, Olympus, USA).
Result In total, 136 subjects were used for the study. Out of which 90 subjects presented with NCPH. The prevalence of NCPH to become CLD was 24.44% (15.57%-33.32%). And mean time for NCPH subjects to become CLD was 3.68 years.
Conclusion The prevalence of NCPH to become CLD was more in middle aged people than compared to children. And mean time for NCPH subjects to become CLD will be at least 3 years. Within this period of time patients presenting with NCHP can be diagnosed.
References
1. Khanna R, Sarin SK. Non-cirrhotic portal hypertension–diagnosis and management. J Hepatol. 2014; 60:421-41.
2. Jayanthi V, Jain M, Vij M, Varghese J. Natural history of non-cirrhotic portal fibrosis-a tropical experience. Gastroenterol. Hepatol. Open Access. 2017; 6:00185.
3. Patwary MI, Rahman M, Mojumder K. Non-cirrhotic portal hypertension: current concepts and modern management. Bangladesh Medical Journal. 2014; 43:170-6.
Keywords Cirrhosis, Hypertension, Portal pressure, Venous pressure
209
Single centre experience on outcome of idiosyncratic drug induced liver failure treated with low volume plasma exchange and low dose steroid
Kunwar Ashish Singh, Santhosh Kumar E, Uday Zachariah, Vinoi David, Dolly Daniels, Subramani Kandasamy, Kishore Pichamuthu, Ashish Goel, C E Eapen
Correspondence – Kunwar Ashish Singh - [email protected]
Department of Hepatology, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Background We present our experience with low volume PLEX (50% of estimated plasma volume exchanged per session) and low dose steroids to treat idiosyncratic drug-induced liver injury (I-DILI) patients with liver failure.
Methods We analyzed data on patients with I-DILI (diagnosed as per RUCAM score), treated with low volume plasma exchange (PLEX) and low dose steroid (Prednisolone: 20 mg OD, with rapid taper) in our department from 2016 to 2022. All eligible patients were counselled regarding liver transplant. Baseline and dynamic parameters (post-PLEX) were assessed as predictors of 1-month outcome.
Results Forty-eight I-DILI patients (probable: possible:: 41:7, 27 males, age 38.5 [14-84] years, median [range]; MELD score: 30 [24-43]) underwent plasma exchange for acute (ALF- 23) and acute-on-chronic (ACLF- 25) failure. Causative agents were complimentary and native medication (50%), antimicrobials (22%), antiepileptics (8%), antitubercular drugs (5%), hormonal pills (5%) and others (10%). Twenty-seven patients had encephalopathy (ALF:23, ACLF:4). Study patients underwent 3 (1-7) PLEX sessions and 1.4 (0.6-1.6) litres of plasma was exchanged per session. One-month survival was 34/48 (71%) (ALF: 13/23, ACLF: 21/25). None of the patients underwent liver transplant. In the ACLF group, 30-day survival was 84% and 90-day survival being 59%. Of 20 ALF patients who fulfilled Kings College Criteria for liver transplantation,12 patients (60%) survived with plasma exchange. In ALF, none of the baseline parameters predicted survival. Area under ROC for ΔVWF was 0.83 (95% CI: 0.64-1.0) for predicting survival. At least 25% fall in plasma Von Willebrand factor antigen (VWF) from baseline predicted significantly improved survival (HR: 0.28, 95% CI: 0.1-0.81, p-value: 0.012, sensitivity: 73%, specificity: 87%).
Conclusion Plasma exchange appears a promising treatment option in I-DILI patients not opting for liver transplantation with dynamic change in VWF after PLEX predicting survival in patients with ALF.
Keywords ACLF, ALF, DILI, PLEX, VWF
210
Prevalence, predictors and outcomes of multi-drug resistant bacterial colonization in cirrhosis in-patients: A longitudinal study
Nipun Verma, Venkata Divakar Reddy P, Archana Angrup, Manisha Biswal, Arun Valsan, Pratibha Garg, Parminder Kaur, Sahaj Rathi, Arka De, Madhumita Premkumar, Sunil Taneja, Pallab Ray, Ajay Duseja, Virendra Singh
Correspondence – Nipun Verma - [email protected]
Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India
Introduction Due to unclear evidence, we evaluated the prevalence, predictors, and outcome of MDROs colonization in cirrhosis in-patients.
Methods We prospectively recruited cirrhosis patients from a tertiary-care hospital over 1.5 years. Surveillance cultures, phenotypic drug susceptibility, and genotypic testing for MDROs from multiple sites (rectum, nasal, composite skin, and central line hub [c-hub]) were performed at admission and follow-up. Clinical data, risk factors, and outcomes of patients were analyzed.
Results Of 125 patients aged 49 years, 85.6% males, 60.8% ACLF, 99 (79.2%) were identified MDRO colonizers (by phenotype or genotype). MDRO-colonization at rectum, nose, skin, and c-hub was seen in 72.7%, 30.0%, 14.9%, and 3.3% patients, respectively. Patients were colonized with ESBL (71/125), CRE (67/125), MDR-enterococcus (48/125), MDR-acinetobacter (21/125), or MRSA (4/125). Among colonizers with phenotypic resistance (91/99), the isolates were MDR (80.2%) or PDR (19.8%). The commonest genotype among all-GNBs, Enterococcus, and Staphylococcus sp. was NDM (56.8%), VanA (42.5%), and MecA (66.7%), respectively.
MDRO colonizers were likely to have alcoholic hepatitis, smoking, upper-middle socioeconomic status, healthcare exposure, systemic infections, broad-spectrum antibiotics exposure, and norfloxacin prophylaxis in the past 3 months than non-colonizers (p<0.05).
MDROs colonization increased the risk of infection by MDROs at admission (OR: 8.45, 95% CI: 1.09-65.58, p=0.017) or follow-up (OR: 7.46, 95% CI: 2.39-23.28, p<0.001). MDRO colonizers had a higher prevalence of cerebral failure (p<0.05). Patients with multiple sites (≥1) MDRO colonization (prevalence: 30%) were associated with multi-organ failures and poorer 30-day survival than those with none or single-site colonization (22.2% vs. 52.4%, p=0.004). MDROs infection (prevalence: 57.6%) (HR: 1.874) and MELD (HR: 1.048) were independent predictors of 30-day mortality after adjusting for age and colonization status.
Conclusions A high burden of MDROs colonization and infections is hazardous in cirrhosis. MDROs colonization, especially at multiple sites increases the risk of MDRO infections, multi-organ failures, and mortality in cirrhosis.
Keywords Cirrhosis, Colonisation, CRE, ESBL, Infections, Mortality, MRSA, Multi-drug resistance
211
Bispectral index: A bedside tool for assessment of hepatic encephalopathy in patient with acute-on-chronic liver failure
Surender Singh Sehrawat, Madhumita Premkumar, Jasvinder Nain, Rohit Mehtani*, Yogendra Kumar, Ajay Duseja, Sunil Taneja, Kamal Kajal, Shiv Soni
Correspondence – Madhumita Premkumar - [email protected]
Department of Hepatology. Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India, and *Amrita Hospital, Mata Amritanandamayi Marg Sector 88, Faridabad 121 002, India
Introduction Hepatic encephalopathy (HE) is clinically assessed by using West Haven Criteria (WHC) and hepatic encephalopathy scoring algorithm (HESA). These scoring tests show inter-observer variability. So, we conducted a prospective, observational study to objectively assess hepatic encephalopathy (HE) in patients with acute-on-chronic liver failure (ACLF) by using the Bispectral index (BIS). The primary outcome was correlation of BIS with the grade of HE.
Methods Thirteen patients of CANONIC ACLF with HE grades ≥2 were prospectively enrolled and followed for 90 days. Assessment of HE was done using WHC and HESA scoring tests. Optic nerve sheath diameter (ONSD) was measured with ultrasound and available for nine patients. Average BIS over 10 minutes was assessed on day 1, day 4 and day 7. BIS was measured post 1hour of stopping sedation for patients who were on mechanical ventilation. Spearman’s rank correlation coefficient was used to find the correlation between BIS and severity of HE.
Results A total of 31 BIS recordings were made in 13 patients on day 1, day 4, and day 7. BIS had a negative correlation with WHC grade (Spearman’s rank correlation coefficient (ρ) = -0.5622, p=0.001). BIS was increased on day 7 (82.8±14.32) compared to day 1 (80.23±20.46). However, the ONSD (mm) values are also increased on day 4 (4.533±1.042) and day 7 (4.764 ± 0898) as compared to day 0 (4.422±1.118).
Conclusion Bispectral index is a helpful tool for objective assessment of HE, and it moderately correlates with grade of HE in ACLF. So, BIS can be used in the objective assessment of HE grades. However, the presence of artifacts, low signal quality index and high EMG activity hamper its clinical utility.
Keywords Acute-on-chronic liver failure, Bispectral index, Hepatic encephalopathy, Optical nerve sheath
212
Incidence of first episode of overt hepatic encephalopathy in patients with liver cirrhosis
Buddhi Meena , Haribhakti Seba Das, Chittaranjan Panda, Pankaj Bharali, Prajna Anirvan. Mrinal Gogoi, Padmalochan Prusty, Samir Kumar Hota
Correspondence – Buddhi Meena - [email protected]
Department of Gastroenterology, Srirama Chandra Bhanja Medical College and Hospital, Behera Colony, Mangalabag, Cuttack 753 001, India
Background Hepatic encephalopathy (HE) is a watershed moment in the natural history of cirrhosis and its development indicates poor prognosis. Many factors associated with development of overt HE. However, there are few studies available in this part of world. Our study aimed to assess incidence of first episode of overt HE.
Methods One hundred and one consecutive patients with cirrhosis (Child A-C) and portal hypertension without previous HE were enrolled in this study, from June 2021 to November 2022. The incidence first episone of HE, model for end-stage liver disease-sodium (MELD-Na) score and the bilirubin–albumin–beta-blocker–statin score (BABS) were calculated.
Results 62.3% patients were males and 37.7% patients were females. 7.7%, 41.6% and 29.7% patients belonged to Child A B and C respectively. The most common cause of cirrhosis was alcohol followed by hepatitis B and non-alcoholic steatohepatitis (NASH) related and the mean MELD- Na was 17.9 and BABS score was -3. 15 patients developed HE over mean follow-up of 1 year.
Conclusion Out of total 101 patients, 14.85% patients developed first episode of HE. Majority of patients who developed HE belonged to Child C category and had higher MELD-Na scores.
Keywords Hepatic encephalopathy
213
“Restricted sedative use” policy may improve survival in patients with rodenticide induced hepatotoxicity
Asisha Janeela , Ashish Goel, Uday George Zachariah, Kundavaram Paul Prabhakar Abhilash, Kishore Pichamuthu, Ebor Jacob James, Debasis Das Adhikari, Subramani Kandasamy, C E Eapen
Correspondence – C E Eapen - [email protected]
Department of Hepatology, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Background Acute liver dysfunction may affect drug metabolism in liver, lead to sedative overdose, drowsiness, respiratory depression and contribute to mortality. This study aims to analyze use of sedatives in patients with rodenticidal hepatotoxicity.
Methods Details of sedative use and outcomes were studied from IP charts and e-pharmacy records of patients admitted with rodenticide ingestion under Department of Hepatology (2014 – 2021).
Results Of 120 patients with rodenticide hepatotoxicity (F: 71; age: 22 years, median; acute liver injury: 72, acute liver failure: 41), 103 consumed yellow phosphorus. All patients were managed as per standard-of-care including plasma exchange (54/120 patients). None underwent liver transplant. 25/120 (20.8%) patients received sedatives (all intravenously) - dexmedetomidine (9), midazolam (9), haloperidol (9), lorazepam (5) and fentanyl (5). Indications for sedative use: agitation (19/25), endotracheal intubation (12/25). All received standard doses of sedatives. 15/25 patients who had received sedative, had worsening of oxygen saturation, 15/25 (60%) patients had worsening sensorium and died. Hospital stay was prolonged in patients who received sedatives (8.16 vs. 7.88 days). Mortality was significantly higher in patients with sedative use (15/25, 60%) as compared to patients with no sedative use (9/95, 9.5%); (HR: 14.3, 95% C.I: 5 – 41, p-value: <0.001). Of 21 patients who had low sensorium at admission; there was only 1 death in 8 patients who did not receive sedatives compared to 8/13 (61.5%) deaths in those who received sedatives (p-value -0.1).
Conclusion Most (95%) rodenticidal hepatotoxicity patients were managed without sedatives. Sedative use was associated with respiratory depression, worsening sensorium and increased risk of death. A “restricted sedative use” policy in these patients may improve survival.
Keywords Poisoning, Rodenticide, Sedative
214
Cutaneous aspergillosis precipitating acute-on-chronic liver failure in alcohol associated cirrhosis: A case report
Ganesh C P , Jayant Agarwal, Nipun Verma, Harsimran Kaur, Shiva Prakash, Sunil Taneja, Ajay Duseja
Correspondence – Nipun Verma - [email protected]
Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India
Introduction Cutaneous mycosis is generally not angio-invasive and improves with topical treatment. We report an interesting case of angio-invasive cutaneous aspergillosis resulting in acute-on-chronic liver failure (ACLF) and mortality in a cirrhosis patient.
Case Summary A 32-year-old male, alcohol consumer and smoker had a hospitalization 1.5 months back for 7 days with alcoholic hepatitis, liver, coagulation, and renal failure for which he was managed conservatively and improved. On 1 month follow-up he developed spontaneous bacterial peritonitis without any organ failures, for which he received injection polymyxin that was continued as outpatient-parenteral-antimicrobial-therapy (OPAT). Seven days post-therapy patient had a recurrence of fever and jaundice and was hospitalized. Sepsis screen revealed sterile blood/urine/ascitic fluid cultures, elevated galactomannan (2.6), normal leukocyte counts, and necrotic plaques with yellowish brown crusting with surrounding brown reticular purpura and irregular margins of 4 × 5 cm at the right forearm near intravenous cannulation site (Fig.1A) and similar plaque of 2 × 3 cm at the dorsum of the left hand (Fig.1B). Investigations showed hyperbilirubinemia (7.2 mg/dL), coagulopathy (INR: 1.6), no-SBP (ANC:170), and normal paranasal sinuses, renal, cerebral, pulmonary and circulatory functions. With the diagnosis of acute decompensation, he was managed with intravenous liposomal amphotericin B (LAMB: 3 mg/kg), polymyxin, and tigecycline. Biopsy of skin lesions and mycological cultures was performed after a dermatology consult, which showed dermal panniculitis (HPE) and growth of aspergillus flavus sensitive to LAMB (Fig.1C-E). Despite LAMB treatment, he developed acute-on-chronic liver failure in next 7 days with coagulation and renal failure. Salvage treatment with anidulafungin was initiated but he further deteriorated with cerebral and circulatory failures in the next 3 days and succumbed to illness despite intensive care, ventilation, and hemodialysis support.
Conclusions OPAT should be cautiously advised with utmost hygiene in cirrhosis patients. Even cutaneous mycosis can be angio-invasive, precipitate ACLF, and deleterious in cirrhosis patients despite antifungal therapy.
Keywords ACLF, Acute-on-chronic liver failure, Aspergillosis, Cirrhosis, Fungal infection, Mortality, Mycosis
215
An interesting case of hepatic visceral larva migrans
Ravi Kishore , Praveer Rai
Correspondence – Ravi Kishore - [email protected]
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareili Road, Lucknow 226 014, India,
Twenty-three-year-old female without any co-morbidities, presented with right upper quadrant abdominal pain, low grade fever, loss of appetite and malaise for 2 months. No jaundice, vomiting, GI bleed, no passage of worms in stools or urticaria. She was a vegetarian, with history of pets at home. On examination there was mild pallor. Vitals were stable. Abdominal examination revealed tender hepatomegaly (liver span:16 cm), splenomegaly (15 cm). Other systemic examination was unremarkable. Investigations Blood investigations revealed microcytic hypochromic anaemia (Hb=8.4 g/dL) and eosinophilia (eosinophil count being 18%, AEC:16200/mm3). ALP was raised (163 IU/L) other liver and renal parameters were normal. Serum α-fetoprotein was within normal limits (1.43 ng/mL), CA 19.9 2.41 U/mL. USG abdomen showed large solid cystic lesion (10.7 × 14.3 cm) in right lobe of liver. CTA : liver enlarged (17.5 cm), hypo attenuating lesion (15.3 × 8.5 × 8.6 cm) is noted in the right lobe involving segments V, VI, VIII. Without arterial enhancement. Heterogenous enhancement in porto venous phases. Ultrasound-guided biopsy from liver sol showed infiltrates comprises of predominantly eosinophils, lymphocytes, plasma cells and neutrophils along with multiple charcot-leydencrystals. Large areas of necrosis are identified. On special stains, no larva and hook lets are identified. The findings were suggestive of eosinophilic abscess, based on corroborating radiological and histopathological findings and a final diagnosis of hepatic visceral larva migrans was made. She was treated successfully with albendazole 400 mg BD for 4 weeks.
Discussion T canis and Toxocara cati are most important causes of VLM. The clinical triad of toxocariasis is unexplained eosinophilia, liver or lung nodules on imaging studies. Hepatic nodules due to visceral larva migrans (VLM) should be considered as one of the diagnostic possibilities in cases with multiple hepatic lesions. Eosinophilia is a useful clue but is not completely specific for VLM. Cytology/histology along with clinical correlation help exclude other causes like malignancies.
Keywords Charcot-leyden crystals, Eosinophilia, Visceral larva migrans
216
Spontaneous hepatogastric fistula in liver abscess: Case series of a rare complication
Sayan Malakar , Akash Mathur, Anshuman Elhence * , Uday C Ghoshal
Correspondence – Uday C Ghoshal - [email protected]
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareili Road, Lucknow 226 014, India, and *All India Institute of Medical Sciences, Gate No, 1, Great Eastern Road, AIIMS Campus, Tatibandh, Raipur 492 099, India
Introduction Spontaneous hepatogastric fistula is a rare complication of liver abscess. It was previously reported in hepatocellular carcinoma following interventions. Most hepatogastric fistula cases complicating liver abscess can be managed conservatively. Here we present two cases of hepatogastric fistula.
Methods Two patients presented to us with a history of pain abdomen and fever. After initial workup and imaging, esophagogastroduodenoscopy (EGD) was performed to confirm hepatogastric fistula and they were managed accordingly.
Results Two patients with hepatogastric fistula were diagnosed using contrast-enhanced computed tomography of the abdomen and EGD. The first patient was a chronic alcoholic. He had three amebic liver abscesses, an abscess in the left lobe ruptured into the stomach. Another large abscess in the right lobe was managed with percutaneous drainage of the abscess. Later, on follow-up imaging left lobe liver abscess was resolved with conservative treatment. The second patient had choledocholithiasis with ascending cholangitis. Cholangitic liver abscess was complicated with intragastric rupture. He was managed successfully with emergency endoscopic retrograde cholangiopancreatography (ERCP) and stone removal. A percutaneous drainage was done for the ruptured abscess. Both patients were managed conservatively without surgery.
Conclusion Intragastric rupture of liver abscess can occur in amebic as well as bacterial cholangitis-related abscesses. They can be managed without surgery.
Keywords Cholangitis, Hepato-gastric fistula, Liver abscess, Percutaneous drainage
217
Hepatocellular carcinoma in young adults- An audit from a tertiary cancer center
Prachi Patil , Vaneet Jearth, Omkar Salvi, Sridhar Sundaram, Shaesta Mehta
Correspondence – Prachi Patil - [email protected]
Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Homi Bhabha National Institute, Room No 1233, Homi Bhabha Block, Tata Memorial Hospital, Parel, Mumbai 400 012, India
Introduction Hepatocellular carcinoma (HCC) is uncommon in young adults. There is a dearth of literature evaluating clinical features of young patients with HCC (yHCC), especially from India. We compared the clinical characteristics of yHCC patients with older patients with HCC (oHCC).
Methods All consecutive untreated HCC patients who were recruited on another ongoing IEC approved project were evaluated. Patients aged ≤ 40 years at diagnosis of HCC were defined as yHCC. Their demography and clinical features were compared with that of oHCC (>40 years).
Results Of 508 HCC patients, 75 (14.8%) were yHCC. The mean age at diagnosis was 34.1 years for yHCC (range 20-40 yrs) as compared to 59.6 in oHCC (range 41-84 yrs). There was no significant difference in the male:female ratio in the 2 groups (yHCC 7.3:1 vs oHCC 6.9:1, p=0.866). yHCC patients had a higher rate of hepatitis B virus (HBV) infection (77.3% vs. 44.3%, p=<0.001) and higher mean albumin levels albumin (3.64 vs. 3.42 p=0.003). Although yHCC patients had a lesser incidence of cirrhosis (70.7% vs. 79.2%, p=0.099), and more patients with Child-Pugh class A cirrhosis (57.4% vs. 48.8%, p=0.242), the difference was not significant. There also was no significant difference in the two groups with respect to the alfa feto protein (AFP), bilirubin, ALT or INR levels. yHCC had more advanced disease with bigger lesions (size of largest lesion in cms:10.00 vs. 8.36, p=<0.001), and a higher incidence of extrahepatic metastasis (35.1% vs. 19.7%, p=0.003). The BCLC stage was as follows: yHCC- A-1, B-23, C-43, D-8; oHCC 0-3, A-31, B-139, C-189, and D-71).
Conclusion HBV infection was the predominant etiology in most yHCC. yHCC is often diagnosed at an advanced stage despite relatively preserved liver function. HCC surveillance may benefit young hepatitis B carriers, however further research is needed to understand who is at a higher risk.
Keywords HBV, Liver cancer, Young HCC
218
Rishyagandha induced possible autoimmune-like liver injury in an elderly couple with diabetes mellites
Sayan Malakar , Anshuman Elhence * , Uday C Ghoshal
Correspondence – Uday C Ghoshal - [email protected]
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareili Road, Lucknow 226 014, India, and *All India Institute of Medical Sciences, Gate No, 1, Great Eastern Road, AIIMS Campus, Tatibandh, Raipur 492 099, India
Introduction Rishyagandha (Withania coagulans) is a well-known herbal remedy popularly sold as “paneer ka phool” in India. Rishyagandha fruit extract has a strong anti-hyperglycemic effect. This is the first case series reporting the hepatotoxicity of the herb.
Results A 65-year-old diabetic female presented to us with a history of progressive jaundice for four months without any cholestatic or prodromal features. Her 72-year-old diabetic husband also presented with similar history for three months. Before the onset of jaundice, they had started ingesting rishyagandha seed extract as a remedy for their diabetes for the last 11 months. Bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) of the wife at presentation and after three months of stopping the extract were 14.4 mg/dL, 1173 IU/L, 523 IU/L, 163 IU/L and 3.4 mg/dL, 257 IU/L, 321 IU/L, 149 IU/L, respectively. Her husband’s course was also similar. Their anti-nuclear antibodies were positive (2+, 1:100) and immunoglobulin-G levels were high. Liver biopsies were compatible with autoimmune injury without any evidence of cirrhosis in both. A Roussel Uclaf causality assessment method (RUCAM) score calculated for rishyagandha suggested it to be the “possible” culprit (RUCAM score of five for both). Jaundice resolved after four months of stopping the offending drugs.
Conclusion Rishyagandha, a popular herbal remedy for diabetes, can lead to autoimmune-like liver injury.
Keywords Autoimmune like-liver injury, Herb induced liver injury, Rishyagandha
219
Microbacterial spectrum of cirrhotic ascites in tertiary care hospital
Zahid Zubair, Arvind Kelkar, Kamal Chetri, Mukesh Aggarwala, Roshan Aggarwala, Mrinal Debbarma
Correspondence – Zahid Zubair - [email protected]
Department of Gastroenterology and Hepatology, Apollo Hospitals, Lotus Tower, International Hospitals, G S Road, Christian Basti, Guwahati 781 005, India
Background Spontaneous bacterial peritonitis (SBP) is the most common infection among patients with cirrhosis and ascites with an incidence of 10% to 30%. So this study was done to study the microbiological spectrum of ascites in North east Indian region and to determine the sensitivity pattern and prevalence of MDR organisms in this region.
Aims To determine the prevalence of ascitic fluid infection in cirrhotic ascites and to determine the prevalence of MDR organisms in ascitic fluid infections.
Methods One hundred and forty six patients with PHT related ascites were studied for microbiological spectrum and culture sensitivity pattern. The association of various parameters with ascitic fluid infection was also studied.
Results Majority of patients belonged to CTP class C (59.6%) and. Majority of patients had MELD Na > 15 (80.2%). Ascitic fluid infection was documented in 24% of cases, out of which SBP constituted 60% and CNNA 40%. Gram negative organisms were most commonly isolated, especially E. coli, Klebseilla. 33.3% of isolates were multidrug resistant organisms. Recent hospitalization and antibiotic usage predisposed to both ascitic fluid infections and MDROs. Recent paracentesis predisposed to both ascitic fluid infections and MDROs.
Conclusion MDR bacterial infections are common being isolated in 33.3% of isolates. Recent hospitalization, antibiotic usage, recent paracentesis increase the risk of ascitic fluid infections and drug resistant organisms. Patients with no risk factors for MDROs can be treated with third generation cephalosporins or floroquinolones, but patients with risk factors should receive broad spectrum antibiotics like piperacillin-tazobactum or carbapenems till results of culture and antibiotic sensitivity pattern are available. Our study doesn’t support the use of empirical gram-positive coverage as Gram positive organisms were less commonly isolated.
Keywords Multidrug resistant organisms, Spontaneous bacterial peritonitis
220
Efficacy and safety of saroglitazar in diabetic versus non-diabetic non-alcoholic fatty liver disease cohorts- A 24-week, real-world experience
Jayanta Mukherjee
Correspondence – Jayanta Mukherjee - [email protected]
Department of Gastroenterology, ILS Hospitals, 2nd Floor, 3rd Ave, D D Block, Sector 1, Bidhan Nagar, Salt Lake, Kolkata 700 064, India
Introduction Type 2 diabetes (T2DM) is a well-known risk factor for non-alcoholic fatty liver disease (NAFLD). However, NAFLD is also very common in nondiabetic adults. The aim of this study was to evaluate the efficacy of saroglitazar 4 mg OD in diabetic vs. non-diabetic NAFLD cohorts, in routine clinical practice.
Methods A total of 123 NAFLD patients (males 75.6%, non-diabetics 63.4%) diagnosed either on Fibroscan or USG imaging or elevated LFT along with exclusion diagnosis and prescribed on saroglitazar 4 mg OD, were evaluated for changes in LSM, LFT, TG, and LDL along with the non-invasive NFS score. The overall improvement and improvements in diabetic (FBS median [IQR] 128 [75] mg/dL) vs. non-diabetic (median FBS 99 [17.5] mg/dL) NAFLD cohort, is measured at baseline and 24 weeks. The statistical significance was established using paired sample t-test.
Results The study shows significant improvements in all measured parameters from baseline in both diabetic and non-diabetic NAFLD cohorts. The LSM improved by 19.6% and 16.7%, ALT by 40.8% and 50.5%, AST by 40.9% and 38.2%, TG by 33.1% and 36.1% and LDL by 21.3% and 23.4% respectively in diabetic and non-diabetic NAFLD. The overall NFS score improved by 29.5% with 44% (n=54) patients in the intermediate or high NFS range at baseline reduced to 26.8% (n=33) patients after 24 weeks. All the improvements are statistically highly significant (p < 0.001).
Conclusions Saroglitazar 4 mg OD was found equally effective and safe in both diabetic and non-diabetic NAFLD. More studies, including well-designed clinical trials, will show further light on effect of saroglitazar 4mg in NAFLD with different underline co-morbidities.
Keywords LSM, NAFLD, NFS score, Saroglitazar, T2DM
221
Plasma proteomics unravels pathways driving acute-on-chronic liver failure phenotype in patients with acute decompensation of cirrhosis
Pratibha Garg , Nipun Verma, Maryada Sharma, Trayambak Basak * , Shreya Singh, Vivek Sarohi * , Sahaj Rathi, Arka De, Madhumita Premkumar, Sunil Taneja, Ajay Duseja, Virendra Singh
Correspondence – Nipun Verma - [email protected]
Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India, and *Indian Institute of Technology, Mandi, India
Background Progression from acute decompensation (AD) to acute-on-chronic liver failure (ACLF) associates with poor prognosis cirrhotic patients. We employed untargeted plasma proteomics to discern molecular determinants of AD and ACLF.
Methods Patients admitted with AD or ACLF (EF-CLIF criteria) and healthy controls (HC) were enrolled. Plasma samples bio-banked at baseline were subjected to LCMS based proteomics following top abundant protein depletion. Inferential statistics was performed to identify differentially expressed proteins (DEPs), while pathway analysis was performed using gene ontology (GO) and KEGG database.
Results Twenty-nine AD patients (93.1% males, median age: 40 years), 55 with ACLF (87.2%, 43 years) and 10 HC were enrolled. Alcoholic hepatitis was the predominant etiology of AD/ACLF (65.5% and 67.2%, respectively). ACLF patients had higher median WBC count (14.7 vs. 7.3 × 109/L), procalcitonin (1.3 vs. 0.42 ng/mL), SIRS (2 vs. 1), CLIF-C-OF (12 vs 7), and mortality (74.5% vs. 17.2%) than AD patients (p<0.001, each). Five hundred and twelve proteins were identified, 30 were DEPs (15 upregulated, 15 downregulated) between AD and ACLF (p<0.05); 85 exclusively expressed in ACLF. Pathways related to immune system activation, phagocytosis, chemotaxis, complement were upregulated in AD vs. HC, while plasma lipoprotein transfer, homeostasis and cell death regulation were underexpressed (Fig. 1A). Pathways of immune cell activation, cell motility, response to stress and stimuli were overexpressed, while positive regulation of protein processing, coagulation and phagocytosis were downregulated in ACLF vs. HC (Fig. 1C). Response to stress and infections, negative regulation of oxidative stress were over-activated, whereas carbohydrate and lipid metabolism were severely impaired in ACLF vs. AD, translating to immunometabolism failure in ACLF. Proteolysis increased significantly from HC, AD, to ACLF. ACLF patients had hypercoagulatory phenotype compared to AD (Fig.1B).
Conclusion Proteomics revealed in a novel single platform, a progressive aberration in immune system, metabolism, proteolysis, complement and coagulation system in ACLF patients.
Keywords ACLF, LCMS, Proteomics
222
Effect of saroglitazar on FIB4 index and metabolic parameters in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis population - A 24-week, real-world experience from the eastern part of the country
R P Ray
Correspondence – R P Ray - [email protected] Gastroenterology
Department of Gastroenterology, Anandaloke Multi Speciality Hospital, Paresh Nagar, Sevoke Road, Ward 44, Dasrath Pally, 2nd Mile, Siliguri 734 001, India
Background and Aims Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver damage and may progress to cirrhosis, liver failure, and hepatocellular carcinoma, if not managed well. It is strongly considered the hepatic manifestation of metabolic syndrome. Fibrosis-4 index (FIB-4) has been shown to be a prognostic marker of liver-related outcomes in patients with NAFLD. Saroglitazar 4 mg is the only approved therapy for NAFLD and non-alcoholic steatohepatitis (NASH). We tried to evaluate the efficacy and safety of saroglitazar 4 mg OD on non-invasive FIB-4 index and various metabolic parameters in NAFLD/NASH patients, in routine clinical practice.
Methods A total of 73 documented NAFLD patients (males 80.8%) prescribed saroglitazar 4 mg OD, were analyzed for changes in liver biochemical parameters and lipid profile at 24 weeks. The study population was of median age of 35 (10) years and a median BMI of 27.3 (6.1) kg/m2. 32.9 % study population was diabetic, 35.6% are hypertensive and 61.6% are dyslipidemic. The median baseline FIB4 Index was 0.66 (1.2) with 38.4% of patients in the intermediate or high-risk group. The data at baseline and 24 weeks were analyzed and statistical significance was established using paired sample t-test.
Results The study shows statistically significant improvements in fat and liver-related parameters (LDL 13.5%, TC 23.8%, TG 37.6%, AST 35.5%, ALT 41.9%) from baseline. Also, there was a significant improvement in the overall FIB-4 index by 35.7%, with 38.4% (n=28) of patients in the high and intermediate risk category at baseline reduced to 9.6% (n=7), at 24 weeks. There was no single episode of any drug-related side effects and therapy discontinuation.
Conclusions The study shows saroglitazar 4 mg OD as a safe and effective treatment option for NAFLD/NASH, with significant improvement in all fat and liver-related parameters including the non-invasive FIB-4 index.
Keywords NAFLD, NFS score, Saroglitazar
223
Skin and soft tissue infections in decompensated chronic liver disease – A case series
Parag Papalkar, Ramakrishna B S, Babu Vinish D, Kayalvizhi J, Rohan Yewale, Naveenchand M, Muthukrishnan P
Correspondence – Parag Papalkar - [email protected]
Department of Gastroenterology, SIMS Hospital, Metro No.1 Jawaharlal Nehru Road, Vadapalani, Chennai 600 026, India
Introduction Skin and soft tissue infections (SSTI) are one of the most common types of infections seen in the hospitalized patients with decompensated chronic liver disease (DCLD) and account for significant morbidity and mortality. However, there is scarcity of focussed literature on this widely prevalent infectious complication in patients with DCLD. We aimed to retrospectively analyse SSTI in DCLD over the last four years in our hospital.
Methods The case records of patients with DCLD in our hospital were retrieved and the data analyzed.
Results Out of total 450 DCLD patients, 40 had cellulitis (mean age 59.1±13 years, M:F 2.63). Non-alcoholic steatohepatitis was the most common cause of cirrhosis (65%). Twenty-one patients (52%) had diabetes mellitus. Complications during admission included ascites (90%), renal dysfunction (62.5%), spontaneous bacterial peritonitis (22.5%) gastrointestinal bleed (12.5%) and hepatic encephalopathy (55%). Out of the 40 patients, 16 (40%) had cellulitis in the past and 30 (75%) patients had history of recent hospitalization for DCLD complications. Nine (22.5%) patients had history of trauma. Nine (22.5%) of the 40 patients were on Rifaximin prior to admission. Out of 40 patients 6 (15%) required surgical management while most patients were treated with Piperacillin Tazobactum. Length of hospital stay was 9.08±7.7 days and 12 (30%) of the patients required intensive care.
Conclusions Prevalence of cellulitis was 8.8% in hospitalized DCLD. Appropriate use of antibiotics resulted in a favorable outcome and lesser surgical intervention.
Keywords Cellulitis, Liver disease
224
Study of spectrum of upper gastrointestinal bleed in patients with cirrhosis of liver
Satish Shahu, Parimal Lawate
Correspondence – Satish Shahu - [email protected]
Department of Internal Medicine, Jehangir Hospital, 32, Sassoon Road, Sangamvadi, Pune 411 001, India
Objective Study the causes of upper gastrointestinal (UGI) bleed in liver cirrhotics, clinical presentation, endoscopic findings and outcomes during hospitalization including mortality.
Methodology Fifty-seven patients of UGI bleed were included comprising those diagnosed with liver cirrhosis. After initial stabilization each patient underwent gastroduodenal endoscopy by an expert Gastroenterologist and finding documented. If multiple lesions seen in endoscopy, then among them most possible cause of UGI bleed is identified. Treatment given, any complications and outcome including mortality at the time of discharge were noted.
Results Of 57 cases, 38 (66.7%) had variceal type of bleeding and 19 (33.3%) had non-variceal type of bleeding. Majority (34) had esophageal varices (59.6%), 5 (8.8%) had duodenal ulcer, 4 (7.0%) had gastric varices, 4 (7.0%) had portal hypertensive gastropathy, 3(5.3%) had gastric ulcer, 3 (5.3%) had erosive gastritis, 2 (3.5%) had esophagitis, 1 (1.8%) had esophageal ulcer and 1 (1.8%) had Mallory-Weiss tear. Peptic ulcer disease (duodenal ulcer+gastric ulcer) accounted for 8 (14% of total UGIB while 42.1% in nonvariceal causes). Distribution of incidence of mortality differs significantly between group of cases with different CTP classes (p-value<0.05). Of 13 cases with Class A, none expired; of 20 cases with class B, 3 (15.0%) expired and of 20 cases with class C, 8 (40.0%) expired. Incidence of mortality was higher in variceal group than in nonvariceal group (28.6% vs. 5.6%%).
Conclusion In cirrhotics, UGI bleed from ruptured varices is most common However, cirrhotic patients do not always bleed from varices. About one-third patients can also bleed from non-variceal causes of which most common is peptic ulcer; duodenal followed by gastric ulcers. Length of hospital stay and Incidence of mortality is higher in patients of variceal bleed group and patient having higher CTP class.
Keywords Upper gastrointestinal bleed, Liver cirrhotics, Variceal group
225
Rate of decline of HBsAg load among Indian patients with chronic hepatitis B virus infection
Pallavi Garg , Kaushal Madan, Richa Bhargava, Ayushi Singh, Muzafar Shawl, Vikas Singla, Amita Thakur, Abhaya Indrayan
Correspondence – Kaushal Madan - [email protected]
Centre for Gastroenterology, Hepatology and Endoscopy, Max Institute of Liver and GI Sciences, 1 2, Press Enclave Marg, Saket Institutional Area, Saket, New Delhi 110 017, India
Introduction Functional cure in hepatitis B virus (HBV) infection involves clearance of HBsAg from the sera of infected individuals and reflects the intracellular ccc-DNA activity, but it is a rare event. Data on the dynamics of HBsAg load among patients with CHB is limited. Aim To measure the rate of decline of quantitative HBsAg among Indian patients with chronic HBV infection.
Methods Retrospective follow-up study. Patients of chronic HBV infection being followed up at our hospital and had at least two values of quantitative HBsAg were included.
Results Twenty-eight patients were included (67% males; median age 45.5 [33.5-70] years). The median HBsAg load available at the time of enrollment in the study was 2120 (552.5 to 42179) IU/mL. The HBsAg load declined from the baseline to the last available value in 12 (75%) patients, increased in 5 (17.9%) patients and remained the same in 2 (7.1%) patients. Among patients with a decline in HBsAg load, the median rate of decline was 581.9 IU/mL per year (based on the first and last available values), but was not linear.
Conclusion The rate of HBsAg decline among Indian patients with chronic HBV infection, is slow and non-linear.
Keywords HBV, India, Quantitative HBsAg
226
Association of GH and IGF1 levels with frailty, sarcopenia, bone health, and prognosis in decompensated cirrhosis patients
Parminder Kaur 1 , Nipun Verma 1 , Pratibha Garg, Sahaj Rathi, Arka De, Madhumita Premkumar, Sunil Taneja, Ajay Duseja, Virendra Singh
Correspondence – Nipun Verma - [email protected]
Department of 1Hepatology, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh 160 012, India
Background Impairment of GH-IGF1 axis and its association with frailty, sarcopenia and bone health is less well characterized in cirrhosis. We evaluated the association of GH and IGF1 levels with frailty, sarcopenia, bone health, prognosis in decompensated cirrhosis patients.
Methods Adult decompensated cirrhosis presenting to outpatient services at a tertiary care institute over 1 year were examined for frailty with liver frailty index (LFI), sarcopenia with DEXA (ASMI), anthropometry, plasma GH-IGF1 levels with ELISA, clinical decompensations and outcomes.
Results Patients (n=46) were male (42 [95.5%]) with mean age of 49.6±9.87 years. 93.2% (patients had ascites [Grade-I: 40.9%, Grade-II: 25%, Grade-III: 27.3%] and 4.5% patients had HE [grade-I]). Median MELD-Na was 15.5 (IQR:12.9-19.1) and CTP was 7.5 (7-9) [CTP A-18.2%, CTP B-65.9%, CTP C-15.9%]. Median GH (ng/mL) and IGF1(ng/mL) were 3.16 (1.62-5.25) and 35 (24.6-54.5). IGF1 levels were 0.53 times (IQR:0.38-0.90) the lower limit of age and gender matched reference. 75% patients were pre-frail and 25% patients were frail. Median ASMI (Kg/m2) was 6.59 (5.49-7.60), 66.7% patients were sarcopenic and 34.5% had osteodystrophy. IGF1 showed strong correlation with frailty (p=-0.419, p<.001) and moderate correlation with CTP (ρ=-0.32, p=0.034), and appendicular skeletal muscle mass (ρ=0.314, p=0.075). IGF-1 levels were reduced in patients with osteodystrophy (27 [IQR:16.4-38.4] vs. 45.4 [IQR:25.4-71.1], p=0.034). On regression, IGF-1 levels were associated with frailty (β= -0.63, SE=0.214, p=0.005) and ASMI (β=2.50, SE=1.21, p=0.047). AUROC of IGF-1 for 3-month mortality was 0.756 (p=0.094) showing a trend toward higher mortality. LFI had strong negative correlation with ASMI (ρ=-0.32, p= 0.034). Osteodystrophy had strong positive association with LFI (ρ=0.525, p=0.002). GH had no significant associations with ASMI, LFI and osteodystrophy.
Conclusion Reduced IGF-1 levels are associated with sarcopenia, frailty, osteodystrophy, increased severity in cirrhosis. Sarcopenia and frailty are interrelated, common, and associate with osteodystrophy in cirrhosis. Modulation of GH/IGF1 axis is a potential therapeutic target in cirrhosis.
Keywords Frailty, IGF1, Sarcopenia
227
Long-term outcome of patients with decompensated autoimmune liver diseases treated with steroids and azathioprine
Ashiesh Khandelwal
Correspondence – Ashiesh Khandelwal - [email protected]
Department of Gastroenterology, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi 110 060, India
There was a transplant free survival in 16/24 (66.6%) of patients over a median follow-up of 38.5 months. Sepsis, diabetes and cytopenia are common however drugs could be restarted or modified in all patients.
Keywords CLD
228
Minimal hepatic encephalopathy in patients with hepatic venous outflow tract obstruction: Evaluation of pre-intervention status and factors predicting outcome
Kashmira Datta, Amrit Gopan, Abhijeet Karad, Aditya Kale, Akash Shukla
Correspondence – Akash Shukla - [email protected]
Department of Gastroenterology, Seth G S Medical college and KEM Hospital, Multistoried Building, 9th Floor, Acharya Donde Marg, Parel. Mumbai 400 012, India
Introduction Prevalence of hepatic encephalopathy (HE) in hepatic venous outflow tract obstruction (HVOTO) is lesser than other chronic liver diseases due to lower prevalence of advanced cirrhosis. Minimal HE (mHE) is unexplored in HVOTO.
Aims and Methods To study prevalence of mHE in HVOTO and its outcome following endovascular intervention. One hundred and twenty-seven newly diagnosed un-intervened HVOTO patients (18-65y) between July 2017 to January 2020 screened. Patients with MMSE score ≥24 subjected to a pencil-paper based psychometric hepatic encephalopathy test (PHET), comprising number connection test A, figure connection test-A, digit symbol test, serial dotting test and line tracing test. PHET scores expressed as z scores (-3 to +1) (pre-intervention, post intervention days 1, 7, 30, 90 and 12 mo). Comparisons done based on severity of disease (MELD ≥/<15) and presence or absence of baseline mHE pre-intervention.
Results Thirty patients (27.5 [22,32] y,17 [56.7%] males) were compliant to complete follow-up regimen and were included. Median (IQR) symptom duration was 4.5 (1, 24) mo, jaundice (24,80%) and ascites (11,36.7%). Fifteen (50%) had mHE at baseline. Age (p=0.93), MELD score (p=0.30), CTP (p=0.27), Na (p=0.25) and total bilirubin (p=0.44), were not significantly different across groups with (bmHE+) or without (bmHE-) baseline mHE. In bmHE- group (n=15), PHET assessment showed development of new onset mHE significantly higher in those with MELD ≥15 at 3 (p=0.039) and 12 (p=0.039) mo but not at 7day (p=0.53) and 30-day (p=0.22) post intervention. In bmHE+(n=15), and overall (n=30) there was no such significant difference. In bmHE- group, those with improvement/normalization of total serum bilirubin at 30 days show a significantly lower 30-day mHE (p=0.039) with significant correlation between the two parameters (p=0.04, r=0.53). In the overall population, age at intervention predicted 30-day mHE with cut-off of 27.5y (AUROC 0.74, Sn 85.7%, Sp 60.9%, p=0.05, fig 1) and those with severe disease (MELD ≥15) show a significantly poor response in bilirubin improvement (p=0.004).
Conclusion Age at intervention, baseline disease severity, baseline mHE and trend of liver functions at 30 days influence development or persistence of mHE in HVOTO.
Keywords Minimal hepatic encephalopathy, Hepatic venous outflow tract obstruction, Outcome
229
Engaging, educating, enabling, and empowering the clinicians towards liver diseases: A comprehensive training program
Aayushi Rastogi , Akanksha Bansal, Ankur Jindal, Vinod Arora
Correspondence – Aayushi Rastogi - [email protected]
Department of Clinical Epidemiology, Institute of Liver and Biliary Sciences, D 1, Vasant Kunj, New Delhi 110 070, India
Objectives Chronic liver diseases (CLDs) account for significant morbidity and mortality throughout the world. It is important to empower clinicians for better management of liver disease patients. A comprehensive program on liver diseases was conceptualized under ILBS-ECHO (Institute of Liver and Biliary Sciences - Extension for Community Healthcare Outcomes). The present study aims at assessing the advancement in knowledge of the clinicians related to liver diseases after attending a 6-months virtual training program.
Methods A 6-month training program titled ‘Liver and Infections’ was designed for physicians practising across India. A total of 69 questions distributed across eight modules were shared with the registered participants before the start of each module using an online link. An online link consisting of similar questions was shared at the end of the sessions to assess change in knowledge after the session. One mark was allotted for each correct response. At the end of the program, an online exit exam consisting of 50 marks was conducted among participants who had attended 80% of the program. The data was analyzed using IBM-SPSS version-22.
Results A total of 84 clinicians across 16 states attended the virtual training on liver diseases with a mean age of 40.8±11.90 years, and approximately 76% were males. The mean pre-knowledge score of the participants was found to be 42.71±9.1, whereas the post-knowledge score was 54.02±10.6 out of 69. The overall pre- and post-knowledge scores were statistically significant (<0.001), as seen in Table 1. Approximately, 73% of the clinicians scored above 60% in the exit exam, indicative of learning from the comprehensive training program.
Conclusion Similar comprehensive training programs on liver diseases should be encouraged in developing countries as they play an important role in strengthening the clinicians for better management of liver disease patients.
Keywords Chronic liver diseases, Liver and infections, Training program
230
A comparison of factors influencing occurrence of acute and chronic portal vein thrombosis in a cohort of 502 patients with decompensated cirrhosis
Shivabrata Dhal Mohapatra, Minu Kumar, Srijaya Sreesh
Correspondence – Srijaya Sreesh - [email protected]
Department of Gastroenterology, Govt Medical College, 15 D Cordial Prabha Marappalam Pattom, Palace P O, Trivandrum 695 004, India
Background and Aims Portal vein thrombosis (PVT) due to portal flow stasis, complex thrombophilic disorders and factors leading to endothelial dysfunction, is an increasingly recognized complication in patients with cirrhosis. We assessed various parameters along with the stiffness of liver and spleen to study the risk factors associated with non-malignant PVT in patients with decompensated chronic liver disease (DCLD). We prospectively enrolled 502 patients with DCLD (CHILD B/C). All patients underwent detailed clinical evaluation, baseline investigation and ultrasonography of abdomen.
Results Thirty-nine patients were excluded. Of the 463 patients included, 51 had PVT (11%). It was observed that non-malignant PVT group patients had smaller liver size (11.8;1.8 vs. 12.4;1.5, p=0.032), higher spleen size (14.9;2.3 vs. 13.5;2.2, p;l;0.01), higher portal vein diameter (PVD, 14.4; 3.2 vs. 12.2; 1.7, 0.01), lower portal vein velocity (PVV, 11.5; plusmn;3.6 vs. 16.7;3.6, p 0.01), higher liver stiffness (61.3; 21.7 vs. 55.2;17.1, p=0.02), higher splenic stiffness (50.3;15.1 vs. 36.7;7.5, p; 01) as compared to non-PVT group. On plotting ROC; PVV;12.5 cm/sec (AUROC 0.86, sensitivity 74%, specificity 88%, NPV 95.9%), PVD;13.7 cm (AUROC 0.75), liver stiffness; 66.5 kPa (AUROC 0.72), liver size;11.95 cm (AUROC 0.63) were significantly associated with the development of non-malignant PVT (p 0.01). On multiple logistic analysis, PVD;13.75 cm (B=1.21, OR:95% CI 3.36 (1.05-10.7), p=0.04), PVV;12.5 cm/sec (B= -1.06, OR:95% CI 0.35 (0.13-0.09), p=0.03) were significant risk factors for PVT development in DCLD. Age, CHILD status, MELD Na score, presence of sarcopenia, Number of prior EVL banding, liver stiffness and splenic stiffness were comparable between the 2 groups of acute and chronic PVT patients, but the differences did not reach statistical significance.
Keywords Portal vein thrombosis
231
Rare cause of multuple liver abscess in an immunocompetent individual
Minu Kumar , Srijaya Sreesh
Correspondence – Minu Kumar - [email protected]
Department of Gastroenterology, Kerala University, 15 D Cordial Prabha Marappalampattom Palace P O, Trivandrum 695 004, India
Tuberculosis (TB) is caused by Mycobacterium tuberculosis and still remains a major public health problem in developing countries. Mycobacterium tuberculosis is an aerobic, acid fast, non-motile, non-capsulated and non-sporing organism. It shows propensity to grow in oxygen rich environment, so demonstrates a predeliction for the lungs [1]. Though pulmonary TB is the most frequent presentation, extrapulmonary diseases involving the gastrointestinal tract especially terminal ileum, lymph nodes, peritoneum etc are not infrequent. Hepatobiliary Tuberculosis is uncommon and accounts for less than 1% of all tuberculous infections.
Keywords Liver abscess by TB
232
Impact of minimal hepatic encephalopathy on the health-related quality of life among patients with cirrhosis
Gaurav Kapur, Srijaya Sreesh, Ann Mary George, Minu Sajeev Kumar, Akhil N V, Aditya Verma, Jacob Raja, Krishnadas Devadas, Manoj Yadav
Correspondence – Gaurav Kapur - [email protected]
Department of Medical Gastroenterology, Government Medical College, Ulloor-Akkulam Road, Chalakkuzhi, Thiruvananthapuram 695 011, India
Introduction Minimal hepatic encephalopathy (MHE) is the mildest form in the spectrum of Hepatic Encephalopathy (HE), seen in 30% to 84% of patients with cirrhosis, that adversely affects their day-to-day activities. Identifying the factors associated with the Health-Related Quality of Life (HRQoL) will help improve patient care, limit complications and guide future research. Our aim was to evaluate the HRQoL in patients with cirrhosis and MHE.
Methods Cross-sectional study was performed in outpatient cirrhotics without overt HE and hepatocellular carcinoma. Malayalam version of chronic liver disease questionnaire (CLDQ) was developed and used for measuring HRQoL. Factors affecting HRQoL such as Child- Turcott Pugh (CTP) score, model for end stage liver disease (MELD) score, minimal hepatic encephalopathy (MHE) and others were studied. MHE was evaluated using number connectivity tests NCT A and NCT B. Univariate and multivariate regression analysis was performed.
Results Two hundred and eleven patients were included in the study. The mean age was 52 years and 79.6% were males. Alcohol remained the major etiology accounting for 49.8% cases. MHE was present in 51.2% of subjects. Mean CLDQ global was 5.27;1.05 for the study subjects. 28.9% of the patients had poor HRQoL with low global CLDQ (and lt;5). 45% of the patients fared poorly on emotional component of CLDQ. Among 61 patients with poor HRQoL, 86.9% had MHE. Viral etiology, presence of MHE, high CTP, MELD scores and BMI were found significant in multivariate analysis for predicting HRQoL.
Conclusion In this study, viral etiology, the severity of liver disease, presence of MHE and high BMI were the factors found to determine HRQoL. Majority of the patients with poor HRQoL had MHE. Hence patients with cirrhosis should be evaluated for MHE and treated to improve the HRQoL.
Keywords Cirrhosis, Health related quality of life, Minimal hepatic encephalopathy
233
The effect of Kirathathikthakadi yogam on hepatitis B virus DNA load in patients with chronic hepatitis B without advanced fibrosis: Pre-post analysis
Akhila Kurup 1 , Sreejaya Sreesh 2
Correspondence – Sreejaya Sreesh - [email protected]
1Department of Dravyaguna Vigyanam, Government Ayurveda College, Pulimoodu, Thiruvananthapuram 695 007, India, and 2Department of Gastroenterology, Govt. Medical College, Thiruvananthapuram 695 011, India
Background and Aim Chronic hepatitis B (CHB) is a global health burden. Many patients with this lifelong illness approach Ayurveda physicians seeking remedy. Kirathathikthakadi-yogam (KTY) is a polyherbal formulation described in Punaravarthaka jwara chikitsa of Caraka Samhita. In this study, the effect of KTY in reducing HBV DNA load was evaluated in CHB patients attending OPD, Govt. Ayurveda College Hospital, Thiruvananthapuram and CHB patients attending for follow up in Govt. Medical College, Thiruvananthapuram.
Method Fifty-seven CHB patients were screened by history and routine blood examination, Fibro scan/shear wave elastography and HBV DNA level by quantitative RT PCR. Twenty-three patients with HBV DNA level >500 IU/mL if there is no evidence of advanced fibrosis or cirrhosis and ALT is normal; or DNA 500-20,000 IU/mL with persistently high ALT were selected and provided with KTY Tablet 1000 mg twice daily for 90 days. Nineteen patients of external control was on follow-up at Govt. Medical College, Thiruvananthapuram. HBV DNA level at 91st day of treatment group was compared using Paired t test. Pharmacognostical and phytochemical evaluation of ingredients of KTY and itself were done as per standard procedures of Ayurveda Pharmacopeia of India.
Result KTY arm showed significant reduction in HBV DNA load in between day 0 and day 91 (p<0.05). There was significant increase in HBV DNA in external control arm. There was 82.6% reduction in viral load in KTY group (p<0.004). New SOP for standardization of KTY Tablet was developed.
Conclusion The KTY was found effective in reducing HBV DNA load (p <0.05) in CHB patients. There was 82.6% reduction in viral load in KTY arm.
Keywords Ayurveda, Chronic hepatitis B, HBV DNA load. Kirathathikthakadi yogam, Punaravarthaka jwara
234
Metabolic co-morbidities are common in patients with chronic viral-related hepatocellular carcinoma
Priya Singh, Ajay Duseja
Correspondence – Ajay Duseja - [email protected]
Department of Hepatology, Nehru Hospital Extension Block, Room No. 30, Sector 12, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012, India
Background and Aim Metabolic risk factors including obesity and type 2 diabetes mellitus are common risk factors for hepatocellular carcinoma (HCC). The aim of the present study was to compare the presence of metabolic risk factors in chronic viral hepatitis (hepatitis B virus [HBV] and hepatitis C virus [HCV]) related HCC and non-alcoholic fatty liver disease (NAFLD) related HCC.
Methodology Among 119 patients with HCC diagnosed from August 2021 to May 2022, 96 patients with either NAFLD-HCC (38 [39.5%]), HBV-HCC (23 [23.9%]) or HCV-HCC (35 [36.4%]) were included in this ongoing prospective study. Baseline clinical and laboratory parameters at the time of diagnosis of HCC were compared among three groups of patients.
Results Age of patients with NAFLD-HCC (62.4±10 years) was significantly higher than that in HBV-HCC (56.8±10.3 years, p=0.03) but similar to HCV-HCC (58.6±11.2 years, p=0.74. BMI was significantly higher in NASH HCC in comparison to CHC HCC and CHB HCC. Metabolic risk factors (T2DM, obesity, hypertension and dyslipidemia) were compared among three groups (Table).
Conclusion Metabolic co-morbidities of type 2 diabetes mellitus, hypertension, and dyslipidemia are as common in viral hepatitis-related HCC as in NASH HCC. However, patients with NASH-HCC have a higher BMI and are more likely to be obese.
Keywords HCC, Hypertension, obesity
235
Serum fibrinogen VS INR in predicting rebleeding and mortality in cirrhotic patients
Rishikesh Malokar , Shubham Jain, Sanjay Chandanani, Pravin Rathi
Correspondence – Rishikesh Malokar - [email protected]
Department of Gastroenterology, Topiwala National Medical College and B Y L Nair Hospital, Mumbai Central, Mumbai 400 008, India
Introduction Patients with cirrhosis develop unique changes in hemodynamic and hemostatic pathways that may result in life-threatening bleeding and thrombosis. At present no single parameter can accurately predict future bleeding risk and prognosis.
Aim To study the role of fibrinogen level and INR in patients with cirrhosis of the liver with bleeding to predict future bleeding risk, hospitalization, and mortality.
Methods It is an interim analysis of a prospective observational study involving 54 cirrhosis patients who presented with bleeding. At presentation, common coagulation parameters (INR, fibrinogen levels) and a complete hemogram were obtained in all patients, and patients were followed up for 1year for rebleeding episodes, future hospitalization, and mortality. Correlation of low fibrinogen (<120 mg/dL) and high INR (>1.5) with the first bleeding episode, rebleeding, repeat admission, and mortality were obtained.
Results The median age of the study population (n= 54) was 44 years (range 19-76 years). The mean fibrinogen value was 159.69±40.3 mg/dL, and the mean INR was 1.42±0.36. Out of 54 patients, 11 patients had low fibrinogen (<120 mg/dL), and 19 patients had an INR of more than 1.5. In the low fibrinogen group (n=11), 6 patients (54.54%) had rebleeding, 6 patients (54.54%) needed repeated admission, and 5 (45%) patients died. In the high INR group (n=19), 8 patients (42.1%) had rebleeding, 7 patients (36.84%) needed repeated hospitalization, and 9 patients (47.36%) died. The difference between both groups regarding the number of rebleeding episodes (p=0.09), number of repeat hospitalization (p=0.11), and mortality (p=0.91) at 1 year was not statistically significant.
Conclusion Neither low fibrinogen nor raised INR can predict the bleeding and rebleeding episodes and future hospitalization and mortality in patients with cirrhosis.
Keywords Chronic liver disease, Fibrinogen, PTINR
236
Impact of past decompensation, with or without acute-on-chronic liver failure (ACLF), on severity and outcomes of current ACLF
Akash Gandotra , Ajay Duseja, Madhumita Premkumar, Arka De
Correspondence – Ajay Duseja - [email protected]
Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India
Introduction Evidence suggests that past decompensation may impact the prognosis of acute- on-chronic liver failure (ACLF). However, the effect of past decompensation in Asian Pacific Association for the Study of the Liver (APASL). ACLF has not been explored. In this study, we aim to assess the impact of previous decompensations on the severity and outcomes of current ACLF (APASL and CANONIC).
Methods All adult patients with ACLF satisfying either or both Asia Pacific Association of Study of Liver (APASL) and European Association for the Study of the Liver (EASL) Chronic Liver Failure Consortium (CLIF-C) (CANONIC) definitions were followed-up for 6-months after informed consent. Detailed history regarding past decompensations and past ACLF episodes was taken. Baseline ACLF severity scores were assessed using CTP and MELD-Na, APASL ACLF Research Consortium (AARC) and CLIF-C ACLF scores.
Results Out of 103 ACLF patients, 23 (22.33%) were APASL-ACLF and 40 (38.83%) were CANONIC-ACLF. 40 (38.83%) patients fulfilled both the criteria. Nineteen (18.44%) patients had past history of ACLF. Mean age was 44±10.6 years with male sex predominance (89.32%). Commonest acute precipitant was alcohol (36.89%) and most common underlying aetiology for chronic liver disease was also alcohol (79.61%). Baseline liver severity scores (CTP and MELD-Na) were 12 and 32. Within ACLF with PD, only 1 (2.3%) patient was APASL ACLF, 43 (97.7%) were CANONIC and 6 (13.6%) fulfilled both criteria. Similarly, in ACLF without PD, 20 (33.9%) were APASL, 3 (5%) were CANONIC and 29 (49.2%) fulfilled both criteria. Presence of past decompensation in ACLF patients didn’t affect overall mortality in ACLF patients (70.45%, ACLF with PD; 55.93%, ACLF without PD; p=0.199).
Conclusion Past decompensation with or without ACLF doesn't affect outcomes in current ACLF.
Keywords Acute on chronic liver failure
237
Prediction of hepatocellular carcinoma by REACH-B score in patients with chronic B virus infection
Yeshika Bhatia, Ajay Duseja
Correspondence – Ajay Duseja - [email protected]
Department of Hepatology, Nehru Hospital Extension, Room No 30, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012, India
Background Risk prediction models are available to calculate the risk of hepatocellular carcinoma (HCC) development in patients with chronic HBV infection. Aim of the present study was to predict HCC development by using REACH-B score in patients with chronic hepatitis B (CHB) and HBV related cirrhosis.
Methods The study included 100 patients with CHB with or without liver cirrhosis (mean age 43.4 years±13.9, 82 [82%] males) managed in a tertiary care hospital in last two years (January 2020 to January 2022). The diagnosis of CHB (HBeAg positive and HBeAg negative) and cirrhosis was made on the standard criteria. Seventeen point risk score called REACH-B was used to calculate the HCC risk using variables of age, gender, serum ALT levels, HBeAg status and HBV DNA level.
Results Of 100 patients, 21 patients had CHB-HBeAg positive disease, 45 had CHB-HBeAg negative disease and 34 had HBV cirrhosis. Three-year and 10-year risk of HCC in CHB-HBeAg positive group was 0.1% and 64.4%. In the CHB-HBeAg negative group 3-year and 10-year risk of HCC was 0.1% and 84% and in HBV cirrhosis it was 0.3% and 84%. (p=<0.05).
Conclusion Based on the REACH-B score, patients with CHB HBeAg negative disease and HBV related cirrhosis have similar 3-year and 10-year HCC risk and both have a higher 10-year HCC risk in comparison to CHB HBeAg positive disease.
Keywords CHB, HCC, Patients
238
Treatment outcome of Saroglitazar in improving the non-alcoholic fatty liver fibrosis score in the diabetic and non-diabetic group of patients Diagnosed with non-alcoholic fatty liver disease
Nisar A 1 , Shashipal Sharma 2 , Mohammad H Bhat 3 , Irfan Ali 2 , Showkat A Kadla 1 , Praveen Shah Gupta 4
Correspondence – Nisar A - [email protected]
Departments of 1Gastroenterology, 2Medicine, 3Endocrinology, Superspeciality Hospital, and 4Pharmacology, Government Medical College, Bemina, Srinagar 190 010, India
Introduction Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease (CLD) worldwide. It is a serious illness which have severe and widespread consequences due to the lack of a definite treatment. Other than lifestyle changes advice and Vitamin E we are still looking for a drug which can improve the prognosis and clinical outcomes in this group of patients. We aimed to see the treatment outcome of Saroglitazar 4 mg OD in the patient with and without diabetes, diagnosed to have NAFLD.
Methods In this prospective observational study of 48 weeks, Saroglitazar 4 mg OD was evaluated for its safety and efficacy in NAFLD patients with and without diabetes mellitus (DM). The primary efficacy point was the improvement of NAFLD fibrosis score (NFS). Total 292 patients with written informed consent, meeting inclusion-exclusion criteria were enrolled, out of which only 257 individuals completed the study. Eligible patients were put on Saroglitazar 4 mg per day for 24 weeks and followed on OPD basis up to 48th week for primary efficacy point in addition to secondary parameters like body mass index (BMI), glycalated hemoglobin A (HbA1c), lipid levels and liver biochemistry (transaminases). Statistical analysis used- repeated measures ANOVA on Statistical Package for the Social Sciences (SPSS) Version 20.0 (SPSS Inc., Chicago, Illinois, USA).
Results After 24 weeks therapy with Saroglitazar, there was a significant improvement in the NFS by 56.05 % in the Diabetic Group and 51.63% in non - Diabetic group of patients, the results were well sustained till the end of 48th week of follow-up.
Conclusions Saroglitazar 4 mg OD is an efficacious pharmcotherapy in improving NFS, liver and lipid parameters of NAFLD patients with or without Diabetes.
Keywords NAFLD fibrosis score, Peroxisome proliferator activated receptors, Saroglitazar
239
Efficacy and safety of Saroglitazar 4 mg OD in reducing the disease parameters in the non-alcoholic steatohepatitis patients with moderate to advance liver fibrosis- A 53 weeks prospective study analysis
Jatinder Pal Singh , Jahnvi Dhar
Correspondence – Jatinder Pal Singh - [email protected]
Department of Gastroenterology, Sohana Hospital, Mohali Multi Super Specialty Hospital, SH12A, Sector 77, Sahibzada Ajit Singh Nagar 140 308, India
Introduction Recent studies suggest that a large percentage of south Asian population having non-alcoholic fatty liver disease (NAFLD) are in the progressive non-alcoholic steatohepatitis (NASH) stage.
Methods This single center 52 weeks prospective study aimed at evaluating the role of Saroglitazar 4 mg OD dose in improving the treatment outcome of moderate to advance fibrotic NASH patients. Total 178 patients were enrolled between December 2020 to March 2022 out of which only 112 patients continued for 01-year follow up. The patient diagnosed on the basis of disease history, biochemical parameters and transient elastography (TE) with their liver stiffness measure (LSM) ≥ 7.5 kpa were selected and put on Saroglitazar 4 mg OD therapy for an year. The disease parameters were checked at the end of 06 and 12 months. The primary efficacy point was the improvement of LSM, APRI and FIB 4, in addition to secondary parameters like body mass index (BMI), lipid levels and liver biochemistry (transaminases). Statistical analysis- The data was analyzed using paired T-Test on Statistical Package for the Social Sciences (SPSS) Version 1.0.0.1406.
Results
Table 1- Changes in liver stiffness measure, APRI and FIB-4 from baseline
Conclusion Saroglitazar 4 mg OD is an efficacious therapy in regressing the moderate to severe fibrosis in NASH patients as observed on transient elastography and non-invasive Scoring tests- FIB4 and APRI, however histological data is warranted to confirm the changes.
Keywords Liver Fibrosis, NASH, Saroglitazar
240
Efficacy of saroglitazar in improving liver steatosis and liver stiffness on transient elastography in diabetic versus non-diabetic patient population-A 52 weeks retrospective study
Varun Mehta , Yogesh Gupta
Correspondence – Varun Mehta - [email protected]
Department of Gastroenterology, Dayanand Medical College and Hospital Tagore Nagar, Civil Lines, Ludhiana 141 001, India
Background and Aims Non-alcoholic fatty liver disease (NAFLD) has become one of the most prominent forms of chronic liver disease worldwide progressing to end-stage liver disease requiring liver transplantation. We tried to evaluate the effect of Saroglitazar 4 mg in diabetic and non-diabetic cohorts in terms of reduction in liver steatosis (CAP) and liver stiffness measure (LSM) on Fibroscan.
Methods A total 60 documented NAFLD patients (mean age 47.5+11.01 yrs, male 56.7%, non-diabetic 80%) prescribed on Saroglitazar 4 mg OD were analyzed for improvement in baseline mean CAP (324.9+39.6) and LSM (6.9+3.1) at 24 and 52 week interval. The improvements in primary endpoints were measured in diabetic vs. non-diabetic cohorts, along-with the overall study population. The statistical analysis was done using paired sample T- test.
Results The study shows significant improvements in CAP and LSM parameters along with all other secondary parameters (AST, ALT, and TG) from baseline in both diabetic and non-diabetic NAFLD cohort. The LSM improved by 15.3% and 25.9% in diabetic cohort compared to 15.2% and 23.4% in non-diabetics at 24% and 52 week respectively. The improvement in steatosis (CAP) was 8.13% and 14.7% in diabetics compared to 6.3% and 14.7% in non-diabetics at 24 and 52 week time interval respectively.
Conclusions Saroglitazar 4mg OD significantly improved Liver Stiffness Measure, and steatosis in both the diabetic and non-diabetic population and seems to be equally effective in these two cohorts. More studies, including well-designed randomised trials will show further light on the effect of Saroglitazar 4mg in NAFLD with different underline co morbidities.
Keywords Diabetes, Fibroscan, Saroglitazar
241
Efficacy and safety of different pharmacological strategies (Saroglitazar, vitamin E, ursodeoxycholic acid, and Saroglitazar with vitamin E) in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis population - A 24-week, real-world evidence from a tertiary care specialty center of Northern India
V K Dixit
Correspondence – V K Dixit - [email protected]
Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221 005, India
Background and Aims Non-alcoholic fatty liver disease (NAFLD) is an umbrella term and is the most common chronic liver disease worldwide. Its prevalence is estimated to be around 32.4%. Saroglitazar is the only approved drug for the treatment of NAFLD/NASH in India, although there is certain evidence-based therapy also being used that had shown effectiveness. We tried to evaluate the effectiveness of 4 different pharmacological strategies for the management of NAFLD/non-alcoholic steatohepatitis (NASH) in routine clinical practice.
Methods The NAFLD/NASH patients (n=884, male 70.8%, non-diabetic 87.5%, obese 76.13%) visited in outpatient Gastroenterology Department of Banaras Hindu University (BHU), Varanasi, and were prescribed Saroglitazar 4 mg OD (n=254), or Vitamin E 400 IU BD (n=248), or ursodeoxycholic acid (UDCA) 300 mg BD (n=131) or Saroglitazar 4 mg along with Vitamin E 400 IU (n=251), were assessed for changes in LFT and NFS score in 24 weeks. The data at baseline and 24 weeks were analyzed and statistical significance was established using paired sample T-test.
Results Compared to baseline, after 24 weeks the % changes in ALT were 47.7, 27.1, 34.7, and 46.7%, in AST was 39.2, 17.2, 27.7, and 35.6% and in NFS score was 33.5, 8.9 (ns), 7.24 (ns), 38.1% respectively in Saroglitazar, Vitamin E, UDCA, and Saroglitazar along-with Vitamin E group. The improvement in LFT profile was significant in all the groups but NFS Score improvement was statistically significant in Saroglitazar or Saroglitazar with Vitamin E group only.
Conclusions The study shows that Saroglitazar 4mg OD alone is an effective treatment option compared to Vitamin E or UDCA or a combination of Saroglitazar with Vitamin E. In the future, more studies including a well-designed controlled comparative clinical trial will be needed to throw more light on the comparative effectiveness of these agents.
Keywords NAFLD, NFS score, Saroglitazar, UDCA, VIT. E
242
Correlation of serum zinc levels with hepatic encephalopathy and its severity
Rahul Sangwan, Ritesh Kumar Gupta, Lokesh Sharma
Correspondence - Rahul Sangwan - [email protected]
Department of General Medicine, Atal Bihari Vajpayee Institute of Medical Sciences (ABVIMS) and Dr. Ram Manohar Lohia Hospital, Baba Kharak Singh Road, Type III, Connaught Place, New Delhi 110 001, India
Chronic liver disease (CLD) is a major public health disease. One of the most dreaded complications of chronic liver disease is hepatic encephalopathy. Unless the underlying hepatic disease is treated successfully, HE has a high recurrence chance and is associated with poor survival and prognosis. Zinc plays an important role in CLD as it is involved in hepatic urea cycle functioning and zinc deficiency will eventually lead to hyperammonemia due to impaired urea cycle. The present study aimed to determine the distribution of serum zinc levels and the prevalence of zinc deficiency in CLD patients and its association with hepatic encephalopathy (HE) and its severity.
The cross-sectional observational study was conducted for a period of 1 year and 6 months on 105 patients of the 18-65 years age group, who presented with chronic liver disease irrespective of severity and underlying etiology. All patients were evaluated for presence of HE and its grade. Also, serum zinc was collected, and its value was compared with the occurrence and severity of HE.
HE occurred in patients with lower zinc levels. Mean serum zinc values in patients with HE were 35.1 µg/dL as compared to 65.7 µg/dL in those who didn't have this complication. Zinc deficiency was more pronounced in patients with increasing severity of HE. Mean S. zinc values were 65.7 µg/dL, 40.6 µg/dL, 34.2 µg/dL, 30.3 µg/dL, 24.7 µg/dL in HE grade 0,1,2,3,4 respectively.
Zinc deficiency is commonly encountered in chronic liver disease. Zinc deficiency is aggravated with the severity of chronic liver disease. Zinc is required in the urea cycle and is a cofactor of ornithine transcarbamylase (OTC). Hence, zinc shall be measured routinely in patients of chronic liver disease as it may be a precipitating factor for hepatic encephalopathy.
Keywords Chronic liver disease, Hepatic encephalopathy, Zinc
Biliary Tract
243
Can esophagogastroduodenoscopy replace endoscopic retrograde cholangiopancreatography for stent removal?
Isha Bansal, Amol Dahale, Debabrata Banerjee
Correspondence - Amol Dahale - [email protected]
Department of Medical Gastroenterology, Dr D Y Patil Hospital and Research Centre, Sant Tuka Ram Nagar, Pimpri, Pune 411 011, India
Endoscopic retrograde cholangiopancreatography (ERCP) is a modern and universally established modality in the evaluation and treatment of suspected biliary and pancreatic disease [1]. Follow-up ERCP procedures are routinely performed to remove biliary stents. Alternatively, the stents can be removed via upper endoscopy which appear to be more feasible, cost effective and are technically less challenging. There is no consensus or the guidelines on protocol to be followed for stent removal in post common bile ductstone clearance and after cholecystectomy.
We have collected data on stent removal approach by gastroenterologist in post-ERCP, post cholecystectomy patient. We formed a questionnaire of 11 questions and studied the responses among the gastroenterologists as to what they do in their institute or private practice. We have received 133 responses for the same. 66% responders were from private setup while rest are from government setup. 56.4% doctors responded are from academic institute. Maximum responded doctors (67%) are in practice for 5-10 years.
According to our survey 45% of doctors remove the stent via upper GI endoscopy and remaining 45% uses side view endoscopy +/- check cholangiogram +/- balloon sweep for stent removal. There is highly variable protocol followed by experts in gastroenterology among all over India. As per one previous abstract, follow-up ERCP was required in 90% of patient with choledocholithiasis, contrary to this what our survey showed.
Keywords CBD stent, ERCP, Upper GI endoscopy
244
Study of clinical profile of benign biliary strictures in a tertiary care centre: An observational study
Motij Dalai , Meghraj Ingle, Vikas Pandey, Shamshersingh Chauhan, Saiprasad Lad, Gaurav Singh
Correspondence – Meghraj Ingle - [email protected]
Department of Gastroenterology, College Building, 1st Floor, Room No. 2, LTMMC and MGH, Sion Hospital, Mumbai 400 022, India
Background Benign biliary strictures (BBSs) may from chronic inflammatory pancreaticobiliary pathologies, postoperative bile-duct injury, or at biliary anastomoses following liver transplantation. Endoscopic therapy, including stricture dilatation and stenting, is effective in most cases and the first-line treatment of BBS. We aim to study the different etiologies of benign biliary strictures and their clinical manifestations and observe their clinical progression over 1 year
Methods It’s an observational study in a tertiary care centre. We took 62 diagnosed patients of BBS and followed them over a period of 1 year. All baseline demographic details, routine blood workup were done tumor marker like CA 19.9 was also obtained and IgG-4 levels was done based on degree of suspicion. Transabdominal USG, MRCP and EUS (endoscopic ultrasound) was done to characterize the nature of lesion and to assess need for drainage procedure, ERCP (endoscopic retrograde cholangiopancreatography) was be performed and brush cytology was collected. All the patients were followed up prospectively for 1 year and their clinical profile was studied.
Results Common etiology in our study were post cholecystectomy and chronic pancreatitis related 25% (16), 16% (10) respectively while in majority cause could not be ascentained i.e. indeterminate 51% (32). 20% (12) Presented in cholangitis and all underwent ERCP; mean duration of stent use was 8.4 months and no. Stents used was 2.67 of which 33% (20) were on stent free trial by end of 1 year.
Conclusion This was a pragmatic approach to diagnosis and treatment of benign biliary stricture in a high-volume centre.
Keywords Benign biliary stricture, Clinical profile, Mangement
245
Opioid biliopathy with hepatitis B reactivation masquerading as perampullary carcinoma
Chhagan Lal Birda, Kaushal Singh Rathore, Subhash Soni, Ashish Agarwal
Correspondence - Ashish Agarwal - [email protected]
Department of Gastroenterology, All India Institute of Medical Sciences, Marudhar Industrial Area, 2nd Phase, M.I.A. 1st Phase, Basni, Basni, Jodhpur 342 005, India
Introduction Opioid addiction is common in western Rajasthan [1, 2]. Opioid causes sphincter of Oddi dysfunction and results in double-duct sign [3, 4]. We hereby report a case of opioid biliopathy who also had hepatitis B reactivation mimicking as periampullary carcinoma.
Case Report A seventy-years-old gentleman, without previous comorbidities presented outside with history of jaundice for two-weeks duration. On evaluation he had abnormal liver function tests (LFT) and ultrasound abdomen revealed dilated common bile duct (CBD). Contrast enhanced computed tomography scan of abdomen and magnetic resonance cholangiopancreatography both revealed double-duct sign without any obstructing calculus/mass/bile duct thickening. A possibility of periampullary carcinoma was kept and endoscopic retrograde cholangiopancreatography (ERCP) was attempted but failed. He was referred to AIIMS, Jodhpur for further treatment.
At AIIMS Jodhpur, on reviewing history he complained of fever, anorexia and myalgia prior to onset of jaundice. Personal history revealed opioid addiction for last forty-years. His HBsAg was positive and HBV DNA titre was 1.2 × 106 IU/mL and coagulation profile was deranged. He was diagnosed as acute liver injury due to hepatitis B reactivation and started on Tenofovir. His side-viewing endoscopy and CA 19-9 both were normal. An endoscopic ultrasound was done which revealed dilated CBD (10.3 mm) and MPD (3.8 mm in the head) without any mass/filling defect All the relevant investigations are summarized in Table 1.
A diagnosis of opioid induced biliopathy with acute liver injury due to hepatitis B reactivation was made. Patient improved symptomatically with treatment and follow-up after four-weeks showed complete normalisation of LFT.
Conclusion Index case highlights concomitant hepatitis B and opioid biliopathy mimicking as periampullary carcinoma. Careful history and exclusion of malignancy (absence of mass on imaging and normal tumor markers) were key in making the diagnosis and avoided unnecessary endoscopic and surgical intervention.
Keywords Hepatitis B reactivation, Opioid biliopathy, Periampullary carcinoma
246
Long-term outcomes of endoscopic transpapillary gallbladder stenting in extrahepatic portal venous obstruction patients with calculous cholecystitis
Surinder Rana, Pankaj Kumar, Amit Yadav, Ravi Sharma, Rajesh Gupta*
Correspondence - Surinder Rana - [email protected]
Departments of Gastroenterology, and *Surgical Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India
Background Endoscopic transpapillary gallbladder stenting (ETGBS) has been advocated to prevent recurrence of acute cholecystitis in high-risk surgical patients. However, there is paucity of literature regarding the safety, efficacy, and long-term outcomes of ETGBS. Also, safety and efficacy of ETGBS has not been evaluated in patients with extrahepatic portal venous obstruction (EHPVO) where presence of venous collaterals may increase the risk of bleeding and cholangitis.
Methods A retrospective analysis of data base of patients with EHPVO and high surgical risk because of presence of extensive intraabdominal venous collaterals with acute calculous cholecystitis who were treated with long-term ETGBS between 2010 and 2022 was done. A single 7 Fr 5 cm double pigtail stent was used for gallbladder drainage in all patients. Patients were regularly followed up every 3-6 months and underwent routine laboratory investigations and abdominal X-ray. Recurrence of acute cholecystitis was treated with stent exchange along with antibiotics.
Results Seventeen patients (M13; age range: 19-48 years) with EHPVO and acute calculous cholecystitis were treated with attempted long term ETGBS. Ten patients had eradicated esophageal varices and two patients had gastric varices obliterated with cyanoacrylate glue. Transpapillary gallbladder stent could be successfully placed in 13/17 (76.4%) patients. Endoscopic sphincterotomy was done in all the patients with successful gallbladder stenting. Post ERCP pancreatitis developed in one patient. Thirteen patients with transpapillary gallbladder stenting were followed up for 2-144 months. Acute cholecystitis recurred in one patient at 118 months after the initial stenting and could be successfully managed with stent exchange and antibiotics. Asymptomatic external stent migration occurred in one patient 9 months after the initial stenting and was managed with stent replacement.
Conclusion Long-term ETGBS with double-pigtail plastic stent seems to be a safe and effective management strategy for patients with EHPVO and acute calculous cholecystitis.
Keywords Extrahepatic portal venous obstruction, Gallbladder, Stent, Varices
247
A case report of secondary bacterial peritonitis and pelvic abscess in a patient of recurrent pyogenic cholangitis
Tony Pious , Muma Devi, B Ramesh Kumar, L Sahitya Reddy
Correspondence - Tony Pious - [email protected]
Department of Gastroenterology, Osmania Medical College, 5-1-876, Turrebaz Khan Road, Troop Bazaar, Koti, Hyderabad 500 095, India
Introduction Recurrent pyogenic cholangitis is a disease characterized by intrabiliary pigment stones, strictures in the biliary tree and recurrent episodes of cholangitis. Recurrent pyogenic cholangitis is also known as oriental cholangiohepatitis, hepatolithiasis, Hong Kong disease and biliary obstruction syndrome of the Chinese. It was first described by Digby in 1930.
This entity is almost exclusively seen in people living in Southeast Asia. The pathogenesis of this condition is incompletely understood even though bacterial and worm infections of the biliary tract are suggested. Patients usually present with recurrent bouts of cholangitis and its complications including multiorgan failure. Biliary strictures and recurrent cholangitis ultimately result in secondary sclerosing cholangitis, secondary biliary cirrhosis, portal hypertension and cholangiocarcinoma.
Management needs a multidisciplinary approach combining antibiotics, endoscopic therapy and surgical intervention.
Background A 44-year-old male presented with progressive abdominal distension and abdominal pain for 7 days, high grade fever with chills for 2 days. Patient had multiple similar episodes in the past. Abdominal examination revealed diffuse tenderness and shifting dullness.
Contrast-enhanced computed tomography (CECT) scan of abdomen showed multiple calculi in right and left hepatic ducts extending into second order biliary radicles. Portal cavernoma replacing portal vein at porta hepatis. 2 CBD stents noted in right and left ductal system. Moderate loculated fluid in the anterior aspect of the abdominal cavity and extending into the pelvis with thick enhancing walls.
Results Patient was treated with Meropenem, Amikacin, endoscopic retrograde cholangiopancreatography (ERCP) with CBD stenting and percutaneous drainage of pelvic abscess under ultrasound guidance. Patient was completely relieved of symptoms with treatment and doing well on follow-up.
Conclusion Recurrent pyogenic cholangitis is an uncommon entity requiring regular follow-up with timely biliary drainage, antibiotic treatment of cholangitis and appropriate surgical interventions including liver transplantation.
Keywords Biliary cirrhosis, Endoscopic therapy, Recurrent pyogenic cholangitis
248
To study the safety and efficacy of intraluminal brachytherapy via percutaneous transhepatic biliary drainage and subsequent endoluminal stenting as palliative treatment for unresectable malignant biliary obstruction
Shikha Sood , John V Alexander, Manish Gupta, Ashish Chauhan
Correspondence - Shikha Sood - [email protected]
Department of Radiodiagnosis, Indira Gandhi Medical College, Ridge Sanjauli Road, Lakkar Bazar, Shimla 171 001, India
Background Percutaneous, endoscopic or surgical biliary drainage forms the mainstay treatment for unresectable cases of malignant biliary obstruction (MBO) with endoluminal stenting providing a better quality of life. Intraluminal therapies like brachytherapy, photodynamic therapy and radiofrequency ablation can locally destroy the tumour and thus increase the catheter/stent patency.
Methods We prospectively analyzed the safety and efficacy of intraluminal brachytherapy (ILBT) with iridium-192 and its correlation with survival and stent patency periods. We enrolled 66 patients who underwent percutaneous transhepatic biliary drainage (PTBD) for unresectable causes of MBO from January 2021 to March 2022 who were unfit for any alternate treatment modalities including surgery, chemotherapy, or radiotherapy. Eleven consenting patients underwent PTBD with internalisation followed by subsequent ILBT once they met our inclusion criteria (ECOG status <4 and total bilirubin fall more than 50% of preprocedural bilirubin level). ILBT was given in two sessions (800 cGy each session– one week apart) with iridium-192 prescribed at 1.5 cm from the central axis of the catheter, via a percutaneous biliary catheter. 2nd session was followed up by endoluminal stenting in the same sitting. Data included biliary stent/catheter patency period (days), survival duration (days), the decline in mean bilirubin level (mg %) and response to treatment. Data were analyzed using Kaplan-Meir tests and multiple comparison tests. Alpha was set at 0.05.
Results The total bilirubin levels showed a median fall of 7.3 (4.75-11.875) mg% after PTBD. The median follow-up period (observation time for those event-free) of the ILBT group was 273.5 (172-430) days. The median survival period and stent/catheter patency period were 172 (84.5-273.5) days and 172 (83-273.5) days for the ILBT group. There was significant symptomatic relief. No major treatment-related complications were seen in any of the patients.
Conclusion ILBT with stenting is a safe and feasible option for improving stent patency and survival with minimal complications
Keywords Intraluminal brachytherapy (ILBT), MBO, Percutaneous transhepatic biliary drainage (PTBD)
249
Common bile duct calculi-break and then stent
Yeruva Deepthi Reddy , Avinash Balekuduru, Narendra Mandalapu
Correspondence - Avinash Balekuduru, - [email protected]
Department of Gastroenterology, M S Ramaiah Medical College, B E L M S Ramaiah Nagar, RIT Post, M S Ramaiah Nagar, Mathikere, Bengaluru 560 054, India
Introduction Extraction of large common bile duct (CBD) calculus has challenged the therapeutic endoscopist. Extracorporeal shockwave lithotripsy (ESWL) is an excellent option for large CBD calculi followed by endoscopic retrograde cholangiopancreatography (ERCP) and CBD clearance. Here we present 2 successful cases of ESWL to large CBD stones followed by ERCP in our center.
Case Reports A 63-year-old male known case of status post ERCP and CBD stenting for choledocholithiasis, status post laproscopic cholecystectomy followed by CBD stent removal 1 year back presented with jaundice, fever and abdominal pain. On examination patient is icteric and investigations showed leucocytosis and obstructive jaundice. Magnetic resonance cholangiopancreatography (MRCP) showed choledocholithiasis, stone size of 2 cms and CBD dilated to 15 mm with distal CBD stricture. Patient underwent ESWL and there is fragmentation of calculi. Post ESWL patient is taken up for ERCP, over the guide wire balloon sweep done, retrieved multiple pigmented calculi and saline flush given till clear. Later 10fr x10 cms, 7 frx10 cms Amsterdam stents was placed in CBD. Post procedure patient is stable.
A 55-year-old male known case of status post ERCP and CBD stenting in 2019 for choledocholithiasis, lost the follow-up and now presented with jaundice and abdominal pain. On examination patient is icteric and investigations showed leukocytosis and obstructive jaundice. MRCP done showed previously placed CBD stent in situ with CBD calculus of 1.8 cms just proximal to stent. patient underwent ESWL, followed by which patient is taken up for ERCP, old CBD stent removed, and clearance done. Later 10 fr x10 cms Amsterdam stent is placed in CBD. Post procedure patient is stable.
Conclusion In view of high efficiency, non-invasive nature and low complication rates, ESWL can be considered for selected patients with large CBD calculi.
Keywords Common bile duct, Endoscopic retrograde cholangiopancreatography, Extracorporeal shockwave lithotripsy
250
The plastic bridge
Shashank Devarasetty, Avinash Balekuduru
Correspondence – Avinash Balekuduru - [email protected]
Department of Medical Gastroenterology, M S Ramaiah Medical College, B E L M S Ramaiah Nagar, RIT Post, M S Ramaiah Nagar, Mathikere, Bengaluru 560 054, India
Introduction Endoscopic ultrasound -guided biliary drainage (EUS-BD) has emerged as an alternative to percutaneous transhepatic biliary drainage (PTBD) in unsuccessful endoscopic retrograde cholangiopancreatography (ERCP), with a high clinical success rate and low risk of complications and morbidity. We present a case of malignant distal biliary obstruction successfully managed with EUS-guided choledochoduodenostomy (EUS - CDS).
Case Report A 62-year-old male known case of diabetes mellitus, now presented with abdominal pain and jaundice for a month and weight loss of 10 kgs in last 3 months, He had iron deficiency anemia with obstructive pattern liver function test. Ultrasonogram showed features of Intra and extrahepatic bile duct dilation. Endoscopy showed ulceroproliferative friable growth noted in the periampullary region and biopsy suggestive of moderately differentiated adenocarcinoma. Contrast-enhanced computed tomography (CECT) abdomen suggestive of ampullary stricture with biliary system dilation with no distant metastasis. Patient planned for Whipple surgery in view of cirrhotic liver and extensive collaterals on laparotomy procedure was abandoned. In view of obstructive jaundice patient was advised EUS guided choledochoduodenostomy. In which common bile duct (CBD) punctured using 22G needle, 0.021 guidewire passed till mid CBD, deep cannulation could not be achieved. Over the guidewire needle knife sphincterotomy done, sphincterotome exchanged over the guidewire and as deep CBD cannulation not achieved a 7Fr X 7 cms double pigtail stent (DPT) stent placed as bridge for placing metallic stent. Patient jaundice resolved and was started on chemotherapy (Gemcitabine), 8 weeks post procedure, Old DPT stent removed and later a 10 mm x 6 cms partially covered metallic stent placed in CBD and free bile flow noted.
Conclusion EUS-guided choledochoduodenostomy with a plastic stent has a high potential as a bridge to mettalic stent in cases of failed deep CBD cannulation.
Keywords Choledochoduodenostomy, Double pigtail stent, Endoscopic retrograde cholangiopancreatography, Endoscopic ultrasoun
251
Intrahepatic cholestasis of pregnancy and impaired health-related quality of life in pregnant women
Jasvinder Nain, Madhumita Premkumar, Anchal Sandhu, Shikha Guleria, Vanita Suri, Vanita Jain, Neelam Aggarwal, Ajay Duseja, Sunil Taneja, Rashmi Bagga, Surender Sehrawat, Vishesh Kumar
Correspondence – Madhumita Premkumar - [email protected]
Department of Hepatology, Sector 12, Kairon Block, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012, India
Background Intrahepatic cholestasis of pregnancy (ICP) is associated with deranged liver function tests, elevated bile acids and pruritus, which affects the daily activities and emotional health of pregnant women. Utilizing the SF36, we evaluated the impact of ICP on health-related quality of life (HRQOL) of women with ICP compared with healthy pregnant women.
Methodology We screened consecutive pregnant women referred to the Liver Clinic/Antenatal Clinic with deranged liver function tests for ICP to estimate the prevalence in our population. The SF36 questionnaire includes social, emotional, general health and physical function of pregnant women with ICP and was compared with healthy controls.
Results A screening of 3900 pregnant women was done who attended the Liver Clinic /Antenatal Clinic at Postgraduate Institute of Medical Education and Research, Chandigarh. Prevalence of ICP was noted as 1.15%. The mean age of patients with ICP (n= 45) was 28.2 ±4.4 years with 11.1% having twin, and 8.8% having modified conception. Among the cases DM 17.7, preeclampsia 8.8, thyroid 11.1% of cases were reported. Mean HRQOL score was worse in ICP (45.8±5.8) vs. controls (64.9±3.9; (p<0.001) Physical function score (52.5 vs. 82.9), role limitation noted due to physical mean score (36.7 vs. 49.0), energy score (46.6 vs. 59.0), emotional well-being (50.4 vs. 59.0), social function (47.8 vs. 62.5), general health (48.0 vs. 62.5) were noted indicating worse functioning in all domains in women with ICP as compared with controls.
Conclusion Women with ICP have poor HRQOL as compared with healthy controls, which needs to be monitored and managed appropriately in addition to pharmacotherapy.
Keywords HRQOL, ICP, Pregnant
252
Predictors of effective drainage during biliary stenting of hilar strictures with liver volume assessment
Rishikesh Malokar , Prasanta Debnath, Shubham Jain, Sanjay Chandanani, Pravin Rathi
Correspondence - Rishikesh Malokar - [email protected]
Department of Gastroenterology, Topiwala National Medical College and B Y L Nair Hospital, Mumbai Central, Mumbai 400 008, India
Introduction Hilar strictures can be both benign and malignant. The optimal strategies for drainage of hilar strictures are still controversial, mainly regarding the extent of drainage required and unilateral or bilateral stenting. The aim of this study was to identify predictors of successful biliary drainage mainly by liver volumetry.
Methods Prospective observational study was conducted. Total 14 patients with hilar strictures of Bismuth type II, III, or IV were studied who had either endoscopic or percutaneous biliary drainage. CT volumetry of 3 main hepatic sectors (left, right anterior, and right posterior) was calculated. The liver volume drained was estimated and classified into 2 classes: less than 50% (Group A) and more than 50% (Group B) of the total volume.
Main Outcome Measurements: Primary outcome was effective drainage which was defined as a more than 50% fall in bilirubin at day28 post-intervention. Secondary outcomes studied include complications, reintervention, and survival and mortality rates.
Results Mean age of study population was 55 years with 78.65% females. The commonest symptom other than jaundice was weight loss (85%). Most common type of block was type 2 (57.1%) followed by type 4 (35.7%) with commonest etiology being cholangiocarcinoma (57.1%), Ca gallbladder (35.7%). Nine patients (64.3%) had more than 50% drainage (Group A) and 5 patients (35.7%) (Group B) had lesser than 50%. Mean total bilirubin in Group A on day 0 was 16.43, Group B was 19.4, day 28 was 0.77 and 1.125 respectively. The difference in mean total bilirubin on day 28 was not statistically significant (p value 0.46). Group B patients had more complications and lesser survival.
Conclusion Draining more than 50% of the liver volume is not required for 50% fall in bilirubin but had better survival and lesser complications. Type 2 Hilar block is most common type and has best prognosis. A pre-ERCP assessment of hepatic volume distribution on cross-sectional imaging may optimize endoscopic procedures.
Keywords Biliary drainage, Hilar block, Liver volumetry
253
Spectrum of IgG4-related hepato-pancreato-biliary diseases- an experience from tertiary care center in Western India
Aditya Kale , Michael Kuruthukulangara
Correspondence - Michael Kuruthukulangara - [email protected]
Department of Medical Gastroenterology, Seth G S Medical College and K E M Hospital, Ward 32A, 9th Floor, New Building, Parel, Mumbai 400 012, India
Introduction IgG4-related disease is systemic immune mediated sclerosing disease characterized by infiltration of organs with IgG4 positive plasma cells and elevated serum IgG4 levels.
Methods Medical records retrospectively reviewed from 2018-2021 to identify 13 patients with IgG4-related disease affecting liver, biliary system, and pancreas. Demography, clinical presentation, radiological, pathological investigations, therapy, and response were noted.
Results Median age was 55 years (interquartile range [IQR]=46-66 years). Nine male patients. Pancreatitis, biliary strictures, gallbladder thickening, and hepatic mass were presentation in 5, 4, 2 and 2 respectively. One patient had multisystem involvement affecting pancreas, lymph nodes and nasal polyp. Out of 8 patients with hepatobiliary disease 3 had obstructive jaundice, 5 abdominal pain, 2 abdominal lump. Computed tomography (CT) showed bile duct thickening in 4 cases, liver masses mimicking cholangiocarcinoma-2, gallbladder thickening mimicking malignancy-2, intrahepatic biliary dilatation-3, atrophy-hypertrophy complex-2, abdominal non-necrotic lymphadenopathy-2. Magnetic resonance cholangiopancreatography (MRCP) showed type II hilar stricture in 3 and type IV in 1. Three had obstructive jaundice, one each had recurrent pancreatitis and chronic pancreatitis respectively. CT showed diffuse involvement in 2 cases and 3 had pancreatic head mass. One had pancreatic duct stricture. Six cases required biliary drainage. All had elevated IgG4 levels. Histology showed lymphoplasmacytic infiltration with IgG4 positive cells in all, obliterative phlebitis (8,61.53%), storiform fibrosis (9,6923%). Six underwent biliary drainage with endoscopic retrograde cholangiopancreatography (ERCP) and single (2) and multiple (4) plastic stents. Six patients (2-pancreatic mass, 2-liver lesions, 2 biliary strictures) underwent surgery with presumptive diagnosis of cancer. Others (7 patients) received steroids followed by azathioprine. At six months, patients showed response to therapy in the form of reduction in size of mass. Strictures were persistent despite therapy and required elective stent exchanges.
Conclusion IgG4-related diseases have varied clinical manifestations and mimic malignancy clinic-radiologically. IgG4 levels and histology differentiate from malignancy. It responds to steroids and/or immunosuppressors.
Keywords IgG4 related disease, Immunosuppression, Malignancy, Steroids
254
Bacteriological profile in patients with biliary obstruction in a tertiary care center
Neelakanth Parappanavar, P Shravan Kumar
Correspondence - Neelakanth Parappanavar - [email protected]
Department of Medical Gastroenterology, Gandhi Medical College, Musheerabad, Padmarao Nagar, Secunderabad 500 003, India
Introduction The bacterobilia is common in patients presenting with biliary obstruction. Acute cholangitis carries mortality rate as high as 30% [1]. Choledocholithiasis is most common cause followed by neoplasm and benign biliary strictures for obstruction [2]. Because of widespread use of antibiotics over years lead to change in sensitivity pattern of organisms that requires change in empiric antibiotic usage [3].
Methods Study was conducted in Department of Gastroenterology, Gandhi Medical College, Secunderabad. We studied 45 patients with biliary obstruction who have undergone endoscopic retrograde cholangiopancreatography (ERCP). Study population included 27 females and 18 males. Thirty-three cases were of benign causes and 12 were malignant. After biliary cannulation bile was aspirated and sent for microbiological analysis.
Results Majority of patients were in age group of 40-65 yrs. Bile cultures were positive in 27 patients. 20 of them had benign etiology, gallstone being most common and 7 had malignant cause. Organisms grown are mainly gram negative, most common being E. coli and Klebsiella followed by pseudomonas species. Response to cephalosporins were good, resistance to fluroquinolones was observed in few patients. Higher grades of cholangitis seen in patients with pseudomonas bacterobilia and multidrug resistant bacteria.
Conclusions Study confirms the significance of obtaining routine bile sample during ERCP in obstructed biliary system to predict and prevent dreaded complications of cholangitis.
Keywords Bacterobilia, Biliary obstruction, Cholangitis, ERCP
255
Long-term patency rates of transmural and transpapillary endoscopic ultrasound guided biliary drainage – Time to choose transmural over transpapillary?
Mangesh Borkar, Harsh Bapaye*, Jaseem Ansari, Ajay B R, Sanjana Bhagwat, Ashish Gandhi, Rajendra Pujari, Harshal Gadhikar, Amol Bapaye
Correspondence – Amol Bapaye - [email protected]
Department of Gastroenterology, Deenanath Mangeshkar Hospital and Research Centre, Deenanath Mangeshkar Hospital Road, Erandwane, Pune 411 004, India, and *Department of Medicine, Byramjee Jeejeebhoy Government Medical College and Sassoon General Hospitals, Medicine, Jai Prakash Narayan Road, Railway Station Road, Pune 411 001, India
Introduction and Aim Endoscopic ultrasound guided biliary drainage (EUS-BD) is accepted treatment modality after failed endoscopic retrograde cholangiopancreatography (ERCP) in patients with malignant biliary obstruction (MBO). EUS–BD can be performed by transpapillary (TP) (antegrade [AG], rendezvous [RA]) or transmural (TM) (hepatogastrostomy [HG]), choledochoduodenostomy (CDS), choledochoantrostomy (CA) approach. This study compares long-term success rates of EUS-BD by transmural or transpapillary approach.
Methods Retrospective analysis of prospectively maintained database of patients undergoing EUS-BD for MBO and failed ERCP. Study duration–11 years (2011–2022). Patients underwent EUS BD by TP or TM approach using self-expandable metal stents (SEMS). Patients were followed up until stent occlusion or death, whichever was earlier. Stent patency, adverse events, reintervention rates and survival during follow-up were compared. P value<0.05 was considered significant. After initial clinical follow-up, later follow-up was taken telephonically.
Results Total n=163; TM–119 (73%), TP–44 (27%). Mean age=65.18 (±13.48) years, 92 (56.4%) were male. Follow-up–median 85 days (32-240) for cohort, TM–84 (35–267) days, TP–86 (24.75–171.25) days; (p=0.26). Lost to follow-up–10 (6.1%) for cohort, TM-8 (6.7%), TP-2 (4.5%); (p=1.0). Technical success of EUS-BD achieved-161/163 (98.8%) for cohort, TM-118 (99.2%), TP-43 (97.7%); (p=0.468). Clinical success was seen significantly more in TM group [TM–(101/119), 85.6%, TP–(31/44),72.1%, p=0.049]. Overall stent related adverse events were significantly more in TP group (TP–17/44, 38.6%, TM–17/119, 14.3%, p <0.001). Stent occlusion was significantly more frequent in TP than TM group [TM–6/119, (5%), TP–16/44, (36.4%); p<0.001]. Stent migration was more frequent in TM group but was not statistically significant (TM-7/119, [5.9%], TP-1/44, [2.3%]; p=0.684). Median stent patency after TM=68.5 days (32.75-238.5) and TP=54 days (18.5-134) (p=0.126). Re-intervention rates were more in TP group (TP-10/44, [22.7%], TM-6/119, [5.0%], p=0.002). Kaplan-Meier survival graph revealed superior survival for TM group (mean survival TM-221.09 days, TP-132.42 days, p=0.033).
Conclusions For patients undergoing EUS-BD for MBO, using either transmural or transpapillary approach stent occlusion and reintervention rates were significantly low and survival was significantly higher in transmural group as compared to transpapillary group. Further randomized studies are recommended to confirm these findings.
Keywords Stent patency, Transmural, Transpapillary
256
Jaundice with double duct sign: Not always periampullary malignancy
Chhagan Lal Birda , Kaushal Singh Rathore, Subhash Soni, Ashish Agarwal
Correspondence – Ashish Agarwal - [email protected]
Department of Gastroenterology, All India Institute of Medical Sciences, Marudhar Industrial Area, 2nd Phase, M.I.A. 1st Phase, Basni, Basni, Jodhpur 342 005, India
Introduction Jaundice with double duct sign is usually raise suspicion for periampullary malignancy. We report a case of opioid biliopathy with hepatitis B reactivation mimicking as periampullary malignancy.
Case Report A 70-year-old gentleman, without previous comorbidities presented outside with history of jaundice associated with fatigue and pruritus. On evaluation he had jaundice (total bilirubin/direct bilirubin–15/10.4 mg/dL), SGOT/SGPT/ALP–885/956/332. USG abdomen revealed dilated common bile duct (CBD). He underwent contrast enhanced computerised tomography (CECT) scan of abdomen and magnetic resonance cholangiopancreatography (MRCP) both revealed double duct sign without any obstructing calculus/mass/bile duct thickening. Endoscopic retrograde cholangiopancreatography (ERCP) was attempted but CBD cannulation could not be achieved and was referred to All India Institute of Medical Sciences (AIIMS), Jodhpur for further treatment.
History was reviewed, he was smoker and opioid addict for last 40 years and he gave history of fever, anorexia, and myalgia prior to onset of jaundice. His HBsAg was positive and hepatitis B virus DNA titre was 1.2 × 106 copies and there was no evidence of cirrhosis. He was started on Tenofovir. His outside imaging was reviewed and reported same as dilated CBD and main pancreatic duct (MPD) without any mass lesion/calculus. An endoscopic ultrasound (EUS) was done which revealed dilated CBD (9.5 mm) and MPD (4 mm in head of the pancreas) without any mass/filling defect and CA 19-9 was normal. A diagnosis of opioid induced biliopathy with acute liver injury due to hepatitis B reactivation was made. Patient improved symptomatically and discharged. Follow-up after 4 weeks showed complete normalisation of liver biochemical tests.
Conclusion Index case highlights concomitant hepatitis B and opioid biliopathy mimicking as periampullary carcinoma. Careful history and exclusion of malignancy (absence of mass and normal tumor markers) was key in making the diagnosis and avoided unnecessary endoscopic and surgical intervention.
Keywords Opioid biliopathy double duct sign periampullary malignancy
257
A rare case of placing a metal stent in stent and successful dilatation of malignant biliary stricture and a review of literature on biliary self-expanding metal stents
Prithvipriyadarshini Shivalingaiah
Correspondence – Prithvipriyadarshini Shivalingaiah - [email protected]
Department of Clemenceau Medical Center, Healthcare city Dubai, United Arab Emirates
For patients presenting with biliary obstruction in an unresectable pancreatic malignancy, endoscopic retrograde cholangiopancreatography (ERCP) with biliary stent placement is the treatment of choice. Except one case report, there are no further studies reported installing a metal stent into an already existing bare metal stent in the common bile duct (CBD). We describe a rare case of a stent-in-stent dilatation of the CBD for the patient presenting with jaundice and recurrent cholangitis in setting of biliary obstruction from pancreatic adenocarcinoma with previously inserted biliary metal stent in situ. The biliary obstruction was relieved with a decrease in bilirubin levels post-stenting with no post procedure complications and rapid improvement in general condition.
Self-expanding metal stents (SEMS) - both covered and uncovered are used for palliation of patients with malignant biliary obstruction. There have been previous studies showing plastic biliary stents that were combined with biliary metal stenting. SEMS in the management of malignant biliary obstruction is associated with significantly longer stent patency, fewer ERCPs, and longer patient survival according to recent meta-analysis.
To our knowledge there are no existing guidelines for treatment of recurrent biliary obstruction with metal stent in situ. In this case, even though the patient had an existent biliary stent, accessing the CBD was difficult due to tumor invasion and bloody debris and extremely narrow channel in the common bile duct making it technically challenging. Despite the difficulties, the outcome was excellent with no complications.
Keywords Biliary SEMS, Malignant biliary obstruction, Pancreatic cancer, Stent in stent
258
Case of cholecystoduodenal fistula complicated with upper gastrointestinal bleeding and gallstone ileus
Vijay Rampally, Ravi Shankar Bagepally
Correspondence – Ravi Shankar Bagepally - [email protected]
Department of Gastroenterology, Yashoda Hospital, Alexander Road, Kummari Guda, Shivaji Nagar, Secunderabad 500 003, India
Introduction Gallstone ileus is a rare complication of gallstone disease. It occurs mostly after the formation of a biliary enteric fistula, especially with the duodenum, causing small bowel obstruction [1]. Bleeding due to biliary-enteric fistula is rare.
Case Report A 79-year-old male k/c/o HTN, T2DM, CAD, recurrent biliary colic, was brought to casuality with history of 3 bouts of hematemesis. No history of malena. Physical examination normal, except tachycardia. Lab work revealed hemoglobin 13 g/dL. On endoscopy showed large deep duodenal ulcer with adherent clot, with suspicion of fistula. Patient was shifted to ICU, CT abdomen was reported intraluminal calculus of 2.2 × 1.8 cm in proximal jejunum and cholecystoduodenal fistula. On day 2 patient had abdominal pain and distension, contrast-enhanced computed tomography (CECT) abdomen showed distended small bowel loops max diameter 35 mm, intraluminal calculus of 27 × 22 mm at distal jejunal loop and cholecystoduodenal fistula. In view of intestinal obstruction, surgery was done. Laparoscopy assisted enterotomy and removal of gallstone+enterotomy closure was done.
Discussion Gallstone may cause biliary-enteric fistula and complicated by gallstone ileus. The most common fistulas are cholecystoduodenal. The most common site of obstruction is at the ileocecal valve, especially when the stone size is > 2.5 cm [2]. Gallstone ileus mostly presents in the form of small bowel obstruction. Only roughly 50% of gallstone ileus were noted with a history of previous biliary symptoms [3]. Cholecystoduodenal fistula rarely causes gastrointestinal bleeding, which occurs mostly from a branch of cystic artery due to duodenal ulcer or erosion by a gallstone (4). The best management of gallstone ileus remains controversial. Although the recurrence rate for gallstone ileus is approximately 5%, enterolithotomy alone is the treatment of choice in gallstone ileus, especially in patients with hemodynamically unstable or significant comorbidities [5].
Conclusion Gallstone ileus and gastrointestinal bleeding are rare but important complications of cholelithiasis with cholecystoduodenal fistula. Good judgment in selecting the surgical procedure is required, especially in elderly patients with a high incidence of comorbidities
Keywords Cholecystoduodenal fistula, Enterotomy, Gall stone, Gallstone ileus, Hematemesis
259
Profile of choledocholithiasis patients undergoing endoscopic retrograde cholangiopancreatography: An eight-year single-centre experience from eastern India
Haribhakti Seba Das, Chittaranjan Panda. Prasanta Kumar Parida, Sambit Kumar Behera, Kaibalya Ranjan Dash, Prajna Anirvan, Pankaj Bharali, Mrinal Gogoi, Buddhi Prakash Meena, Padma Lochan Prusty, Samir Hota, Sananda Kumar Sethi, Rakesh Mohanty, Pravin Kumar Mishra
Correspondence - Haribhakti Seba Das - [email protected]
Department of Gastroenterology, Sriram Chandra Bhanj Medical College and Hospital, Behera Colony, Mangalabag, Cuttack 753 001, India
Background Choledocholithiasis is one of the most prevalent gastroenterological diseases with considerable geographical variation. The profile of patients presenting with choledocholithiasis and the procedural outcomes in this part of India has not been explored. We evaluated patients with choledocholithiasis undergoing endoscopic retrograde cholangiopancreatography (ERCP) in the Department of Gastroenterology and the procedural outcomes.
Methods This was a prospective study which was done at SCB Medical College and Hospital, Cuttack, Odisha from January 2014 to March 2022. ERCP was performed by different gastroenterologists using the standard technique. Data were expressed as percentages and mean ± SD.
Results Seven hundred and nine patients underwent ERCP for choledocholithiasis over the eight-year study period. The mean age of patients was 48.3±15.29 years. 45% patients were males while 55% patients were females. Cholangitis was present in 11.1% patients. Only 12 (1.7%) patients had a palpable gallbladder on abdominal examination. 36.6% patients had associated cholelithiasis with choledocholithiasis. 51.2% patients had single CBD calculus. 4.6% patients had associated stricture. Precut papillotomy was done in 52.3% cases while direct cannulation and sphincterotomy was done in 47.7% cases. Sphincteroplasty was done in 32.7% cases. Repeat ERCP was required in 21.2% cases. While complete stone clearance was achieved in 74.3% cases, in 17.5% patients, stenting and clearance were done. ERCP failed or was abandoned in 8.2% patients. The reasons for failure were: cannulation failure (52.5%), duodenal deformity (38.98%), impacted stone (3.38) and failure of positioning (5%). Post ERCP pancreatitis occurred in 10.4% patients. Bleeding occurred in 9 (1.3%) patients while perforation occurred in 5 (0.7%) patients.
Discussion In our series, female patients predominated. One-tenth of the patients had cholangitis. Half of the patients required precut papillotomy. Repeat ERCP was required in one-fifth cases while rates of bleeding and perforation were low.
Keywords Bile duct stone, ERCP, Patient profile
260
Opioid pancreatobiliopathy: A mimicker of periampullary malignancy in opioid addicts
Chhagan Lal Birda , Pranav S Kumar, Taruna Yadav, Binit Sureka, Ashish Agarwal
Correspondence – Ashish Agarwal - [email protected]
Department of Gastroenterology, All India Institute of Medical Sciences, Marudhar Industrial Area, 2nd Phase, M.I.A. 1st Phase, Basni, Basni, Jodhpur 342 005, India
Introduction Opium use disorder is common in western Rajasthan. Chronic opioid use has multitude of gastrointestinal effects including dyspepsia, slow transit constipation and narcotic bowel syndrome. Chronic opium use can also result in gastrointestinal ulcers and strictures and these patients presents with recurrent partial bowel obstruction, anemia and malabsorption syndrome. Opioids increase the tone of the sphincter of Oddi, thus resulting in biliary stasis. There is sparse literature on opioid induced pancreatobiliopathy.
Results We hereby report prospectively maintained and retrospectively analyzed case series of seven patients of opioid pancreatobiliopathy presented to Gastroenterology OPD during July 2021 to June 2022. Median age of the patients was 60 (IQR -56-61) years and all were male. Majority were consuming opium in form of afeem (85.7%). The median duration of opium addiction was 25 (IQR-24.5-29) years. The median amount of opium consumption was 50 gms (IQR 45-50 gms) per month and money spent was 7000 rupees (IQR – 5500-7250) per month. Most common presentation were- pain abdomen (85.7%), constipation (71.4%), anorexia (57%) and weight loss (57%). Baseline investigation revealed mild anemia (median Hb 10.9 gm/dL, IQR 10.1-12.4) and hypoalbuminemia (median albumin 3.2 gm/dL, IQR – 2.6-3.4). Liver biochemical tests and tumor markers like CEA and CA19-9 were negative in all of the patients. Endoscopic ultrasound and contrast-enhanced computed tomography (CECT) abdomen revealed dilated common bile duct (median 12 mm, IQR 8.7-16.5) and main pancreatic duct (median 4 mm, IQR 4-5 mm) without any mass/obstructing calculus/stricture. All the patients were managed conservatively, and psychiatry consultation was taken for opioid deaddiction.
Conclusion Opioid pancreatobiliopathy is a common cause of double duct sign in opioid addicts and often mimic periampullary malignancy. High index of suspicion is required as clinical presentation is variable. Diagnosis should be considered in patients with chronic opioid use after carefully excluding ampullary obstructing lesions and pancreatic pathologies.
Keywords Double duct sign, Opioid pancreatobiliopathy, Periampullary malignancy
261
Comparison between endoscopic retrograde cholangiopancreatography guided brush cytology and single operator cholangioscopy guided biopsy in diagnosis of intraductal biliary strictures
Aeshal Parmar
Correspondence – Aeshal Parmar - [email protected]
Department of Gastroenterology, Sri Balaji Action Medical Institute, Paschim Vihar, New Delhi 110 063, India
Introduction Biliary strictures are defined as abnormal narrowing of bile duct. Biliary strictures are caused by various benign and malignant conditions. However, differentiating malignant from benign stricture is challenging. The most convenient and widely used method for tissue sampling from biliary stricture is endoscopic retrograde cholangiopancreatography (ERCP) guided brush cytology. ERCP brush cytology has low sensitivity and low negative predictive value. Single operator cholangioscopy (SOC) is a new modality and can be easily performed during ERCP. Advantage of SOC over other modalities is that it provides direct visualization of biliary epithelium and gives opportunity to take direct visual guided biopsy of the target lesion. However, limited data is available on comparison between ERCP guided brush cytology and SOC guided biopsy in diagnosing etiology of intraductal biliary strictures.
Methods We conducted a prospective observational study over the duration of one year and collected data of 25 patients who fulfilled the inclusion criteria of the study. The sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) and accuracy of ERCP brush cytology and SOC biopsy were calculated.
Results In our study out of 25 patients, nine patients had final diagnosis of malignant biliary stricture and 16 patients had final diagnosis of benign biliary stricture. The SOC biopsy had better sensitivity (77.8% vs. 55.6%), NPV (88.8% vs. 80%) and accuracy (92% vs. 84%) compared to ERCP brush cytology. However, specificity (100% for both) and PPV (100% for both) were comparable between two modalities.
Conclusion In our study we found that SOC biopsy had higher sensitivity, NPV and accuracy compared to ERCP brush cytology to diagnose malignancy in intraductal biliary strictures. Furthermore, direct visualization of intraductal lesion also had additional benefit in diagnosing malignancy. However, multicentre large study is required for further evaluation and conclusion.
Keywords Biliary stricture, Biopsy, Brush cytology, ERCP, SOC
262
Bacteriological evaluation of bile in patients with malignant biliary obstruction
Siva Sankar Reddy Gangireddy , Tarun Joseph
Correspondence – Siva Sankar Reddy Gangireddy - [email protected]
Department of Digestive Diseases, Tata Medical Center, 14, MAR (E-W), D H Block (Newtown), Action Area I, Newtown, Kolkata 700 160, India
Introduction Cholangitis is a life-threatening complication in extrahepatic biliary obstruction. Malignant biliary obstruction is one of the predisposing factors for cholangitis. Most of the patients with bactibilia are asymptomatic. If incomplete biliary drainage is anticipated, prophylactic antibiotic treatment is advocated even in asymptomatic patients. Bacteriological evaluation of bile helps in choosing prophylactic antibiotic in such patients.
Methods Bile was aspirated immediately after cannulating the CBD in native papilla during endoscopic retrograde cholangiopancreatography (ERCP) in malignant biliary obstruction and sent for culture sensitivity testing in patients presented with obstructive jaundice from February 2017 to June, 2022 at Tata Medical Center, Kolkata.
Results ERCP was perfomed in 381 patients with malignant obstructive jaundice with native papilla. Bactibilia was seen in 128 patients (33%). E. coli is the major bacterium isolated (35%), followed by Enterobacter species (20%) and Klebsiella species (17%). Of the 128 patients with bactibilia only 27 patients (21%) had features of cholangitis and 19 patients (14%) had bacteremia.
Conclusion Asymptomatic bactibilia is common. E. coli is the commonly isolated bacterium.
Keywords Bactibilia, ERCP, Malignant biliary obstruction
263
Microbial profile of biliary infection in patients who underwent therapeutic endoscopic retrograde cholangiopancreatography at a tertiary care center in Western India
Apurva Shah , Aastha Shah, Alok Sahu, Shravan Bohra
Correspondence – Apurva Shah - [email protected]
Department of Gastroenterology, Apollo Hospital International Limited, Plot No, 1A, Gandhinagar - Ahmedabad Road, GIDC Bhat, Ahmedabad 382 428, India
Background Bile ducts are usually sterile under physiologic conditions. Bacteria could remain, colonize and replicate in a relatively stagnant bile environment if a biliary obstruction exists, resulting in increase of pressure, eventually spreading to blood and causing systemic complications.
Aim To identify the microbial profile from bile samples aspirated during endoscopic retrograde cholangiopancreatography (ERCP), the antibiotic susceptibility profile of the bacteria and the risk factors for bacterial colonization of biliary tree.
Method Our study is a retrospective study where all patients, who underwent therapeutic ERCP for various indications from June 2020 to June 2022 at a tertiary care hospital in Western India were included. Approximately 2-10 mL of bile was collected in sterile containers and sent for culture. Statistical analysis was performed using Chi-square test.
Results Total 61 patients were included, 62.2% were males and mean age was 58 +/- 18 years. Most common presentation was abdominal pain (63.9%). Six patients had a history of biliary intervention. Bile culture was found positive in 45 patients (73.8%) with 60% had monomicrobial and 40% had multimicrobial growth. Culture positivity was 83.4% with previous biliary intervention. Meropenem had highest susceptibility (82.3%), while Cefotaxime had worst susceptibility (28.9%). Most common organism was E. coli followed by Klebsiella pneumonie. Multi drug resistant (MDR) strains found in 17.5% of the ERCP naïve patients and in 60% with previous biliary interventions with significant p value.
Conclusion In conclusion, our results show that 70% to 75 % of patients who underwent ERCP had bacteriobilia. The most commonly isolated bacteria were Gram-negative bacteria including Escherichia coli and Klebsiella pneumoniae. Monomicrobial infection was more prevalent compared with multimicrobial infection and high MDR rates among patients with previous biliary interventions. The identified risk factors associated with positive bile culture included old age, previous history of ERCP and larger common bile duct diameter (>12 mm). Keywords Microbiology bile ERCP western India
264
An interesting case of obscure gastrointestinal bleed
Pratik Chhabra
Correspondence – Pratik Chhabra - [email protected]
Department of Medical Gastroenterology, Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500 082, India
Introduction Angiodysplasia of common bile duct is extremely rare. It has been reported in patients with hereditary hemorrhagic telangiectasia.
Case Report A 67-year-old male with hypertension presented with progressive dyspnea on exertion, and easy fatigability for 3 weeks. He also noticed passing black tarry stools intermittently for last 2 months along with mild abdominal pain. Physical examination was unremarkable except for pallor. There was no mucocutaneous telangiectasia. Initial laboratory parameters were significant for an iron deficiency anemia with a hemoglobin of 4.0 g/dL (baseline, 12 g/dL). Patient’s clinical presentation and laboratory parameters were suggesting subacute upper gastrointestinal bleeding. Esophagogastroduodenoscopy demonstrated altered blood around the major ampulla on limited tangential views. Side-viewing scopy showed major ampulla emanating dark blood-stained bile, concerning for hemobilia or hemosuccus pancreaticus (Fig. 1). A follow-up CT abdominal angiography and even conventional angiography did not show any contrast extravasation or pseudoaneurysm (Fig. 2). Magnetic resonance cholangiopancreatography (MRCP) showed pancreas divisum without any mass lesion or intraductal filling defect in bile duct (Fig. 3). Endoscopic retrograde cholangiopancreatography and SpyGlass® (Boston Scientific, Marlborough, MA) cholangioscopy was done, which showed jet of dark blood-stained bile (Fig. 4) and post irrigation and suction, clear visualization of common bile duct and common hepatic duct showed multiple ectatic blood vessels throughout with intermittent oozing of blood, consistent with angiodysplasia (Fig. 5). The size of the lesion was estimated to be less than 3.3 mm. Endotherapy using argon plasma coagulation was not performed due to nonavailability of compatible probe with SpyGlass® cholangioscopy. This case highlights importance of having dedicated therapeutic accessories compatible with SpyGlass® cholangioscopy. He was initiated on systemic thalidomide with hematinics expecting resolution of biliary angiodysplasia. He was passing normal stools with stable hemoglobin at 1month follow-up.
Conclusion This case highlights importance of having dedicated therapeutic accessories compatible with SpyGlass® cholangioscopy for hemostasis.
Keywords Biliary angiodysplasia and GI bleed
Pancreas
265
Pancreatic steatosis: Knowledge about its emerging spectrum and clinical implications
Manoj Yadav, Sudhir Maharshi, Shyam Sunder Sharma
Correspondence – Manoj Yadav - [email protected]
Department of Gastroenterology, Sawai Man Singh Medical College, New SMS Campus Road, Gangawal Park, Adarsh Nagar, Jaipur 302 004, India
Background Pancreatic steatosis (PS) is the accumulation of fat in pancreas and when there is presence of obesity or metabolic syndrome; it is called non-alcoholic fatty pancreas disease (NAFPD). Fatty liver is associated with insulin resistance, dyslipidemia, and obesity and is therefore considered a phenotype of metabolic syndrome. However, less is known regarding the metabolic abnormalities associated with NAFPD.
Methods Patients with diabetes mellitus (DM)/non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome/obesity with PS were prospectively enrolled in the study. PS was diagnosed with trans-abdominal ultrasonographic findings and grading was also done.
Results Total 42 patients enrolled in the study with mean age of 45.2 ±10.2 years, out of them 27 (64.3%) were males and 15 (35.7%) were females. Out of total, 14 (33.3%) patients were diabetic and 12 (28.5%) had metabolic syndrome. Mean body mass index (BMI) and waist circumference of the study population was 25±2.7 kg/m2 and 89.9±8.2 cm respectively. Mean amylase and lipase levels were 52.5±19 U/L and 57.4±35.3 U/L respectively. Mean triglyceride and cholesterol level in study population were 168.2±50.7 mg/dL and 193±33.2 mg/dL respectively. Four patients (9.5%) had grade IV PS, while grade III and grade II PS were seen in 17 (40.4%) and 15 (35.7%) patients respectively and only 6 (14.2%) patients had grade I PS. Fatty liver on ultrasonography were seen in 40 (95.2%) patients and 30 (71.4%) patients had transaminitis on biochemical investigations.
Conclusion PS was associated with higher BMI, DM, metabolic syndrome and NAFLD in our study. PS and NAFPD were not associated with elevation of pancreatic enzymes, however further studies with large sample size needed to draw definite conclusion.
Keywords Diabetes mellitus, Metabolic syndrome, Steatosis
266
Undiagnosed sarcoidosis presenting as acute pancreatitis – A case report
Matta Rakesh
Correspondence - Matta Rakesh - [email protected]
Department of Gastroenterology, M S Ramaiah Medical College, M S Ramaiah Nagar, Mathikere, Bengaluru 560 054, India
Introduction Sarcoidosis is a systemic non-caseating granulomatous disease involving many organs. Pancreatic involvement is unusual and hypercalcemic pancreatitis as initial presentation is very rare.
Case Report A 37-year-old female, k/c/o hypothyroidism, came with chief complaints of acute upper abdominal pain, associated with non-bilious vomiting since 2 days. There were no history of addictions. On examination, patient had epigastric tenderness and splenomegaly. On routine blood work up, patient had leukocytosis, elevated serum amylase and lipase levels; infiltrative pattern LFT and thrombocytopenia was noted. Ultrasonography revealed bulky and heterogenous pancreas with peripancreatic stranding (pancreatitis), moderate ascites, splenomegaly and mesenteric lymphadenopathy. On etiological work up of pancreatitis, serum calcium levels were elevated (14 mg/dL) and triglyceride levels were normal. On further work up for hypercalcemia, she had normal PTH, low vitamin D3 (16.03 ng/mL) and elevated serum ACE levels (176.58 U/L, normal 12-68 U/L). Endoscopy done in the view of ascites and splenomegaly revealed grade 3 esophageal varices; henceforth, diagnosis of presinusoidal portal hypertension was made. In view of infiltrative pattern of LFT and signs of portal hypertension, liver biopsy was done; which showed non caseating granulomas. The patient underwent whole body PET-CT scan to rule out pulmonary sarcoidosis and to evaluate extent of extrapulmonary sarcoidosis. The PET-CT revealed multiple enlarged abdominal lymph nodes (mesenteric, retroperitoneal, suprapancreatic, left gastric); multiple bilateral lung nodules, hepatosplenomegaly with splenic hilar lymph nodes. Patient was managed conservatively with IV fluids, IV analgesics.
Conclusion Acute pancreatitis can be a presenting symptom of sarcoidosis, although it appears to be extremely rare. Therefore, sarcoidosis should be considered a cause of acute pancreatitis, even in the absence of more common organic involvement such as pulmonary sarcoidosis, and especially when there is evidence of hypercalcemia.
Keywords Hypercalcemia, Pancreatitis, Sarcoidosis
267
Etiology, clinical profile and outcome of acute pancreatitis in a tertiary care centre
Ishan Mittal, Shishirendu Parihar, Aakash Shah, Nitesh Bassi, V K Dixit, S K Shukla, D P Yadav, Anurag Tiwari, Vinod Kumar Yadav
Correspondence – Ishan Mittal - [email protected]
Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221 005, India
Background Acute pancreatitis is an inflammatory condition of the pancreas with wide clinical variation. Acute pancreatitis may vary in severity ranging from mild self-limiting disease to pancreatic necrosis which may lead to life-threatening sequelae.
Aim and Objectives The present study was aimed to assess the etiology, clinical profile and outcome of acute pancreatitis in a tertiary care teaching hospital in eastern UP.
Methodology All patients admitted with a diagnosis of acute pancreatitis in Medical Gastroenterology Department, IMS, BHU between April 2021 to July 2022 were included in this retrospective study. Clinical history, examination, laboratory investigations and outcome was noted. Severity of AP was assessed using the modified Atlanta classification.
Results A total of 134 subjects were included in the study. The mean age was 40.9, ranging between 15 to 75 years. Among the study population, 88 (65.6%) were male and 46 (34.4%) were female. Epigastric pain with pain radiation to the back (90%) was the most common clinical presentation. The most common etiology was alcohol 48 (35.8%) followed by gallstone 40 (29.8%) then idiopathic 24 (17.9%). Mild, moderately severe, and severe pancreatitis was present in 40 (29.9%), 54 (40.2%) and 40 (29.9%) patients respectively. Acute fluid collection was the most common local complication seen in 18 (13.4%) cases whereas respiratory system involvement was the most common organ involvement seen in 28 (20.9%) of cases. Mortality was seen in 4 (2.9%) patients, all of which had severe pancreatitis.
Conclusion Alcohol intake is the predominant etiological risk factor for acute pancreatitis in Eastern UP followed by biliary etiology. Most of severe pancreatitis patients are due to alcohol related. Patients with body mass index ≥25 kg/m2, C-reactive protein (CRP) ≥150 mg/L and Hematocrit (HCT) ≥44% had an increased risk of developing severe AP.
Keywords Acute pancreatitis, Clinical profile, Etiology, Outcome
268
Pancreaticopleural fistula- An unusual complication of pancreatitis
Sharathchandra Khanappanavar, Nandeesh H P, Ganesh Koppad, Deepak Suvarna, Vijaykumar T R, Majaradya H V
Correspondence – Sharathchandra Khanappanavar - [email protected]
Department of Gastroenterology, J S S Hospital, Mahatma Gandhi Road, Fort Mohalla, Mysuru 570 004, India
Background and Aim Pancreaticopleural fistula (PPF) is a rare complication of pancreatitis. It has been reported to occur in about 0.4% cases of pancreatitis mainly in chronic cases. It's defined as an abnormal connection between the pancreas and the adjacent pleural cavity. It's difficult to demonstrate the fistula tract on imaging like CT or MRCP but amylase-rich pleural fluid (greater than the upper limits of normal for serum amylase) is highly suggestive of the diagnosis. There's no guidelines for treatment and we are presenting a case of PPF that was treated endoscopically.
Methods and Results Twenty-seven-year-old male alcoholic who presented with worsening dyspnea, orthopnea, left-sided chest pain and pain abdomen. Patient was found to be tachypneic, tachycardic and with no breath sounds on the left side of the chest. Labs were notable for a leukocytosis of 18,810 and lipase 3000. CXR showed a white-out of the left hemithorax. MRCP abdomen showed acute on chronic pancreatitis with left pancreatico-pleural fistula and effusion. 1 liter of pleural fluid was drained, and fluid analysis showed an amylase of 4721. PPF diagnosis was made and he was started on octreotide drip and kept NPO. Patient had rapid reaccumulation of fluid in left pleural cavity, hence he was advised for pancreatic endotherapy. ERCP was performed and pancreatogram showed contrast leak from the tail of the pancreas extending into the left pleural cavity, PD stent was placed. Serial chest X-rays showed resolution of left sided pleural effusion.
Conclusion Pancreaticopleural fistula is a serious complication of acute or chronic pancreatitis. Modalities of treatment are conservative management with octreotide and chest tube drainage for extended period, endoscopic stenting of the disrupted PD or surgical intervention. We present a case who has been successfully treated with endoscopic PD stenting in case of PD disruption.
Keywords ERCP, Fistula, Stenting
269
Forward viewing echoendoscope guided combined coil and glue injection in bleeding gastric varices secondary to splenic vein thrombosis in chronic pancreatitis
Surinder Rana, Pankaj Kumar, Nikhil Bush, Ravi Sharma, Rajesh Gupta*
Correspondence - Surinder Rana - [email protected]
Departments of Gastroenterology and *Surgical Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India
Background and Aims Gastric variceal (GV) bleeding secondary to splenic vein thrombosis (SVT) in pancreatitis is rare and surgery has been the conventional treatment. The role of endoscopic ultrasound (EUS) guided combined coil and glue injection in bleeding GV in chronic pancreatitis (CP) has not been evaluated. We conducted this study to evaluate safety and efficacy of EUS guided combined coil and glue injection in bleeding GV due to CP induced SVT.
Methods A retrospective analysis of data base of 6 patients (all males; mean age: 36.1 ± 6.7 years) with bleeding GV with underlying CP was done. The details about clinical presentation, laboratory data, radiological studies, details of EUS guided intervention and long-term outcomes were retrieved. Patients were treated with EUS guided injection using a forward viewing echoendoscope (FVE).
Results Endoscopy revealed isolated fundal GV in all patients with one patient having active bleeding at time of endoscopy and remaining 5 patients having stigmata of recent GV bleed. EUS guided combined injection was technically successful in all patients with no instrument related technical difficulty in any patient. A single coil was placed in 4 (66%) patients and two coils in two (34%) patients and median volume of glue injected was 1 mL (range 1-2 mL). GV were obliterated in all patients and none of the treated patients had either early or delayed re-bleeding.
Conclusion EUS guided combined coil and glue injection using a FVE seems to be safe and effective treatment for bleeding GV due to SVT in patients with CP.
Keywords Chronic pancreatitis, Coil, Endosonography, Gastric varices, Glue
270
Role of per-rectal diclofenac with IV ringer lactate infusion in prevention of pancreatitis after endoscopic ultrasound-guided fine needle aspiration cytology and biopsy from pancreatic lesions
Bharat Nandaniya, G S Lamba, Monika Jain
Correspondence - Bharat Nandaniya - [email protected]
Department of Gastroenterology, Sri Balaji Action Medical Institute A 4 Block, A 6 Block, Paschim Vihar, New Delhi 110 063, India
Introduction Endoscopic ultrasound-guided fine needle aspiration cytology (EUS-FNAC) and fine needle biopsy (FNB) are currently the most commonly used procedure for obtaining tissue specimens of pancreas lesions. It is accurate, minimally invasive, safe, and cost-effective. Procedure-related acute pancreatitis is one of the serious complications. Its reported incidence is up to 2.5% to 3%. Studies for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis have shown the significant benefit of per-rectal diclofenac plus iv ringer lactate infusion. However, the use of these in the prevention of acute pancreatitis in post-EUS-guided pancreatic FNAC/FNB is not well studied.
Methods This prospective study includes 238 EUS-guided pancreatic FNAC and biopsy cases over the period from January 2018 to July 2022. Among 238 cases, 205 cases (86%) were solid lesions and 33 (14 %) were cystic lesions. All patients were administered per-rectal diclofenac (100 mg 30 minutes before the procedure) with IV ringer lactate solution (20 ml/kg 30 minutes before the start of the procedure and continue during a procedure, followed by 3 mL/kg/h for 6 hours after the procedure). The primary endpoint was the incidence of post-EUS -guided FNAC/FNB pancreatitis.
Results A total of 238 consecutive patients with a pancreatic mass underwent EUS- FNAC and biopsy. No major complications were encountered in any patient. Mild acute pancreatitis occurred in 1 of 238 (0.4%), who had mild epigastric pain, and enzymes were mildly raised (amylase/lipase: 268/372). He was managed conservatively by IV fluids and analgesics without any complications.
Conclusion Per-rectal diclofenac with IV ringer lactate infusion can be an important tool to prevent pancreatitis after EUS-guided FNAC/FNB from pancreatic lesions. However, to conclude it, further large RCT (Randomized control trails) are required.
Keywords Acute pancreatitis, Endoscopic ultrasound, Fine needle aspiration cytology
271
Study to evaluate red cell distribution width and its ratio to total serum calcium and platelet count as a major predictor of severity in acute pancreatitis
Jayanth Peddu , Gaurav Gupta
Correspondence - Jayanth Peddu - [email protected]
Department of Gastroenterology, Sawai Man Singh Medical College, J L N Marg, Jaipur 302 004, India
Background Cases of acute pancreatitis are on the rise and now it is one of the most common reason for hospitalization with gastrointestinal conditions. The present study was undertaken for evaluating red cell distribution width and its ratio to total serum calcium and platelet count as a major predictor of severity in acute pancreatitis.
Methods Thirty-five cases of mild acute pancreatitis and 35 of severe acute pancreatitis were enrolled in this study. Diagnosis of acute pancreatitis was done according to the Revised Atlanta Classification. Assessment of red cell distribution width (RDW) at 0h (RDW0h) and RDW at 24H (RDW24h) was done. Additionally, RDW0h-to-total serum calcium ratio and RDW0h-to-platelets ratio was evaluated. RDW and other parameters were compared with validated and widely used acute pancreatitis prognostic scores, including Ranson, BISAP and Modified Marshall scores.
Results Mean RDW0hr levels and RDW24hr levels among the patients of mild acute pancreatitis was 12.32 and 12.26 respectively, while among the patients of severe acute pancreatitis was 14.11 and 14.26 respectively. Mean RDW0hr to calcium ratio and RDW0hr to platelet ratio among the patients of the mild acute pancreatitis group was 1.35 and 0.059 respectively while among the patients of severe acute pancreatitis was 1.78 and 0.067 respectively. While analysing statistically, it was seen that RDW0hr, RDW24hr, RDW0hr to calcium ratio and RDW0hr to platelet ratio were significantly higher with p values of 0.001, 0.023, 0.017, 0.011 respectively in patients of the severe acute pancreatitis group in comparison to mild pancreatitis group.
Conclusion RDW and its associated parameters have better prognostic value for severe acute pancreatitis patients than the Ranson, BISHAP or Modified Marshall score. Clinicians could use RDW as a valuable indicator for early recognition of SAP patients as it is cheap and easily available, and promptly provide more active therapies.
Keywords Acute pancreatitis, RDW, SAP
272
Tuberculous pancreatic abscess: A rare case presentation
Yash Gangadia, G S Lamba, Monika Jain
Correspondence - Yash Gangadia - [email protected]
Department of Gastroenterology, Sri Balaji Action Medical Institute, A3/281 A, 2nd Floor, Goel Niwas, Paschim Vihar, New Delhi 110 063, India
Introduction Primary pancreatic tuberculosis (TB) is a rare, reported condition. It can present as pancreatic SOL. Being a curable disease, distinguishing it from malignancy is very important. endoscopic ultrasound (EUS) guided fine needle aspiration cytology (FNAC)/ fine needle biopsy (FNB) can be useful tool for this differentiation.
Methods A, 33-year-old Indian female with no significant past history, was admitted with complaints of epigastric pain, vomiting and anorexia since 2 months. She had a history of weight loss of about 10 kg. Physical examination was unremarkable. Computed tomography (CT) scan of thorax was unremarkable. Contrast-enhanced computed tomography (CECT) whole abdomen showed well defined mass lesions in body and tail of pancreas with peripancreatic lymph nodes. Endoscopic ultrasound guided biopsy from pancreatic mass showed necrotizing granulomatous inflammation suggestive of tuberculous abscess. FNAC from peripancreatic lymph nodes showed granulomatous lymphadenitis. Gene xpert from pancreatic mass was positive. A diagnosis of tubercular pancreatic abscess was made. Patient was started with standard 4 drugs anti tubercular therapy (ATT), following which she showed a good clinical and radiological response.
Conclusion This case highlights the unusual presentation of extrapulmonary TB as well as the importance of EUS-guided FNA in diagnosing pancreatic TB which was presumed to be a malignant mass and excellent response to standard ATT.
Keywords Abscess, Endoscopic ultrasound, Pancreas, Tuberculosis
273
A case report on acute necrotizing pancreatitis with collections after organophosphates poisoning
Rajendran Santhosh , Shubha Immineni, Muthukumar K, Aravind A, Caroline Selvi, Premkumar K
Correspondence - Rajendran Santhosh - [email protected]
Department of Medical Gastroenterology, Rajiv Gandhi General Government Hospital, Poonamallee High Road, 3, Grand Southern Trunk Road, Near Park Town, Park Town, Chennai 600 003, India
Introduction Organophosphates widely used as agricultural chemicals are highly toxic to humans. Accumulation of large amounts of acetylcholine results in excessive cholinergic stimulation of many organ systems. Cholinergic stimulation can cause pancreatic hypersecretion and edema. The course of pancreatitis is usually subclinical and mild.
Case Discussion A 21-year-old male was admitted with alleged ingestion of unknown amount of dichlorvos. He presented with complaints of altered sensorium, profuse sweating, abdominal pain and increased oral secretions. As patients’ respiratory effort was high he was intubated. Gastric lavage was done immediately. Loading doe of atropine given and kept on maintenance dose. Injection pralidoxime was given as loading dose followed by continuous infusion. CT abdomen done on admission showed mild acute pancreatitis.
Patient complained of worsening abdominal pain, fever and abdominal distension. Serum amylase was 1832. Repeat CT abdomen was suggestive of acute necrotizing pancreatitis with multiple peripancreatic necrotic collections. Percutaneous drainage was done to remove the necrotic material. Culture of the necrotic material showed growth of Klebsiella susceptible to imipenem. Patient improved after drainage and started on appropriate antibiotics. Patient was weaned off ventilator support. Subsequent imaging revealed improvement in collection. Patients drain was removed. Patient was discharged after 35 days of admission.
Keywords Atropine, CT abdomen, Klebsiella, Necrotic collection
274
Pseudocyst-Portal vein fistula manifesting with hepatic pseudo cysts as rare manifestation of pancreatitis: A case series
Pritam Das, Dhruv Thakur, Gaurav Pande, Samir Mohindra
Correspondence - Pritam Das - [email protected]
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raibareli Road, Lucknow 226 014, India
Introduction Acute pancreatitis may have a varied presentation ranging from symptomatic enzyme elevation, mild abdominal pain, pseudocyst formation, multiple organ failures. Pseudo cyst fistulising to portal vein is a rare phenomenon, however with a high mortality.
Case Series We describe a case series of 3 patients which presented with acute pancreatitis or acute exacerbation of chronic calcific pancreatitis. A 42-yer-old male, chronic alcoholic, presented with chief complaints of pain in epigastric region since 11 months. Triple phase CT abdomen was suggestive of pancreatic head replaced by well-defined peripherally enhancing collection measuring 32 × 28 mm suggesting of walled off necrosis. The collection in the pancreatic head was seen communicating with the lumen of main portal vein and extending to involve its right and left branches with no post contrast enhancement suggesting fistulous communication. The patient improved on endotherapy with controlled monitoring with repeated endoscopic retrograde cholangiopancreatography (ERCP) and drainage of collections. The second patient 52-year-old male, chronic alcoholic came with chief complaints of pancreatic type of upper abdominal pain since 6 months, planned for endotherapy. The third patient, 36-year-old male presented with chief complaints of epigastric pain since 3 months, succumbed to illness.
Discussion Pseudocyst fistulizing portal vein is a rare and morbid phenomenon with a high mortality rate. In our case series, the patient 1 responded to step up decompression therapy, initially the patient was subjected to major duct drainage followed by minor duct drainage. The hepatic pseudocyst resolved gradually and portal vein thrombosis and collateral formation. 18 cases were reported in literature till 2015, around 5 more cases were reported in literature till now.
Keywords Hepatic pseudocyst, Portal vein thrombosis, Pseudocyst, Pseudocyst-portal vein fistula
275
Thrombotic microangiopathy: A rare complication of acute pancreatitis
Aradya H V, Ganesh Koppad, Nandeesh H P, Deepak Suvarna, Vijaykumar T R, Sharathchandra K K, Devansh Bajaj, Abhishek Kabra
Correspondence – Ganesh Koppad - [email protected]
Department of Medical Gastroenterology, J S S Hospital, Mahatma Gandhi Road, Fort Mohalla, Mysuru 570 004, India
Introduction Thrombotic microangiopathy is characterized by thrombocytopenia, hemolytic anemia and end organ dysfunction. We report a case of thrombotic microangiopathy secondary to pancreatitis.
Methods and Results The patient was a 28-year-old male presented with abdominal pain and vomiting since 1 day, he was previously treated for acute pancreatitis (etiology : ethanol) a month ago, O/E abdomen was tender, HR 107 bpm, BP 150/90 mmHg, USG abdomen revealed bulky and hypoechoic head and body of pancreas with adjacent inflammatory changes, serum amylase was 1130 U/L, serum lipase was 3000 U/L, On day 3 patient developed jaundice. Total bilirubin was 24.7 mg/dL, Hb dropped to 5 g/dL from 16 g/dL, platelet counts were 53,000 and peripheral smear showed decreased RBCs, shistocytes, polychromatophils and occasional nucleated RBCs with thrombocytopenia suggestive of microangiopathic hemolytic anemia, Serum LDH was 722 U/L, reticulocyte count 10.4%, Coombs test (DCT/ICT) was negative, serum creatinine was 1.83 and urea 106 mg/dL, urine examination was normal.
Conclusion In view of acute pancreatitis leading to MAHA- T, therapeutic plasma exchange (TPE) and methylprednisolone infusion was initiated after consultation with nephrology team. He also received 2 units of packed RBCs, our patient showed significant response to TPE with rise in platelets, Hb and LDH optimization. TMA is rare complication of acute pancreatitis, the temporal association between pancreatitis and TMA is unclear but it is hypothesized that cytokines (IL-1 and TNF-alpha) cause vascular endothelial damage, ADAMTS13 is inhibited by inflammation leading to platelet aggregation and thrombus formation, Early initiation of TPE yielded a good outcome in this case.
Keywords Acute pancreatitis, Plasma exchange, Thrombotic microangiopathy
276
Diagnostic performance of KRAS and GNAS testing in pancreatic cystic lesions: Experience from a tertiary care centre
Ravi Kumar Sharma, Surinder Rana, Nikhil Bush, Radhika Srinivasan, Ritambhra Nada. Rajesh Gupta, Tarundeep Singh
Correspondence – Surinder Rana - [email protected]
Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh 160 012, India
Objective To prospectively study the diagnostic performance of molecular (KRAS, GNAS) markers in diagnosis of PCLs.
Methods Eighty-five consecutive patients (mean age 49.15±15.9 years, 49 F) with PCLs were prospectively enrolled. All patients underwent EUS-guided cyst fluid aspiration. The cyst fluid was sent for cytological evaluation, amylase, lipase, CEA, VEGF and KRAS (exon 2, codon 12 and 13) and GNAS (exon 8, codon 201) mutation analysis. The final diagnosis was based on histopathology or cytological confirmation in aspirated cyst fluid, or clinical diagnosis with no significant growth on follow-up of >6 months.
Results Of 85 enrolled patients, 28 (33%) patients had mucinous (15 malignant) and 57 (67%) patients had non-mucinous PCL. The final diagnosis was: Mucinous adenocarcinoma in 9, IPMN in 7, mucinous cystadenoma in 12, serous cystadenoma in 20, simple cyst in 9, pseudocyst in 20, and SPEN in 8 patients. The mean cyst size was 4.2±2.8 cm with 42 (49.4%) patients having cyst size >3 cm. The string sign was positive in 12 (14%) patients and all had mucinous tumours. The mean PCL fluid CEA was 504±176.9 ng/μl with 17 patients having CEA >192 ng/μl. The mean VEGF was 2061±291.2 nmol/l and was elevated in 11/20 patients with serous cystadenoma. KRAS point mutation was positive in 13 patients (11 malignant and 2 premalignant). It was negative in 4 patients with malignant PCL. In all 13 patients KRAS mutation was in codon 12 (GGT to GAT) 35G>A. GNAS mutation was negative in all patients. For identifying mucinous lesions, elevated CEA levels performed best and cytology performed best for identifying malignant PCL. The mutational diagnosis changed diagnosis in 1 patient only.
Conclusions KRAS and GNAS mutational analysis did not improve diagnostic ability of conventional testing in PCL’s. The GNAS (exon 8, codon 201) mutation was not found in our patients with IPMN.
Keywords Cyst Fluid analysis, GNAS, IPMN, KRAS, Mucinous cyst, Pancreatic cystic lesion
277
Unusual presentations of autoimmune pancreatitis
Isha Bansal, Girish Muppa, Amol Dahale, Debabrata Banerjee, Abhijeet Karad
Correspondence – Girish Muppa - [email protected]
Department of Medical Gastroenterology, D Y Patil Medical College, Hospital and Research Centre, Pune 411 018, India
Introduction Autoimmune pancreatitis (AIP) cases was first reported in 1960 by Sarles et al. and the term AIP was first introduced in 1995 by Yoshida et al. as a form of chronic pancreatitis with autoimmune etiology [1, 2]. AIP was classified into 2 types. Type 1 AIP was associated with extrapancreatic manifestations and IgG4 related disease. AIP accounted for 5% to 6% of all patients with chronic pancreatitis [3].We report two cases of AIP type 1 presenting with pseudocyst and second case with pain in abdomen and obstructive jaundice, both of which responded with steroid therapy. On H&E sections a dense lymphoplasmacytic infiltrate was seen in the pancreatic tissue.
Case 1 A 36-year-old male was referred to our department in 2020 with clinical symptoms of painless obstructive jaundice and fever. Patient came to our hospital with clinical symptoms of abdominal pain, lump at the epigastric region and left >right peri orbital edema. Computed tomography showed pseudocyst of approx. size 100 × 66 mm with enhancing wall of thickness 3 mm seen in lesser sac anteroinferior to proximal body of pancreas and multiple intrapancreatic fluid collections seen in body of pancreas.
Case 2 A 66-year-old non-alcoholic male gave a history of diffuse abdominal pain since 1 year. His blood sugar and liver function tests were all under normal limits. A contrast-enhanced computed tomography (CECT) scan was done which showed bulky head and obstructive jaundice findings. Endoscopic ultrasound-guided fine needle aspiration biopsy was done showed storiform fibrosis and lymphoplasmacytic infiltration with IgG4 positive plasma cells 18/HPF.
Conclusion Autoimmune pancreatitis is an increasingly recognized clinical condition. Even though a large number of reports on increased serum IgG4 levels and IgG4-positive cells in bile duct biopsy specimens are related the disease, established diagnostic criteria of autoimmune pancreatitis do not reflect the entire spectrum of the disease. Autoimmune pancreatitis is steroid-responsive, but maintaining remission continues to remain challenging.
Keywords Autoimmune pancreatitis, IgG4, Obstructive jaundice, Pseudocyst
278
Characterization of pancreatic head mass in patients with chronic pancreatitis
Randeep Rana , Soumya Jagannath Mahapatra, Shallu Middha, Tanmay Vajpai, Gadella Varun Teja, Anugrah Dhooria, Ashish Dutta Upadhyay, Pramod Kumar Garg
Correspondence – Pramod Kumar Garg - [email protected]
Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029, India
Introduction Patients with chronic pancreatitis (CP) are at risk of developing pancreatic malignancy. It is often difficult to differentiate between malignant and inflammatory head mass in CP.
Methods Consecutive patients with CP presenting with a head mass on imaging (either CT and/or MRI) were included from January 2004 till December 2020. To differentiate inflammation from malignancy, patients underwent endoscopic ultrasound (EUS) and PET-CT. The gold standard was fine needle cytology or resected specimen histopathology. At-least 1 year post diagnosis follow-up was done in those considered having benign mass. A multivariate analysis was done to determine predictors of malignancy and a prediction model was developed.
Results A total of 167 patients with CP and head mass were included. The median age was 45 (38-50) years and 158 (88.6%) were male. Etiology of CP was alcohol in 110 (65.8%) and idiopathic in 56 (33.5%). Of these, 18 patients had pancreatic malignancy and 2 ampullary malignancy of whom 3 had alcoholic, 16 had idiopathic and one had hereditary pancreatitis. On multivariate analysis, idiopathic etiology, alkaline phosphatase (ALP) value >2.5 times ULN and EUS features of malignancy (presence of definite mass with absence of duct penetrating sign) were predictors of malignancy. A prediction model (10*a+12.1*b+14*c, where ‘a’ is idiopathic etiology, ‘b’ alkaline phosphatase >2.5 times and ‘c' is EUS features of malignancy) was developed with a score of ≥24 having sensitivity of 81.8%, specificity of 87.6% and negative predictive value of 97.5% for predicting malignancy with area under ROC of 0.92.
Conclusion Patients with CP and head mass having idiopathic etiology and biliary obstruction as evidenced by raised serum ALP level had higher chances of having malignancy. A prediction model incorporating EUS features in addition to these two parameters could predict malignancy with a high accuracy.
Keywords CA 19.9, Carcinoma pancreas, Chronic pancreatitis, EUS, Inflammatory head mass
279
Pancreatic endotherapy in painful chronic pancreatitis: Predictors and response to therapy
Ankit Agarwal , Soumya Jagannath Mahapatra, Tanmay Vajpai, Shallu Midha, Anshuman Elhence, Shivam Pandey, Pramod Garg
Correspondence – Pramod Garg - [email protected]
Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029. India
Introduction Patients with painful chronic pancreatitis (CP) are initially managed with optimal medical therapy followed by endotherapy and subsequently surgery in a step-up protocol. The aim of our study was to study the predictors of the need for endotherapy, and short- and long-term response to endotherapy in painful CP.
Methods Medical records of consecutive patients with CP were reviewed from a prospectively maintained database from January 2000 till December 2020. The indications for endotherapy (which included extracorporeal shock wave lithotripsy [ESWL] for large stones) were: non-response to optimized medical therapy, dilated pancreatic duct and ductal obstruction due to either stones/stricture. Patients with painful CP with a follow-up of ≥18 months were included. Primary outcome was predictors of need for endotherapy and co-primary outcome was long-term response to endotherapy as compared to no endotherapy patients. Secondary outcome was short-term response to endotherapy.
Results Of 1574 patients, 541 patients had painful CP with a follow-up of at-least 18 months. There was no difference in baseline characteristics of patients who required endotherapy (n=131, 24.2%) as compared to patients who did not. On multivariate logistic regression analysis, female sex (odds ratio [OR] 2.03, 95% CI 1.25-3.28) and a higher baseline pain score ≥8 (OR 2.02, 95% CI 1.30-3.13) were significant predictors for the need of endotherapy while diabetes predicted a lower need for endotherapy (OR 0.63, 95% CI 0.48-0.82). Significant pain-relief occurred after endotherapy (pain score: pre-endotherapy 8 [7-10], vs. 0 [0-2] post endotherapy; p<0.001). The long-term response was not significantly different between the endotherapy and no-endotherapy group over a mean of 60 (32-108) months (complete response in 98 [74.8%] vs. 289 [70.4%]; p=0.64).
Conclusion Female sex and high baseline pain score predicted the need for endotherapy which provided excellent short-term pain relief. Long-term pain relief was similar as for no-endotherapy group despite aggressive initial course.
Keywords Chronic pancreatitis, Endotherapy
280
Accelerated combined catheter plus endoscopic percutaneous treatment for enhanced recovery in patients with infected pancreatic necrosis
Soumya Jagannath Mahapatra, Pramod Garg
Correspondence – Pramod Garg - [email protected]
Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029, India
Introduction Building on our previously reported percutaneous endoscopic necrosectomy step-up approach, we developed an accelerated combined catheter plus endoscopic percutaneous treatment protocol for enhanced recovery (ACCEPTER) for predominantly laterally placed infected necrotic collections.
Methods Patients with predominantly laterally placed infected necrotic collections were included in the study. In case of no response to antibiotics and percutaneous catheter drainage (PCD) within 48-72 hours, rapid tract upgradation was done every alternate day by replacing with bigger catheter to reach 30 F or by placing a fully covered self-expanding metal stent (SEMS, 54F diameter). Thereafter, percutaneous endoscopic necrosectomy (PEN) was done using a flexible endoscope (8.8 mm dia.) through the percutaneous tract or the SEMS. Technical success was defined as clearance of the cavity and clinical success as resolution of sepsis.
Results From March 2019 to April 2020, 19 patients underwent PEN as per ACCEPTER protocol. The baseline CTSI score was 9 (8-10) and the modified Marshall organ failure score was 2 (IQR 0-4). Eleven patients had organ failure at inclusion. The median number of sessions to reach the desired catheter size was 2 (IQR 1-3) over 8 (6-10) days after a median of 32 (23- 42) days from the onset of pancreatitis. SEMS was placed in 15 (78.9%) for rapid tract upgradation. Necrosectomy was completed in a median of 3 (IQR 1-4) sessions done every alternate day. Four patients had bleeding: two due to pseudoaneurysm and two due to ooze during necrosectomy. Five patients needed salvage surgery (3 for sepsis, 2 for bowel fistula); 4 patients died. Technical success was achieved in 18 (94.8%) patients and clinical success in 14 (73.7%) patients. Median comprehensive complication index (CCI) was 8.7 (IQR 0-45.2).
Conclusion The technique of rapid catheter upgradation and PEN as per the ACCEPTER protocol was safe and effective for infected necrotic collections.
Keywords Acute Pancreatitis, Infected necrotising pancreatitis, Percutaneous endoscopic necrosectomy
281
Clinical profile and management of chronic pancreatitis in a tertiary care centr e
Nishanth Paturi, Venkatakrishnan Leelakrishnan, Mukundan Swaminathan, Thirumal P, Kartikayan R K, Arun P, Ravindra K, Swaapnika V, Dhanush T
Correspondence – Nishanth Paturi - [email protected]
Department of Medical Gastroenterology, P S G Institute of Medical Sciences and Research, Avinashi Road, Peelamedu, Coimbatore 641 004, India
Introduction Chronic pancreatitis is a multifactorial disease best defined as a syndrome characterized by chronic inflammation, fibrosis, and eventual destruction of ductal, exocrine (acinar cell), and endocrine (islets of Langerhans) tissue producing varying degrees of symptoms (abdominal pain, nausea/vomiting), functional (exocrine insufficiency [steatorrhea], or endocrine insufficiency [diabetes mellitus]) and structural derangements of the gland based on imaging techniques including US, CT, EUS, MRI, and MRCP.
Aim To study the clinical profile and management of chronic pancreatitis with respect to clinical findings, lab parameters, imaging and management modalities.
Methods A cross-sectional observational study was conducted which included the patients admitted to a tertiary care center presenting with a clinical diagnosis of chronic pancreatitis. The study was conducted over a period of 3 years from August 2019 to July 2022. A total sample size of 200 patients was included.
Results In the study, it was observed that the majority of patients in the age group 50-58 years were male (75%). Alcoholism (42%) was the most common etiology and presented with pain in the abdomen (83%). The most common CT findings were pancreatic calcifications (72%) with the most common complication being pancreatic pseudocyst (30%). In the present study, the majority of patients were managed conservatively (44%) followed by pancreatic endotherapy (32%) and surgery (24%). The distribution of patients according to pain relief by various management showed that the majority were getting pain relief by surgery (68%) followed by endotherapy (44%).
Conclusion Chronic pancreatitis is a progressive inflammatory disease. Conservative management followed by endotherapy is frequently performed at our center with surgery giving relief of pain in most cases. However, surgery is indicated only when medical treatment fails and/or complication arises. The selection of an appropriate method of management for a particular patient varies based on underlying clinical features, imaging, and complications.
Keywords Chronic pancreatits, Clinical profile, Management
282
Internal pancreatic fistulae – A case series from tertiary care center
Amarnath A , Gayathri Gopalakrishnan, Nandish H K, Kiran R, Rangarajan Kasturi
Correspondence – Amarnath A - [email protected]
Department of Medical Gastroenterology, Narayana Hrudalaya, Electronic City, Bangalore 560 100, India
Pancreatic fistula is an abnormal connection between the pancreatic ductal epithelium and another epithelial surface containing pancreas-derived, enzyme-rich fluid [1]. Disruption of the pancreatic duct leads to leak of pancreatic fluid producing erosion and forming different pathways resulting in internal and external pancreatic fistulae [2]. Internal fistulae usually result as a complication of acute and chronic pancreatitis. External pancreatic fistulae are commonly seen post pancreatic surgery or trauma [2]. If duct disruption is anterior, fluid drains into peritoneal cavity, leading to pancreatic ascites [3]. If disruption is posterior, it leads to development of pleural effusions, commonly on left side [3]. However right pleural effusion, bilateral effusions and pericardial effusions have also been rarely reported [4, 5]. Diagnosis is made by fluid amylase levels, usually more than 3 times serum amylase levels [6]. Computerized tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) are useful to identify the fistulous communications, but are not always diagnostic [7].
We report 5 cases of internal pancreatic fistulae managed at our center. All patients were males, aged 18 years to 53 years. Two patients had underlying chronic pancreatitis and three patients presented as sequalae of acute pancreatitis. One patient had right pleural effusion. Two patients had bilateral pleural effusions and the other two had left sided pleural effusion. One patient who had bilateral pleural effusion, presented with pericardial effusion with impending tamponade requiring emergency pericardiocentesis. One of the patients with left side pleural effusion, initially presented with large pseudocysts (drained via EUS guided cysto-gastrostomy) and pancreatic ascites needing multiple large volume paracentesis. All the patients were managed with octreotide, pancreatic endotherapy and were discharged after symptomatic improvement.
Early recognition of fistulae and prompt pancreatic endotherapy results in good outcome. Clinical suspicion along with fluid analysis and cross-sectional imaging (MRI preferred over CT) would aid quick diagnosis and response.
Keywords Acute pancreatitis, Chronic pancreatitis, Pancreatic endotherapy, Pancreatic-pleural fistula, Pleural effusion
283
Percutaneous endoscopic necrosectomy: A safe and effective alternate to surgical necrosectomy - A single-center experience
Pankaj Singh, Vikas Singla, Sawan Bopanna
Correspondence – Pankai Singh - [email protected]
Department of Gastroenterology and Hepatology, Max Super Speciality Hospital, 1 2, Press Enclave Marg, Saket Institutional Area, Saket, New Delhi 110 017, India
Background Traditionally infected/symptomatic walled off necrotic collection that fails to respond to transluminal endoscopic or percutaneous drainage requires necrosectomy. We aimed to evaluated the outcome of percutaneous endoscopic necrosectomy (PEN) as an adjunct to percutaneous catheter lavage for laterally placed WON in para-colic gutters.
Method Retrospective data of 110 consecutive patients with AP was reviewed. Data of 25 patients with ANC/WON±IPN were assessed. EUS guided transluminal drainage (n=15) followed by DEN (n=10) and percutaneous catheter drainage/lavage in combination with PEN for 7 laterally placed WON]. Both DEN and PEN in 3 patients. The primary endpoint was control of sepsis with resolution of necrosis/collections, and removal of drain catheters. The secondary endpoint was mortality, periprocedural complications, overall length of ICU and hospital stays.
Results Out of 25 patients (mean age 37.36 years, M:F=5.25:1, ANC=11, WON=14, IPN=19; twenty underwent endoscopic necrosectomy (PEN=7, DEN=10, both=3), 5 patients were managed either conservatively or with per-cutaneous catheter lavage. The etiology of pancreatitis varied: 6 biliary, 8 alcohol, 9 (idiopathic, 3 post-ERCP) with median size of necrosis of PEN=15.16 cm, DEN=12.5 cm, median number of necrosectomy sessions PEN=5 sessions, DEN=2 sessions. Median procedure time of 50 minutes per procedure for PEN, 35 min for DEN. Necrosis completely resolved in 77.77% following PEN and 92.30% following DEN. Drains removed at an average of 45 days. Peri-procedural complication: 5 intracavitary bleed, 2 colonic fistula, 3 pancreatic fistula. VARD (Videoscopic Assisted Retroperitoneal Debridement) was required in one patient, however none required open necrosectomy. 2 (8%) in hospital mortality. Predictor of mortality was >70% necrosis with abdomen compartment syndrome.
Conclusion Percutaneous endoscopic necrosectomy minimally invasive step-up treatment approach for laterally placed infected necrosis inaccessible to transluminal endoscopic treatment is a safe and effective alternate to Surgical necrosectomy.
Keywords Direct endoscopic necrosectomy, Infected pancreatic necrosis, Necrotizing pancreatitis, Percutaneous catheter drainage, Percutaneous endoscopic necrosectomy
284
Retrospective analysis of moderately severe pancreatitis with visceral aneurysm manifesting as intra-cystic or gastrointestinal bleed: A tertiary centre experience
Pritam Das , Dhruv Thakur, S Rakesh Kumar, Malla V A Gangadhar, Gaurav Pande, Samir Mohindra
Correspondence – Samir Mohindra - [email protected]
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226 014, India
Introduction Visceral aneurysm comprises of major vascular complications in acute moderate severe pancreatitis. Visceral aneurysm manifesting as intra-cystic bleed may lead to delayed diagnosis and lead to poor prognosis. Aneurysmal bleed may also present in a varied manner, ranging from hemosuccus pancreaticus to occult gastrointestinal (GI) bleeding.
Case Review We retrospectively analyzed the patients presenting to Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow with moderate severe pancreatitis in the time period between July 2017 and July 2022. A total of twenty-nine patients had visceral aneurysm complicating the course of pancreatitis. The most common site of aneurysm was splenic artery aneurysm (13 cases, 44.8%), followed by gastroduodenal artery (8 cases, 27.5%), pancreaticoduodenal artery (3 cases, 10.3%), right gastroepiploic artery (2 cases, 6.9%). Coil embolization was done in 18 patients (62.06%) whereas arterial graft was placed in 2 patients. Of them 2 patients had rebleeding, one of them within 6 weeks, with source being a different artery, and the other patient had re-bleeding after 6 months and the patient succumbed to death. 24 (82.75%) patients had peripancreatic collection, predominantly lesser sac collection. Among the total patients, 11 (37.9%) patients had chronic pancreatitis, whereas 6 (20.6%) had recurrent acute pancreatitis. Sixteen out of 24 (66.67%) patients had history of active alcohol abuse.
Conclusion Anatomical location of the collection, nature of collection and active alcohol abuse may be independent risk factor for visceral aneurysm formation in cases of pancreatitis. However, chronicity of pancreatitis and relation with visceral aneurysm needs further studies.
Keywords Aneurysm, GI bleed, Moderate severe pancreatitis, Visceral aneurysm
285
An unusual cause of abdominal pain following extracorporeal shock wave lithotripsy in a young patient of chronic calcific pancreatitis
Animesh Shah , Vikas Bharti, Prabha Sawant, Ankit Dalal, Gaurav Patil, Amit Maydeo
Correspondence – Animesh Shah- [email protected]
Department of Baldota Institute of Digestive Sciences, Gleneagles Global Hospital, Dr E Borges Road, Opp Shirodkar School, Parel. Mumbai 400 012, India
Background Extracorporeal shock wave lithotripsy (ESWL) is the preferred modality for pancreatic calculi measuring >5 mm. Although safe, major complications have been reported in less than 1% of patients.
The Case A 25-year-old female suffering from chronic calcific pancreatitis presented with recurrent left-sided upper abdominal pain with weight loss. Physical examination was unremarkable. She had prior history of ESWL followed by endoscopic retrograde cholangiopancreatography (ERCP) four years ago for pancreatic duct calculi. On present evaluation, a plain abdominal X-ray showed a large radiopaque calculus near the head of pancreas and subsequent computed tomography (CT) scan revealed a dilated and tortuous pancreatic duct with multiple intraductal calculi. So, planned for ESWL followed by ERCP. The first session of ESWL was performed with a total of 7,000 shocks. The patient tolerated the procedure well. On the next day, she had severe abdominal pain with persistent vomiting and a tender abdomen. Laboratory investigations showed increased pancreatic enzymes leukocytosis and raised C-reactive protein levels. She was managed with intravenous (IV) fluids and IV analgesics, and a CT was performed which revealed diffuse atrophy of the pancreas with changes of chronic pancreatitis. Bulky appearing head and uncinate process with multiple ill-defining hypoenhancing areas within the uncinate process was suggestive of early necrosis without vascular involvement. She received nasojejunal tube feeding and recovered gradually hence was discharged on liquid diet. She had an uneventful recovery.
Conclusions Development of acute necrotizing pancreatitis after ESWL is an extremely rare complication. Early detection and timely intervention can safely treat this condition. Clinicians should be aware of this rare entity.
Keywords Abdominal pain, Complication, ESWL, Necrotizing pancreatitis, Outcome
286
A curious case of jaundice
Nitish Ashok Gurav, Sundeep Lakhtakia, P Bharath Kumar Reddy
Correspondence – Nitish Ashok Gurav - [email protected]
Department of Medical Gastroenterology, Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500 082, India
A 54-year-old male patient presented with painless progressive jaundice, generalized itching and clay-colored stools, weight loss of around 3-4 kgs over 2 months. He was incidentally found to have right renal mass in 2007 for which he underwent right nephrectomy (renal cell carcinoma-clear cell variant). One month later, he developed gait abnormality and slurring of speech - right cerebellar space occupying lesion. He underwent posterior fossa craniotomy and lesion removal (multiple dilated capillary network in the background of astrocytes and purkinje cells). Follow-up abdominal imaging 5 years later revealed multiple non enhancing cystic lesions in pancreas, likely benign. Serial imaging showed an increase in number and size of pancreatic cystic lesions.
Patient is born to a non-consanguineously married couple. Two of his younger brothers have developed RCC in the recent past for which they underwent nephrectomy.
Liver function test (LFT) showed cholestatic pattern. Magnetic resonance imaging (MRI) abdomen - large complex cystic lesion (41×36 mm in head and uncinate process of pancreas, ?serous cystadenoma. Distal CBD compression causing upstream dilatation noted.
Endoscopic ultrasonography-multiple pancreatic cysts? serous cystadenoma, largest in pancreatic head compressing CBD. Multiple cysts noted in left kidney. Patient underwent endoscopic retrograde cholangiopancreatography (ERCP), biliary sphincterotomy and plastic stent placement. Follow-up LFT showed improvement.
Patient was suspected to have syndromic association and genetic analysis was done. Custom variant sequencing showed positive for VHL gene rs5030825 (C>T) variant, heterozygous genotype. His siblings too tested positive for the same variant.
As the serial abdominal imaging showed increase in size and number of pancreatic cystic lesions, he was counseled regarding need for total pancreatectomy. His children were advised to undergo genetic surveillance.
Conclusion Patient was diagnosed to have Von Hippel Lindau syndrome. This report emphasizes on the need to evaluate pancreatic cysts which are multiple, progressive, especially in those patients with multisystem involvement.
Keywords Jaundice, Pancreatic cysts, Von Hippel Lindau syndrome
287
Acute pancreatitis complicating dengue fever – A retrospective observational study
Vijay Rampally, Ravi Shankar Bagepally
Correspondence – Ravi Shankar Bagepally - [email protected]
Department of Gastroenterology. Yashoda Hospital, Alexander Road, Kummari Guda, Shivaji Nagar, Secunderabad 500 003, India
Background and Objectives Acute pancreatitis is believed to be a rare complication of dengue fever [1, 2]. This retrospective, observational, South Indian study was undertaken to assess the incidence of acute pancreatitis in dengue patients [3], to determine the mortality rate and risk factors in patients who developed acute pancreatitis.
Methods The clinical, laboratory, and other relevant patient data were collected from the medical records of the patients with confirmed diagnosis of dengue admitted to Yashoda Hospital, Secunderabad. The diagnosis of acute pancreatitis was based on revised Atlanta criteria. The association between acute pancreatitis and mortality in dengue was evaluated using Chi-square test and Fisher’s exact test and a probability (p) value of less than 0.05 was considered as the level of significance.
Results A total of 702 dengue patients (mean age 28.7 years) were included in the study. The severity of infection was recorded as dengue fever, dengue hemorrhagic fever, and dengue shock syndrome in 42.16%, 55.55% and 2.28% of the patients, respectively. Fever, chills, weakness, vomiting, and body pain were the most common presenting features, while thrombocytopenia, leukopenia, raised transaminase levels (SGPT, SGOT) and low serum albumin levels were the important laboratory markers of complications. Acute pancreatitis was diagnosed in 41 (5.8%) patients. Mortality rate in this study population was 1.7%, while mortality rate in patients who developed acute pancreatitis was 7.31%. Increasing age (≥51 years) was a risk factor for acute pancreatitis in dengue patients.
Conclusion In this retrospective, observational study involving 702 Indian patients with dengue, the incidence of acute pancreatitis was found to be 5.8%. Acute pancreatitis may not be a rare complication but may be under-reported in clinical practice. It was significantly associated with mortality. Table 1 Summary
Keywords Dengue, DHF, DSS, Leucopenia, Mortality, Serum amylase, Serum lipase, Thrombocytopenia
288
Fecal Elastase-1 in acute and chronic pancreatitis: A preliminary study
Arun Kumar Sharma , V Sharma, K K Prasad, Anupam Singh, S K Sinha, U Dutta
Correspondence – Arun Kumar Sharma - [email protected]
Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India
Background Pancreatic Elastase-1 is an anionic endoprotease secreted from pancreas and it remains undegraded during intestinal transit. The stool concentration of pancreatic Elastase-1 reflects the exocrine pancreatic function. This study was done to estimate fecal Elastase-1 level in patients of acute and chronic pancreatitis admitted at this centre. Pancreatic elastase were also tested in patients other than that of pancreatic involvement namely patients of dyspepsia in order to know the level of pancreatic elastase in their stool using the same kit. Method Patients of acute pancreatitis, chronic pancreatitis and dyspepsia attending Nehru Hospital, Postgraduate Institute of Medical Education and Research, Chandigarh between January 2020 to May 2022 were included in the study. Stool samples were collected and stored at -20°C. The quantitative estimation of pancreatic Elastase-1 in stool was done by using IDK Pancreatic Elastase ELISA kit (Immunodiagnostik AG, Germany).
Results The level of fecal elastase in 23 patients of acute pancreatitis (median age 36.5 years, M:F-13:9) was 325.43 μg/gm±78.14 (Mean±S.D). The fecal elastase level in 27 chronic pacreatitis (Median age 38.6 years, M:F-22:5) was 154.81 μg/gm±123.01 (Mean±S.D). Pancreatic elastase in 55 dyspeptic patients (Median age 41.5 years, M:F-37:18) was 525.21μg/gm ± 205.06 (Mean ± S.D).
Conclusion Fecal Elastase-1 is considerably reduced in chronic pancreatitis patients compared to acute pancreatitis patients. However more patient studies are needed to know the levels of fecal elastase in patients of chronic pancreatitis in our population.
Keywords Acute pancreatitis, Chronic pancreatitis, Fecal Elastase-1
289
Natural history of asymptomatic walled off necrosis in patients with acute pancreatitis
Manish Kumar * , Siddharth Srivastava, Sanjeev Sachdeva, Poonam Narang, Ashok Dalal, Bhawna Mahajan, Ujjwal Sonika
Correspondence – Manish Kumar - [email protected]
*Department of Gastroenterology, Kailash Hospital, H-33, Shaheed Arjun Sardana Marg, H Block, Pocket H, Sector 27, Noida 201 301, India, and Department of Gastroenterology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, 1, Jawaharlal Nehru Marg, New Delhi 110 002, India
Background and Objectives Studies on natural history of asymptomatic walled-off necrosis (WON) in acute pancreatitis (AP) are scarce. We conducted a prospective observational study to look for incidence of infection in WON.
Methods Thirty consecutive AP patients with asymptomatic WON were included. Their baseline clinical, laboratory and radiological parameters were recorded and were followed-up for 3 months. Mann-Whitney ‘U’/Unpaired t-test was used for quantitative data and Chi- square/Fisher’s exact was used for qualitative data-analysis. “P” value <0.05 was considered significant. Receiver operating characteristic (ROC) analysis was done to identify the appropriate cut-offs for the significant variables.
Results Thirty patients were enrolled, 25 (83.3%) were males. Alcohol was the commonest etiology. Eight patients (26.6%) developed infection on follow-up. All were managed by drainage either percutaneously (n=4, 50%) or endoscopically (n=3, 37.5%). One patient required both. No patient required surgery and there was no mortality. Median baseline C-Reactive protein (CRP) was higher in infection group 76 (IQR 34.8) mg/L vs. asymptomatic group, 9.5 mg/dL (IQR 13.6), p<0.001. IL-6 and TNF-alpha were also higher in infection group. Size of largest collection (157.50±33.59 mm vs. 81.95±26.22 mm, p<0.001) and CT severity index (CTSI) (9.50±0.93 vs. 7.82±1.37, p<0.01) were also higher in infection group as compared to asymptomatic group. ROC curve analysis of baseline CRP (cut-off 49.5 mg/dL), size of WON (cut-off 127 mm) and CTSI (cut-off 9) showed AUROC (Area Under ROC) of 1, 0.97 and 0.81 respectively for the future development of infection in WON.
Conclusion Around one-fourth of asymptomatic WON patients develop infection on 3 months follow-up. Most patients with infected WON can be managed conservatively. Keywords Acute pancreatitis, Asymptomatic, Infection, Walled-off necrosis
290
Neutrophil-lymphocyte ratio as prognostic marker in assessing acute pancreatitis outcome
Rakesh Garlapati, Venkata Ranga Reddy, Mohan Reddy
Correspondence – Rakesh Garlapati - [email protected]
Department of Gastroenterology, Kurnool Medical College, Near, Bhudawarapet Bharath Petroleum, Kisan Ghat Road, Kurnool 518 003, India
Introduction Acute pancreatitis is one of the most common cause of emergency hospital admissions in India. The neutrophil–lymphocyte ratio (NLR), calculated from the white cell differential count, provides a rapid indication of the extent of an inflammatory process and helpful categorising the patients.
Aim To determine an optimal ratio of NLR for severity prediction.
Methods Prospective cross-sectional study was done in Department of Gastroenterology, Kurnool Medical College in 100 consecutive acute pancreatitis (according revised Atlanta criteria) patients visiting gastroenterology OPD. Blood samples were collected immediately on admission and end of 48 hours. Relevant radiological investigations were done.
Results and Discussion Alcohol etiology was common cause of pancreatitis. The mean NLR on admission in mild group was 6.2±1.2 and the moderate group was 9.1±1.6. The mean NLR of severe group was 13.6±2.5. The differences between the severity were statistically significant (p<0.001). The mean NLR at end of 48 hours in Mild was 4.7±0.7, The moderate group was 8.3±1.2 and the mean NLR of severe group was 14.8±1.6. The differences between the severity were statistically very highly significant (p<0.001).
Conclusion NLR can be done at the time of admission and can be serially monitored which can act as a guide to detect those patients progressing to severe pancreatitis. NLR is a cost effective, simple tool which can be calculated in any level care of hospital be it a secondary care or a tertiary care hospital.
Keywords Acute pancreatitis, NLR, Severity
291
Role of C-reactive protein in predicting severity of acute pancreatitis
Bilal Sheik , Venkata Ranga Reddy, Mohan Reddy
Correspondence – Bilal Sheik - [email protected]
Department of Gastroenterology, Kurnool Medical College, Budhwarpet Road, Budhawarapeta, Kurnool 518 002, India
Introduction Acute pancreatitis is a major debilitating disease of the gastrointestinal tract, having high morbidity and creating a huge physical, financial, and emotional stress to the affected individual. C-reactive protein (CRP) is probably the most studied serum biomarker and considered a marker of severity in pancreatitis.
Aim To determine the role of CRP in predicting severity of acute pancreatitis.
Methods Prospective observational study was done in Department of Gastroenterology, Kurnool Medical College in 70 patients admitted to the gastroenterology ward with acute pancreatitis (according to revised Atlanta criteria). Blood samples were collected immediately at the time of admission. Relevant investigations were done
Results and Discussion Alcohol is the common etiological factor for acute pancreatitis. The CRP had good predictive validity in predicting severe acute pancreatitis at a cut-off value of ≥ 174 mg/L. CRP had a sensitivity of 83.33%, specificity of 82.69%, PPV of 62.50%, and NPV of 93.48% with a total diagnostic accuracy of 82.86% making it a good marker for the prediction of severe acute pancreatitis. There was a statistically significant relationship between CRP and severe acute pancreatitis (p-value <0.001).
Conclusion The use of CRP as a way of predicting the severity of acute pancreatitis is a viable alternative to existing prediction methods and is feasible for use in emergency departments.
Keywords Acute pancreatitis, CRP, Severity
292
Infected pancreatic necrosis–Prospective evaluation of interventions and outcomes
Gauri Nayak , Jahangeer Basha
Correspondence – Gauri Nayak - [email protected]
Department of Gastroenterology, Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500 082, India
Background Infected pancreatic necrosis represents a diagnostic and therapeutic challenge. Some form of intervention becomes necessary in such groups of patients to reduce the burden of their morbidity and mortality. Hence, we aim to study the interventions in infected pancreatic necrosis, the timing of the interventions, complications thereof, and the final outcome.
Methodology All patients of infected pancreatic necrosis with clinical suspicion of infection (fever, raised TLC) or evidence of infection on imaging studies and/or persistent organ failure despite conservative treatment were prospectively evaluated in our study. Interventions in patients not responding to conservative management were studied along with the day of pancreatitis on which they were performed. Outcomes were analyzed in the form of mortality, nature, and timing of interventions, need for reinterventions, microbial pattern of infection, etc.
Results One hundred patients qualified the inclusion criteria. 66% were males and majority were in the age group of 18–30 years. The most common cause of pancreatitis was alcohol induced followed by idiopathic cause, hypertriglyceridemia, gallstone induced and traumatic pancreatitis. Forty-three percent of patients had organ failure on Index contact. Seventy-four percent patients had a CT severity score of >5. Twenty patients had pancreatic ascites and 37 patients had abdominal venous thrombosis. Seventy patients underwent percutaneous drainage, 36 underwent endoscopic ultrasound guided drainage and 24 patients underwent both. Forty-three patients underwent necrosectomies (38 percutaneous and 30 endoscopic). Eleven patients had to undergo surgical necrosectomies. Forty-four patients underwent interventions within 28 days (11 endoscopic and 33 percutaneous drainages). Mortality in the early drainages (< 28 days) was 13% and 9% in the late drainage patients.
Conclusion Infected pancreatic necrosis still poses a challenge to treat. selection and performance of an appropriate intervention in the proper clinical setting will decrease the burden of morbidity and mortality.
Keywords Infected pancreatic necrosis, Interventions
293
Factors affecting pain relief in patients undergoing extracorporeal shock wave lithotripsy in chronic calcific pancreatitis
Nitish Ashok Gurav, Chandragiri Praneeth, Nitin Jagtap, Manu Tandon, D Nageshwar Reddy
Correspondence – Nitish Ashok Gurav - [email protected]
Department of Medical Gastroenterology, Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500 082, India
Introduction Paradigm shift in the management of chronic calcific pancreatitis (CCP) with large ductal calculi includes extracorporeal shock wave lithotripsy (ESWL) followed by pancreatic ductal clearance by endotherapy. The safety and efficacy of ESWL for painful CCP is well established. However, independent predictors of persistent pain are not defined yet. Prior knowledge regarding the presence of these factors helps in predicting pain relief response and therapy towards treating these additional factors.
Method A total of 187 consecutive adult patients of CCP, who underwent successful ESWL and ERCP and PD stent placement were prospectively followed for 6 months. The pain was assessed at baseline and at 6 month using Izbicki pain score. The independent predictors of complete pain relief were derived from logistic regression analysis.
Results Of 187 patients, 177 (94.65%) had complete or partial pain relief while remaining 10 had no pain relief. On univariate analysis, older age, male gender, active smoking and alcohol intake, main pancreatic duct (MPD) stricture, stone density, absence of diabetes were associated persistent pain at 6 month after ESWL (p<0.05). While the presence of parenchymal calcification, CBD stricture, small fluid collection, portal vein thrombosis were not associated with persistent pain (p>0.05). On logistic regression analysis; active alcohol abuse (OR 9.36; 95% CI 3.9–22.2), active smoking (OR 3.41; 95% CI 1.1–10.7), MPD stricture (OR 15.5; 95% CI 4.6-51.7), higher stone density (OR 1.002; 95 CI 1.001–1.003); absence of diabetes (OR 2.75, 95% CI 1.2–6.1) were independent predictors of absence of complete pain relief at 6 months.
Conclusion Active alcohol abuse, smoking, MPD stricture, higher stone density and absence of diabetes are independent predictors of persistent pain after ESWL. Response to therapy in CCP patients should be explained considering the above factors as few of these factors are modifiable.
Keywords Chronic calcific pancreatitis, Extracorporeal shock wave lithotripsy, pain
294
Inter-observer agreement on ‘assessment of debris’ during endoscopic ultrasound guided drainage of walled off pancreatic necrosis
Partha Pal , Sandeep Lakhtakia, Nitin Jagtap, Shujaath Asif, Krithi Krishna Koduri, Rajesh Gupta, Jahangeer Basha, Azimudin Haja, Aniruddha Pratap Singh, Ashirwad Pasumarthy, Jagdeesh Rampal Singh, Rakesh Kalpala, Mohan Ramchandani, D Nageshwar Reddy
Correspondence – Sundeep Lakhtakia - [email protected]
Department of Gastroenterology, Asian Institute of Gastroenterology, 6-3-662, Somajiguda, Hyderabad 500 082, India
Introduction Estimation of solid component in a walled off pancreatic necrosis (WOPN) during endoscopic ultrasound (EUS) is important to guide stent selection WOPN drainage but often not objectively quantified. We studied inter-observer agreement (IOA) among endosonographers assessing debris in pancreatic fluid collection (PFC) and their choice of stent.
Methods EUS videos of 15 patients having PFC with concurrent magnetic resonance imaging (MRI) assessment of debris were independently reviewed by 40 endosonographers for percentage of debris (10% increments) and their choice of stent (plastic or metal). The Fleiss’ Kappa (κ) coefficient was used to assess IOA. Post-hoc analysis was done using wider debris intervals (20% increments).
Results A poor agreement was observed for the percentage of debris (κ-0.188) which did not improve (κ-0.196) even after including only expert endosonographers having >10 years experience (n=33). There was fair agreement (κ-0.266) with reference MRI on percentage of debris. On post-hoc analysis, the IOA (κ-0.293, fair agreement) and agreement with MRI (κ-0.456, moderate agreement) improved as the debris intervals widened from 10% to 20%. The agreement for stent selection (plastic vs. metal) was poor (κ-0.174) that did not improve with case volume (κ 0.153 among respondents with >25 EUS guided drainage/year, n=21) or years of experience (κ 0.195 for >10-year experience, n=33).
Conclusions IOA between endosonographers regarding estimation of debris in WOPN and subsequent stent choice for drainage is poor. Experience of endosonographers did not improve IOA. Studies to standardize the EUS criteria for debris assessment in WOPN and subsequent therapeutic approach are warranted.
Keywords Endoscopic ultrasonography (EUS), Interventional EUS, Pancreatic fluid collection (PFC), Training. Walled of pancreatic necrosis (WOPN)
295
Rare complication of acute pancreatitis with an unusual presenting symptom
Digvijaysinha Hodgar , Sandip Pal
Correspondence – Digvijaysinha Hodgar - [email protected]
Department of Gastroenterology, R N Tagore Hospital, Premises No: 1489, Mukundapur Main Road, 124, Eastern Metropolitan Bypass, Mukundapur, Kolkata 700 099, India
Acute severe pancreatitis is associated with many early and late complications involving multiorgan system. Thoracic complications of pancreatitis are rare. Commonly seen thoracic complications are ARDS, pleural effusion. Here, we will be presenting a case of acute pancreatitis with very rare complications viz pancreatico-bronchial fistula along with pancreatic duct disruption.
Keywords Pancreatico-bronchial fistula
Endoscopy
296
Endoscopic ultrasound features of upper gastrointestinal tract and pancreaticobiliary system in the opium addicts: A prospective longitudinal observation study
Amandeep Sidhu, Sudhir Maharshi, Shyam Sunder Sharma
Correspondence – Amandeep Sidhu - [email protected]
Department of Medical Gastroenterology, Sawai Man Singh Medical College, New SMS Campus Road, Gangawal Park, Adarsh Nagar, Jaipur 302 004, India
Objective Asymptomatic dilatation of bile duct and symptomatic sphincter of Oddi dysfunction have been reported in opium addicts. So far, only one study and 2 case reports had been published in the literature. Aim of this study to evaluate various parameters of upper gastrointestinal tract (UGI) and pancreaticobiliary system by using endoscopic ultrasound (EUS) in opium addicts.
Methods A total of 20 opium addicts presenting with upper abdominal pain and fulfilling all the inclusions and exclusion criteria were included in this study. EUS findings of upper GI tract and pancreaticobiliary system were analyzed in these patients.
Results All the 20 patients were males (median age 53.3 years; range 35-70) presented with upper abdominal pain. Median duration of opium addiction was 20.1 years. On EUS common bile duct (CBD) was dilated in all the patients (median 9.3 mm; range 7-12 mm) while PD was dilated in 8 (40%) patients (median 3.7 mm). CBD wall thickening was seen two (10%) patients. Aspartate transaminase, alanine transaminase and alkaline phosphatase were above the normal range in five (25%) and two (10%) patients respectively. Gallbladder (GB) wall was thickened in 3 (15%) patients (median 3.5 mm). EUS findings of esophagus, duodenum, stomach, liver, and pancreatic parenchyma were normal. Surface area of papilla of Vater (SPV= >25 mm2) was increased in 12 (60%) patients.
Conclusion Opium addiction causes obstruction at ampulla. CBD was dilatation in all while PD dilatation was seen in 40% patients. GB wall thickening and increased SPV was a peculiar finding as a result of direct effect of opium on GB and ampulla respectively.
Keywords Common bile duct, Endoscopic ultrasound, Pancreatic duct
297
Challenges faced in endoscopic management of proximal esophageal perforations: Surgery, FCSEMS, clips, combinations- thinking out of the box to achieve good patient outcomes with multidisciplinary management
Sushant Sethi, Rajat Khandelwal
Correspondence – Rajat Khandelwal - [email protected]
Department of Gastroenterology, Apollo Hospitals, Plot No. 15, Sainik School Road, Bhubaneshwar 751 005, India
Upper esophageal perforations/fistulae present a unique challenge to the endoscopist. We present three such cases seen over four months, with varying scenarios.
Case discussion A female aged 55 developed a cervical esophageal perforation on swallowing her denture. Endoscopic removal of the impacted foreign body, done with great patience, revealed a gaping defect in cervical esophagus postero-laterally at 25 cm from incisor teeth. Weighing options of surgery vs. endotherapy, jointly decided to deploy FCSEMS to cover the perforation after a tracheostomy, knowing that the proximal flange would remain in the pharynx. Proximal stent migration occurred despite clip fixation of distal flange, and endoscopic repositioning was required. After 5 weeks stent was removed, and video fluoroscopy showed no leakage of contrast extraluminally. Imaging revealed a minute defect in posterior aspect of esophagus at C7 level which healed in three weeks on continuing NJ feeds. Patient is doing well at one year follow-up.
A 45-year-old male, presented with dysphagia due to a TEF, caused by prolonged (3 months) intubation and ventilation due to severe corona virus disease – 19 (COVID-19) pneumonia. Endoscopic closure of the esophageal fistula was performed using two endoclips. Tracheostomy and TEF closure was performed by surgical colleagues. Endoscopic healing was confirmed at 4 weeks.
A 37-year-old male developed esophageal perforation in posterior surface at D8 vertebral level after ingestion of a chicken bone. Endoscopy showed fistulous opening at 33 cm from incisor teeth however no foreign body was found in the lumen. FCSEMS was deployed to cover the fistula and proximal end fixed with endoclips. Stent migrated distally once causing recurrent vomiting and was repositioned. Endoscopically fistulous opening healed at 4 weeks.
Conclusion A tailored approach with endoscopic tools, and timely surgical intervention may hold the key to improving outcome in management of proximal esophageal perforations.
Keywords Cervical esophagus perforation, FCSEMS
298
Comparison of serum lactic acid and urea-creatinine ratio with Rockall, Glasgow Blatchford and AIMS65 score in risk stratification of patients with acute upper gastrointestinal hemorrhage
Anto Gnana Delasallem, Bailuru Vishwanath Tantry, Sandeep Gopal, Suresh Shenoy, Anurag Shetty
Correspondence - Anto Gnana Delasallem - [email protected]
Department of Medical Gastroenterology, Kasturba Medical College Hospital, Nandigudda Road, Attavar, Mangaluru 575 001, India
Introduction Upper gastrointestinal (UGI) bleeding is a common emergency requiring admission to the intensive care unit. A number of clinical scores have been developed to aid in the prediction of mortality risk. In this study we evaluated the role of serum lactic acid and urea-creatinine ratio (UCR) in risk stratification of patients.
Methods This was a prospective observational study conducted on 30 patients with UGI bleed over a period of 18 months. At admission, baseline blood investigations included measurement of serum lactate levels, and calculation of UCR, Glasgow Blatchford (GBS), Rockall and AIMS65 scores. These were correlated with the primary (inpatient and thirty-day mortality) and secondary outcomes (need for ICU stay, requirement of blood transfusion, re-bleeding and need for endoscopic/surgical/radiological interventions).
Results In this study the mortality rate was found to be 11.3% (8 patients). Mean lactate levels were significantly higher in the non-survivor group (86.48 mg/dL) in comparison to the survivors (32.09 mg/dL). Elevated lactate levels (>45 mg/dL) was found to be a better predictor of mortality (area under ROC curve 0.868, p<0.0.1), when compared to Rockall, GBS and AIMS 65 scores with a sensitivity of 90.9% and a specificity of 81%. However, UCR was a poor predictor of mortality. On analysis of secondary outcomes, a serum lactate of >40 mg/dL at admission was associated with increased length of ICU stay (3.06 days, p<0.01), increased requirement of blood transfusions (2.63 units, p–0.01), increased requirement of inotropic support and endoscopic interventions. UCR was not found to have any significant association.
Conclusion Our study shows that serum lactate levels is useful in predicting in-hospital and thirty-day mortality in patients with UGI bleed. However, UCR showed no similar benefit. Lactate levels can be incorporated into the existing risk stratification scores for better prediction and timely intervention, in patients with UGI bleed.
Keywords Lactate, Upper GI bleed, Urea creatinine ratio
299
Clinical profile, endoscopic finding and outcome of patients with upper gastrointestinal bleed attending a tertiary-care hospital: A retrospective cross-sectional study
Srija Sen , Bailuru Vishwanath Tantry, Sandeep Gopal, Suresh Shenoy, Anurag Shetty
Correspondence – Srija Sen- [email protected]
Department of Medical Gastroenterology, Kasturba Medical College Hospital, Nandigudda Road, Attavar, Mangaluru 575 001, India
Introduction Upper gastrointestinal bleed is a common acute medical emergency. Endoscopy is the gold standard diagnostic and therapeutic tool in the management of upper gastrointestinal bleed. This study was undertaken to look into the clinical profile, endoscopic finding and outcomes in patients with upper gastrointestinal bleed.
Methods A retrospective cross-sectional study was conducted in a tertiary care teaching hospital in Mangalore from June 2020 to November 2021. The sample size was calculated. Eighty patients with upper gastrointestinal bleed were included in the study. Data was analyzed using Statistical Package for the Social Sciences (SPSS) version 22.
Results Variceal hemorrhage was the most common etiology of UGI bleed and was seen in 55% of patients, and the most common lesion within the group was found to be large esophageal varices (73.3%), followed by non-variceal bleed (45%), in which duodenal ulcer was found to be most common (44%). Almost one third of patients had a previous history of upper GI bleed (35.5%) and the most common presenting symptom was hemetemesis (78.57%) followed by melena (68.75%). The mortality at the time of discharge was found to be 11.25% (9 out of 80) and overall mortality at 30 days was 13.75% (11 out of 80). Eight of these patients had variceal hemorrhage and 3 had non-variceal hemorrhage. Mortality rate was higher in those with variceal hemorrhage (18.18%), as compared to non-variceal bleed (8.34%). The mean of the Rockall score, Glasgow Blatchford score and AIMS65 scores were higher in the non-survivors compared to the survivors. Bad prognostic factors were rebleeding, variceal etiology and Rockall score > 6.
Conclusion UGI bleed of variceal etiology presented with a higher Rockall score, had more rebleeding and higher mortality than those with non-variceal etiologies. Early gastroscopy within 24 hours is recommended for diagnosis and timely intervention in upper gastrointestinal bleed that helps in reducing morbidity and mortality.
Keywords Duodenal ulcer, Rockall score, Upper GI bleed, Variceal hemorrhage
300
Endoscopic removal of impacted coin from esophagus: A case report
Shatdal Chaudhary, Nagendra Chaudhary*
Correspondence - Shatdal Chaudhary - [email protected]
Departments of Internal Medicine, and *Paediatrics, Universal College of Medical Sciences, Siddhartha Nagar 32900, Nepal
Introduction Impacted foreign bodies are some of the most challenging emergencies encountered by endoscopists. The commonly ingested foreign bodies are coins, toys, and batteries in children whereas impaction of either bone or meat bolus during eating are common in adults. We have come across case of impacted coin in lower esophagus in a 5-year child.
Methods A 5-year-old boy presented in Pediatric OPD with ingestion of a coin of 13 hours duration. After a quick evaluation, chest X-ray posterior-anterior view and lateral view were performed which has shown an impacted coin in lower esophagus. Written informed consent was taken from child’s parents and upper GI endoscopy was performed under general anesthesia to remove the coin.
Results Coin was impacted in lower esophagus, just above lower esophageal sphincter with aberration of esophageal mucosa at impacted site. Coin slipped in stomach during the procedure. Coin was removed with Roth net. Child was kept for observation for 48 hrs and discharged uneventfully.
Conclusion Foreign body ingestion is commonly seen in children and young adults. Roth net is a safe and effective tool in removing coin from upper gastrointestinal tract.
Keywords Endoscopy, Foreign body, Roth net
301
Real time qualitative endoscopic ultrasound elastography assessment for evaluation of benign and malignant mediastinal and abdominal lymph nodes
S Rakesh Kumar, Ashiq Hussain Dar*, Malla V A Gangadhar Rao, Dhruv Thakur, Pritam Das, Gaurav Pandey, Samir Mohindra
Correspondence - S Rakesh Kumar - [email protected]
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raibareli Road, Lucknow 226 014, India, and *Ganesh Shankar Vidyarthi Memorial Medical College, Swaroop Nagar, Kanpur 208 002, India
Background and Objectives Endoscopic ultrasound elastography (EUE) is a novel method of measuring tissue stiffness during endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA). This prospective study was conducted to evaluate the diagnostic utility of endoscopic ultrasound guided elastography for diagnosing benign and malignant lymph nodes in the mediastinum and abdomen.
Methods A total of 70 patients were enrolled between June 2021 and February 2022 who had lymph node enlargement (mediastinal, abdominal) on computed tomography (CT) examination, and lymph nodes were evaluated by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). EUE of lymph nodes was performed prior to EUS-FNA. A linear probe EUS was used with processor to assess elastographic patterns that were classified based on color distribution as follows: Type 1, predominantly green (green, yellow and red); Type 2, part blue, part green (greenish blue); Type 3, predominantly blue. Pathologic assessment of lymph nodes was used as the gold standard. The elastographic patterns were compared with the final pathologic results from EUS-FNA. For tuberculosis, confirmation histopathology as well as polymerase chain reaction PCR (GeneXpert) method were correlated.
Results On pathological evaluation of the 70 lymph nodes, 26 were malignant and 43 were benign among which 8 were PCR (GeneXpert) positive for TB. Among Type 3 lymph nodes on EUE: malignant in 20/24 (83.3%) and benign in 4/24 (16.7%); for Type 2 lymph nodes, 13/17 (76.4%) were benign and 4/17 (23.6%) were malignant; Type 1 lymph nodes were benign in 27/29 (93.1%), malignant in 1/29 (3.4%). In classifying type 1 as benign and type 3 as malignant taking cut-off elasto score 2; the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were found to be 87%, 91.3%, 83.3% and 93.3% respectively.
Conclusion EUS elastography of mediastinal and abdominal lymph nodes is non-invasive technique that can be performed reliably for assessment and differentiation of benign and malignant lymph nodes.
Keywords EUS elastography, EUS FNA, Malignant lymph node
302
Endoscopic ultrasound-guided combined coil and glue injection for the primary prophylaxis of the gastric variceal bleed
Pankaj Kumar , Surinder Rana * , Rajesh Gupta * , Ravi Kumar Sharma **
Correspondence - Pankaj Kumar - [email protected]
Department of Gastroenterology, Ojas Superspeciality Hospital, Sector 26, Panchkula 134 116, India, *Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012, India, and **Department of University Institute of Biotechnology, Chandigarh University, Mohali 140 413, India
Introduction Gastric varices attributes to 20% of all variceal bleeds and are associated with a high risk of uncontrolled bleeding, rebleeding, and death compared to esophageal varices. Endoscopic ultrasound (EUS)-guided combined coil and glue injection has been shown to be an effective therapy in acute bleeding and secondary prophylaxis of gastric variceal bleed, however, there is a paucity of data on primary prophylaxis.
Methods Single-center retrospective analysis of adult patients with age >18 years who underwent EUS guided combined coil and glue injection for the primary prophylaxis of high-risk gastric varices (gastric varices size >15 mm on EUS or cherry-red spot on endoscopy) between April 2018 and June 2022 was performed. The analysis included technical success, rate of adverse events and risk of bleeding.
Results Eighteen patients (77.2% males) with mean age of 43±11.4 years were included in the study. Fifteen (83.3%) patients had IGV1 varices, whereas GOV2 varices were seen in 3 (16.7%) patients. Mean variceal size was 2.5±0.55 cm. technical success was achieved in 100%, and 100% of patients had EUS confirmation of GV obliteration with EUS at 7 days and at 6 months. Only one EUS session was required in all the patients to obliterate the gastric varices. The mean number of coils used were 2 (1-3) and mean glue volume injected was 2.2 mL (1.5-2.5 mL). Mean follow-up period was 37.8±7.9 months and 2 patients had gastric variceal bleed which was managed successfully with repeat endoscopy sessions. No deaths related to gastric variceal bleed occurred.
Conclusion EUS guided combined coil and glue injection for primary prophylaxis of high risk gastric varices is technically feasible, safe and highly effective in preventing gastric variceal bleed.
Keywords EUS guided coil and glue injection, Gastric varices, Variceal bleeding
303
Predictors of inadequate bowel preparation in patients taking split dose preparation for diagnostic colonoscopy
Aditya Kale , Michael K, Love Garg, Mayur Satai, Nitish Patwardhan, Gautam Jain, Abu Ansari, Tanmay Laxane, Shashank Punjalwar, Akash Shukla
Correspondence – Aditya Kale - [email protected]
Department of Gastroenterology, 9th Floor, Ward 32 A, Seth G S Medical College and K E M Hospital, Parel, Mumbai 400 012, India
Introduction Inadequate bowel preparation results in missing out critical findings like adenomas, increases procedure time, reappointment for procedure, diagnostic delay.
Methods Adult (age >18 years) patients undergoing diagnostic colonoscopy were prospectively included from July 2021-July 2022. Demography, indication of procedure, bowel movements at baseline and after preparation, stool colour, distance from hospital, time interval between preparation completion and procedure, amount of preparation taken, diet and water consumption in preceding 24 hours, history of poor preparation were noted. Boston bowel preparation score (BBPS) <6 was considered poor preparation. All patients received split dose bowel preparations (Polyethylene glycol based or Coloprep containing sodium sulphate+potassium sulphate+magnesium sulphate or sodium phosphate based – Exelyte solution).
Results Total 400 cases (male-217, 54.3%) were included. Median age was 42 years (interquartile range [IQR]-28-54 years). Diagnosis of bowel thickening (85, 21.3%), evaluation of gastrointestinal (GI) blood loss (87, 21.8%), chronic diarrhea (63, 15.8%), constipation (48, 11.5%) were the common indications for colonoscopy. Poor bowel preparation was seen in 43 (10.8%) cases. On univariate regression, number of bowel movements after bowel preparation (0.04), requirement add on T. Bisacodyl (0.001), turbid stool colour (0.024), amount of preparation consumed (0.003) were associated with poor preparation. On multivariate analysis, preparation without Tablet Bisacodyl (0.013), amount of bowel preparation consumed (0.027), amount of free water taken with preparation (0.036), turbid stool after bowel preparation (0.048) were associated with inadequate bowel preparation.
Conclusion Poor bowel preparation was noted in 10.8% cases. Amount of bowel preparation consumed, amount of free water consumed with bowel preparation, preparation without tablet Bisacodyl and turbid stool color after bowel preparation were associated with poor bowel preparation at diagnostic colonoscopy, after split dose bowel preparation regimens. Use of tablet Bisacodyl as add on to bowel preparation may improve the preparation.
Keywords Adenoma detection, Bisacodyl, Boston bowel preparation score, Bowel preparation
304
Forgotten common bile duct plastic stents: An experience from tertiary care referral center
Nitish Patwardhan, Aditya Kale, Shashank Pujalwar, Gautam Jain, Tanmay Laxane, Abu Asim Akhtar Ansari, Amrit Gopan, Arun Vaidya, Akash Shukla
Correspondence - Nitish Patwardhan - [email protected]
Department of Medical Gastroenterology, Seth G S Medical College and K E M Hospital, Mumbai, Multistoried Building, 9th Floor, Acharya Donde Marg, Parel. Mumbai 400 012, India
Background and Aims Plastic stents (PS) placed in common bile duct (CBD) mandates timely stent removal or replacement sessions. Despite appropriate counseling, retention of CBD PS for >3 months often occurs. We assessed the prevalence and impact of retained CBD stents and outcomes of endoscopic endotherapy.
Methods Prospectively maintained endoscopy database was reviewed from November 2019 - April 2022 to identify patients with retained CBD PS (Indwelling stent in CBD for >3 months).
Results Two hundred and fifty-two patients (median age-46 years [interquartile range - IQR-31-56 years], males 150 [61%]) had retained CBD stent of which 180 (71%). Median duration of PS in CBD was 5 months (IQR-4-6 months). Corona virus disease – 19 (COVID-19) pandemic related delay in procedure was reported by 84 (33.3%) patients of which 28 were symptomatic. Sixty-seven (26.6%) were symptomatic with abdominal pain (n=31[12.3%]), cholangitis (n=22 [8.7%]), jaundice (n=14 [5.6%]). Stent migration and stent fragmentation was noted in 5 (2%) patients each. All patients with stent migration were symptomatic (5 vs. 0, p-0.001). Multiplicity or duration beyond 3 months of stents was not associated with reduced risk of symptoms. Fifty-five (21.82%) patients had normal imaging findings while 197 (78.17%) had obstructive dilatation of biliary tree. All patients underwent CBD clearance or stent exchange, retrieval of migrated stent with 100% technical success. Three patients with cholangitis and septic shock died despite stent exchange.
Conclusion COVID pandemic resulted in delayed exchange/removal in one third cases. Retained CBD PS causes significant symptoms, complications, morbidity, and mortality.
Keywords CBD stent retention, Complications, COVID-19
305
Capsule endoscopy for obscure gastrointestinal bleed in tropics: A single center experience on 350 patients
Uday C Ghoshal, Piyush Mishra, Anshuman Elhence, Akash Mathur, Bushra Fatima, Anand Prakash Agrahari, Asha Misra
Correspondence – Uday C Ghoshal - [email protected]
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raibareli Road, Lucknow 226 014, India
Background Obscure gastrointestinal bleed (OGIB) comprises 5% to 10% of all gastrointestinal (GI) bleed episodes and capsule endoscopy (CE) is an indispensable tool for evaluation of such patients. There is paucity of literature on OGIB evaluation from the tropics with majority of previous studies having small sample size.
Methodology We did a retrospective analysis of patients presenting for OGIB evaluation to a tertiary care center from September 2003 till July 2021. CE was done using either PillCam SB or MiroCam capsule after overnight fasting and polyethylene glycol preparation. Clinical demographic data, type of bleed-overt vs. occult, spectrum of lesion and age-wise yield of CE was analyzed.
Results Of 350 patients (aged 52.39±17.36 years, 70.9% male), 107 (30.6%) and 243 (69.4%) had OGIB-occult and OGIB-overt, respectively. Lesions were picked up in 244 (69.7%) with multiple etiologies in 72 (20.6%) and single etiology in 172 (49.1%) patients. Amongst single etiology, lesions identified were vascular malformations in 52 (14.9%), ulcer in 47 (13.4%), tumor in 24 (6.9%), hookworm in 19 (5.4%) and stricture in 15 (4.3%) patients. Amongst multiple etiologies ulcer with stricture was the most common finding in 43 (12.3%) patients. There was no difference in rate of detection of lesions with respect to change in oro-cecal transit time and/or recording duration and lesions were detected in comparable frequency in both groups who underwent 8 (PillCam) or 11 hours (MiroCam) of recording. Young patients (0-39-y) more often had multiple etiologies detected on CE than the older (≥40-y) patients (26/76, 34.2% vs. 46/228, 20.2%, respectively; p=0.001). Lesions were detected in a comparable frequency among patients with obscure overt and occult bleed (173/243, 71.2% vs. 71/107, 66.3%, respectively; p=0.4).
Conclusion CE has a high diagnostic yield in OGIB in the tropics, regardless of the type of bleed or duration of CE procedure. Younger age group more often have multiple etiologies for OGIB as compared to elderly.
Keywords Lesions, Oro-cecal transit time, Tropics
306
Risk factors for early re-bleed following endoscopic variceal band ligation and assessing utility of dedicated score (BICAP score) to identify high risk groups
Ramu Krishnan, Kandasamy Kumar, Poppy Rejoice, A Shafique
Correspondence - Ramu Krishnan - [email protected]
Department of Medical Gastroenterology, Tirunelveli Medical College, 3, High Ground Road, Palayamkottai, Tirunelveli 627 011, India
Background Endoscopic variceal band ligation (EVBL) is a universally accepted and approved treatment for bleeding esophageal varices. Re-bleed is the most common complication following EVBL. Ours is a prospective study analyzing risk factors for early re-bleed (ERB) and creating a laboratory-based score (BICAP) for detecting high-risk groups for re-bleed.
Methods The study period was between March 2021 to March 2022 when 111 patients underwent EVBL in our department. Patients were followed by telephone or direct visits weekly for 1 month. ERB was defined by active variceal hemorrhage presenting as hematemesis in a patient following EVBL within 1 month. Endoscopy was done for all patients after re-bleed to confirm.
Bedside Index for Severity in Acute Pancreatitis (BISAP) score 0 1 2
Bilirubin <3 mg/dL 3-5 mg/dL >5 mg/dL
INR <1.5 1.5- 2.0 >2.0
Creatinine <1 mg/dL 1-1.5 mg/dL >1.5 mg/dL
Albumin >3.5 g/dL 2.8 – 3.5 g/dL < 2.8 g/dL
Platelet count >1.5 L 50,000 to 1.5 L <50,000
Max score is 10
Results Among 111 patients, 26 patients developed ERB with an incidence of 23.4%. ERB was higher in emergency EVBL than elective (29.3% vs. 6.9%, p=0.014). Platelet count of < 50,000 and INR >2.0 were associated with high ERB risk (52.4%, p–0.002) and (60%, p-0.001). Overt encephalopathy was associated with 42.3% risk of ERB (p - 0.009). Usage of high number of bands (>6) were associated with increased risk of ERB (56.3%, p–0.001). Child-Pugh C patients had high risk of ERB (37.5%, p-0.001). BICAP score >7 was associated with increased risk of ERB (80%, p-0.002)
Conclusion Child-Pugh score and BICAP score both can predict high risk groups for ERB, but BICAP score is a dedicated score and can be used even in non-cirrhotic patients. BICAP score is found to have high sensitivity in detecting patients with high risk for early re-bleed.
Keywords BICAP score, Early re-bleed, Endoscopic variceal band ligation
307
Pancreatic hydatid cyst: Expanding the therapeutic armamentarium of endoscopic retrograde cholangiopancreatography
Anupam Kumar Singh 1 , Shreya Shruti2, Chhagan Lal Birda1, Anupam Lal3, Jayanta Samanta1, Saroj Kanrt Sinha1
Correspondence - Saroj Kant Sinha - [email protected]
Departments of 1Gastroenterology, and 3Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh 160 012, India, and 2Government Medical College and Hospital, Sector 32, Chandigarh 160 030, India
A 14-year-old female presented with epigastric pain and recurrent vomiting for five days. She had multiple similar episodes over last 2 years. Physical examination showed mild hepatomegaly and upper abdominal tenderness. Serum amylase/lipase were elevated more than five-fold. Ultrasonography revealed a cystic lesion (suggestive of hydatid cyst) in liver and a solid cystic lesion (70 × 39 mm) in body of pancreas. Pancreatic duct was dilated and contained few tiny cystic lesions. Endoscopic ultrasound and contrast enhanced computed tomography confirmed these findings. Acute pancreatitis was treated conservatively and albendazole was advised (400 mg twice daily for 21 days). Endoscopic retrograde cholangiopancreatography was performed four weeks later. Pancreatic sphincterotomy, papillary balloon dilatation and extraction of membranes from pancreatic duct were done. 10 Fr pancreatic stent was placed into cyst cavity which was removed after six weeks. Histology confirmed the diagnosis of hydatid membranes. Liver cyst was managed by PAIR method. Patient received total 6 cycles of albendazole. Follow-up imaging at 12 and 24 months showed no residual pancreatic lesion.
Discussion Hydatid cysts commonly occur in liver and only rarely in pancreas. Its rupture into pancreatic duct is an extremely rare event and can result in acute pancreatitis. The parasite is known to die on coming in contact with bile or pancreatic juice. Pancreatic ductal rupture of hydatid cyst was exploited to treat it endoscopically and was successful.
Conclusion Hydatid cysts rarely occur in pancreas. Its rupture into pancreatic duct can result in acute pancreatitis but such lesions can be treated endoscopically.
Keywords Hydatid cyst, Pancreas, ERCP
308
Hepatic hydatid cyst with biliary rupture: Balloon dilatation of cystobiliary communication to achieve cure
Anupam Lal 1 , Shreya Shruti2, Anupam Kumar Singh3, Kaushal Kishore Prasad3, Jayanta Samanta3, Saroj Kant Sinha3
Correspondence - Saroj Kant Sinha - [email protected]
Departments of 1Radiodiagnosis, and 3Gastroenterology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India, and 2Government Medical College and Hospital, Sector 32, Chandigarh 160 030, India
A18-year-old male presented with fever, abdominal pain and obstructive jaundice for one month. Examination showed icterus and diffuse hepatomegaly. Liver function showed conjugated hyperbilirubinemia, ultrasonography showed 9 cm size single cystic lesion in liver with floating membranes and dilated common bile duct (CBD) (14 mm). Hydatid serology was suggestive. Magnetic resonance imaging (MRI) abdomen with magnetic resonance cholangiopancreatography (MRCP) confirmed the same. Endoscopic retrograde cholangiopancreatography (ERCP) showed grossly dilated bile duct with irregular filling defects and one large cavity opacified in liver. Endoscopic sphincterotomy was performed and CBD was cleared of membranes. Cystobiliary communication was dilated with biliary balloon (8 mm). 10 F double pigtail biliary stent was placed in CBD which was removed after 4 weeks. He was treated with Piperacillin+Tazobactum for 10 days and Albendazole 400 mg twice daily for 20 days (repeated twice at interval of 3 weeks). Patient improved rapidly. Follow-up ultrasonography at 6 months showed resolution of liver lesion and normal CBD.
Discussion Hepatic hydatid cyst with biliary rupture is traditionally treated surgically. Role of ERCP is limited to biliary drainage and treatment of cholangitis. Parasite dies on coming in direct contact with bile, thus hydatid cyst rarely if ever occur in biliary system. In the index patient, the cystobiliary communication was dilated to increase bile entry into the hepatic hydatid cyst. Cyst resolved without any surgery. Although this strategy was successful in the index patient, it may not be useful in patients with multiple cysts in liver.
Conclusion Solitary hepatic hydatid with biliary rupture can be treated with ERCP and dilation of cystobiliary communication.
Keywords ERCP, Hepatic rupture, Hydatid cyst
309
Significant bradycardias during unsedated diagnostic gastroscopy- An omnipresent risk
Alok Sahu, Aastha Jha, Maitrey Patel, Apurva Shah, Shravan Bohra
Correspondence – Apurva Shah - [email protected]
Department of Gastroenterology, Apollo Hospital International Limited, Plot No, 1A, Gandhinagar - Ahmedabad Road, GIDC Bhat, Estate, Ahmedabad 382 428, India
Introduction Gastroscopy or an upper gastrointestinal (GI) endoscopy, is a relatively safe procedure. Serious complications are seen in 1 case out of 10000 procedures. Complications are most often noted in therapeutic procedures or when intravenous sedation is being used. We present two such cases, where during unsedated diagnostic upper GI endoscopy, patients developed significant bradycardia.
Case Report We present two cases, one 71-year-old female and another 73-year-old male, who underwent diagnostic gastroscopy and developed significant bradycardia (<45 beats per minute), which required immediate abandoning of the procedure. Both of them achieved their base-line heart rate within two minutes of pulling out the scope. Both patients were asymptomatic at routine activities. Both had controlled diabetes mellitus, one of them had coronary artery disease, had undergone bypass grafting 10 years back. Second patient had mild hypertension. Although both patients were on beta-blockers, but their base-line heart rate was more than 70 beats per minute. Both of them underwent electrocardiogram which was normal and echocardiography, which did not reveal any significant wall motion abnormality or low ejection fraction.
Conclusion The likely cause for such bradycardia, without any other obvious causes cause, would be activation of vaso-vagal reflex from esophageal intubation and gastric distention by sudden air insufflation in elderly individuals. Continuation of the procedure would have been risky. Although no such cases have been reported so far as per our knowledge, where patients developed significant bradycardia without administration of intravenous sedation. There are many centers in peripheral parts of our country, performing upper GI scopies without adequate vital monitoring of the patients. These two cases provide an insight as to the need for continuous patient monitoring even during simple diagnostic upper GI endoscopy, which can turn into a fiasco if taken lightly particularly in elderly patients.
Keywords Bradycardia unsedated upper GI scopy
310
Clinical audit of enbloc resection for large colorectal mucosal lesions using endoscopic submucosal dissection from a single centre from a region non endemic for colorectal cancer – Assessing the predictive factors for difficult endoscopic submucosal dissection (ESD) and learning curve for ESD
Jaseem Ansari, Harsh Bapaye*, Hameed Raina, Mangesh Borkar, Ashish Gandhi, Pankaj Bharambe, Ajay B R, Jay Bapaye**, Sanjana Gokhale, Yash Kanani, Rajendra Pujari, Harshal Gadhikar, Amol Bapaye
Correspondence – Amol Bapaye - [email protected]
Department of Gastroenterology, Shivanand Desai Center for Digestive Disorders, Deenanath Mangeshkar Hospital, Kothrud Pune, India, *Byramjee Jeejeebhoy Medical College, Jai Prakash Narayan Road, Railway Station Road, Pune 411 001, India, and **Rorchester General Hospital
Aims Endoscopic submucosal dissection (ESD) for enbloc resection (ER) of large colorectal mucosal lesions are technically difficult and is associated with steep learning curve. This study aimed to identify the factors predicting difficulty to perform colorectal ESD and those increasing the risk of failure of ER and calculate the learning curve to achieve competency to perform colorectal ESD.
Methods Single center retrospective study. Study duration 10 years (2012–2021). One hundred and forty-nine patients with >2 cm colorectal mucosal neoplasms undergoing ESD were abstracted. Primary outcome – Identify factors predicting difficulty while performing ESD. Secondary outcomes – Identify risk factors for failure of ER and to assess learning curve based on ER rate, Speed (S) and Adverse Events (AE).
Results N = 149; mean age – 61.36 years, 101 males (67.8%). Mean size of lesion –46.62 mm (±25.46). ER – 141/149 (94.6%), R0 – 132/142 (92.9%). Mean S (mm2/min) = 9.03 ± 7.94, fastest (rectum) = 10.9, slowest (right colon) = 4.22. Previous resection attempt associated with prolonged procedure time (mean 298.44 min±161.1) compared to naïve (209.77 min ±146.44) (p<0.009). Significant increase in procedure time (Min) as area (mm2) increased, strong positive correlation (rho = 0.64, p=<0.001). For each 100 mm2 increase in area, procedure time increased by 3 min. ROC curve analysis estimated final size ≤68 mm as predictor for ER (positive predictive value [PPV] 95.8%, odds ratio [OR] 14.06, p<0.001). Univariate regression analysis for ER identified lesion size as single independent predictive factor (OR 0.96; 0.95–0.98; p<0.001). Cusum curve analysis showed approximately 47 resections required to achieve compentency in ESD.
Conclusion Increase in lesion size associated with higher risk of failure for ER. Right sided colonic lesions, anastamotic site lesions and previous resection attempts associated with longer procedure time. The learning curve to attain competency in ESD are approximately 47 procedures.
Keywords Enbloc resection, Endoscopic submucosal dissection
311
Frequency, pattern and severity of endoscopic features in patients with inflammatory bowel disease- A retrospective study
Akshatha K, Sandeep Gopal, Bailuru Vishwanath Tantry, Suresh Shenoy, Anurag Shetty
Correspondence – Akshatha K - [email protected]
Department of Medical Gastroenterology, Kasturba Medical College Hospital, Ambedkar Circle, Mangalore 575 001, India, and Manipal Academy of Higher Education, Manipal 576 104, India
Background Inflammatory bowel disease (IBD) is a chronic inflammatory disease of gastrointestinal tract which encompasses ulcerative colitis (UC) and Crohn’s disease (CD). UC usually presents with confluent lesions, and can involve rectum, sigmoid, left sided colitis, entire colon and while CD presents with discontinuous inflammatory lesions and frequently involves the ileocecal region. Present study was undertaken to study endoscopic patterns of IBD.
Method and Results Among total of 1303 lower GI endoscopies, 94 (7.2%) patients found to have UC and 58 (4.4%) patients had CD for duration of one year (1/8/2021 to 30/7/2022) at a tertiary care centre. Among patients with UC, 56 (59.5%) were male and 38 (40.4%) were female. Mean age was 44.47 years. Out of 94 patients, 29 (30.8%) patients had mild disease, 38 (40.4%) had moderately active disease and 25 (26.5%) patients had severe disease. Disease pattern included proctitis in 25 (26.5) patients, proctosigmoiditis in 19 (20.2%) patients and left sided colitis in 14 (14.8%) patients. Pancolitis was observed in 22 (23.4%) patients. Pseudopolyps and malignancy were present in 11 (11.7%) and one patient respectively.
Fifty-eight patients with CD were included in study. Mean age was 27.7 years, Male were 37 and females were 21. CD in remission was seen in 8 (13.7%) and 28 (48.2%) patients had mild disease, 22 (37.9%) had moderately active disease. Disease pattern in endoscopy revealed ileocolitis in 30 (51%) patients, only ileal involvement seen in 6 (10.3%) and diffuse involvement was noticed in 4 cases (6.8%). longitudinal ulcers were present in 8 (13.7%) and 5 (8.6%) had serpigenous ulcers. Luminal narrowing was observed in 6 (10.34%) and 1 patient had ascending colon stricture. Pseudopolyps and cobblestone appearance were seen among 11 (18.96%) and in 3 (3.4%) patients respectively.
Conclusion In our study majority of patients with UC had pancolitis (one fourth) and moderate to severe disease was seen in two third of the patients. In CD almost fifty percent of patients had ileocolonic involvement and fibrostenotic lesions.
Keywords Inflammatory bowel disease, Simple endoscopic score for Crohn’s disease, Ulcerative colitis endoscopic index of severity
312
White light endoscopic findings of gastric and duodenal mucosa in Helicobacter pylori infected patients: Cross sectional observational study in a tertiary hospital of south India
Debapratim Routh Routh, Chezhian Annasamy
Correspondence – Debapratim Routh Routh - [email protected]
Department of Medical Gastroenterology, Madras Medical College, Chennai 600 003, India
Background and Aims H. pylori infection causes variety of upper gastrointestinal tract diseases and can be diagnosed by various non-invasive tests, but they have high false negative results. Endoscopy plays an important role for diagnosis of various gastric and duodenal lesions. This study provides an observation of various endoscopic findings in patients with H. pylori infection (biopsy proven).
Methods It is a cross sectional observational study conducted from April 2021 to September 2021 at Medical Gastroenterology Department of Madras Medical College. Endoscopy and biopsy done at same sitting for patients who met ROME IV criteria for dyspepsia. Endoscopic images of those patients were recorded whose biopsies were positive for H. pylori. Biopsy specimens were collected as per Sydney protocol, stained by H-E staining and examined using a light microscope.
Results Out of total 200 biopsy proven H. pylori infected patients (130 male and 70 female, and mean age 39.7 years), most common endoscopic finding was spotty redness (38.5%) followed by enlarged gastric mucosal fold (20.5%), diffuse redness, mucosal edema, gastric and duodenal ulcers and antral nodularity. Least common findings were erosions (2%) and multiple dots (1%).
Discussion Various related studies support our findings but there are other studies as well which demand more validation.
Conclusion Endoscopic findings can be used as an important diagnostic tool for H. pylori infection but additional studies with larger sample sizes and more diverse populations are required to establish the association of endoscopic features with H. pylori infection.
Keywords Biopsy, Endoscopy, H. pylori, ROME IV criteria
313
A man with innumerable colonic worms
Ashish Jha , Vishwa Mohan Dayal, Arya Suchismita
Correspondence – Ashish Jha - [email protected]
Department of Gastroenterology, Indira Gandhi Institute of Medical Sciences, Bailey Road, Sheikhpura, Patna 800 014, India
A 28-year-old man presented with a 3-months history of diarrhea, abdominal discomfort, mucoid stool, and rectal bleeding. Examination showed pallor. Blood tests revealed hemoglobin of 10.5 g/dL and serum albumin of 3.0 g/dL. Stool examination showed barrel-shaped ova of parasite. A colonoscopy showed carpeting of the entire mucosa (predominantly left colon) with innumerable whipworms (T. trichiura) (Fig. 1). The worms were embedded in the mucosa with their slender anterior end. Mucosa showed scattered hemorrhagic spots (Fig. 1). A diagnosis of trichuris dysentery syndrome (TDS) was made. The patient was successfully treated with a course of oral albendazole (400 mg once daily, X 7-days).
Persons with whipworm infection can present with anemia, abdominal pain, appendicitis, malnutrition, weight loss, perforation, obstruction, or dysentery. The heavy worm load can cause TDS, which is characterized by mucoid or bloody mucoid diarrhea, tenesmus, and iron-deficiency anemia. Growth retardation and rectal prolapse are also seen in children. Trichuriasis can be diagnosed with identification of barrel-shaped ova in stool. Diagnosis of trichuriasis is often missed on stool microscopy in patients with light infection. Alternatively, it can be diagnosed with colonoscopy. Whipworm infestations usually do not cause mucosal changes in the colon. Colonoscopic findings may include peri-appendicular ulcers or erosions, erythema, petechial hemorrhagic spots, mucosal edema, exudates and mucosal oozing.
Whipworm is usually treated with 3-days course of oral mebendazole (100 mg twice daily) or oral albendazole (400 mg once daily). Unlike other nematodes, cure rates for T. trichiura infections are low. Endoscopic retrieval of worms followed by 3-days course of anti-helminths are effective in patients with light infection. Longer duration therapy (5-7 days) have a higher cure rate in heavily infected (more than 1000 eggs/g) patients.
Keywords Colonoscopy,Trichuris dysentery syndrome, Trichuris trichiura, Whipworms
314
Comparison of endoscopic ultrasound guided fine needle aspiration cytology and endoscopic ultrasound guided needle core biopsy in the diagnosis of abdominal Masses
Mohd Rafiq Najar , Monika Jain, Gurwant Singh Lamba, Aeshal Parmar
Correspondence – Mohd Rafiq Najar - [email protected]
Department of Gastroenterology, Sri Balaji Action Medical Institute, Paschim Vihar, New Delhi 110 063, India
Introduction The management of patients with solid abdominal masses is dependent on obtaining an accurate tissue diagnosis. Endoscopic ultrasound (EUS) guided FNAC and EUS-FNB are safe and preferred method for tissue acquisition from solid gastrointestinal and extraintestinal lesions. This technique enables precise visualization of the lesion and tissue acquisition.
Aim To compare the diagnostic accuracy of EUS-FNB and EUS-FNAC in the diagnosis of solid abdominal masses.
Methods This prospective observational study was conducted in 58 patients who underwent EUS-FNB and EUS-FNAC for diagnosis of solid abdominal masses on cross-sectional imaging. Needle size of 22 gauge were used for sample collection. Technical success and number of needle passes for tissue acquisition were noted for both the techniques. Histopathology and FNAC reports were followed.
Results Number of passes required for the tissue acquisition were less in EUS-FNB compared to EUS-FNAC, but the difference was not statistically significant. Diagnostic accuracy was higher in EUS-FNB (57/58, 98.30%) as compared to EUS- FNAC (54/58, 93.10%) but the difference was not significant statistically. The sensitivity of EUS-FNB was higher (52/53, 98.1%) compared to the sensitivity of EUS-FNAC (49/43, 92.4%) which was statistically significant (p value 0.04). Negative predictive value of EUS-FNB (5/6, 83.2%) was higher than the negative predictive value of EUS-FNAC (5/9, 55.5%) which was statistically significant (p value < 0.0001). Positive predictive value, specificity, technical success for tissue acquisition and complication rate were statistically comparable for both the methods of tissue acquisition.
Conclusion The EUS-FNAC and EUS-FNB are effective methods of tissue acquisition. EUS-FNB has better sensitivity and negative predictive value than EUS-FNAC. Diagnostic accuracy of EUS-FNB was higher compared to EUS-FNAC but not of statistical significance.
Keywords EUS, EUS-FNAC, EUS-FNB and abdominal masses.
315
The unexpected and unique balloon stuck complication during endoscopic retrograde cholangiopancreatography in a patient with choledocholithiasis
Bilal Mir , Brij Sharma, Rajesh Sharma, Vishal Bodh, Ashish Chauhan, Tahir Majeed, Rajesh Kumar
Correspondence – Bilal Mir - [email protected]
Department of Gastroenterology, Indira Gandhi Medical College, Ridge Sanjauli Road, Lakkar Bazar, Shimla 171 001, India
Background Common bile duct (CBD) clearance for choledocholithiasis using balloon catheter is well established approach during endoscopic retrograde cholangiopancreatography (ERCP). The most common and well known ERCP related complications include pancreatitis, bleeding, perforation, and infection. We reported a unique complication of stuck balloon in CBD and is probably first ever case recorded in literature. Case presentation: A middle aged female underwent ERCP for symptomatic choledocholithiasis. During procedure, CBD balloon (biliary extraction balloon, Boston scientific) got stuck-in while doing balloon sweep and neither came out nor got deflate despite different and exhaustive manoeuvring. Given the uniqueness of complication and failure of endoscopic approach, we cut the balloon catheter distal to inflation and wire entry port and removed the duodenoscope leaving behind the stuck balloon with remaining catheter. Patient was taken up by surgery team and managed with open cholecystectomy with choledochotomy with T tube-drainage along with removal of stuck CBD balloon. While the stuck stone near proximal summit of balloon explains the failure of balloon coming out and complete extrinsic compression of air passage of catheter by surrounding stones probably explains the failure of balloon inflation-deflation process.
Conclusion It seems pertinent to provide patients prior information about unique complications such as balloon stuck and balloon burst in addition to well-known complications and we should have back-up to deal with such cases. Hereby we reported a unique case of ERCP related complication and its subsequent surgical management.
Keywords Balloon catheter, Choledocholithiasis, Endoscopic Retrograde Cholangiopancreatography
316
Plastic stents versus metal stents for endoscopic ultrasound-guided transmural drainage of walled-off necrosis with significant solid debris: A randomized controlled non-inferiority trial
Rinkalben Kakadiya , Gaurav Muktesh * , Jayanta Samanta, Jimil Shah, Harshal Mandavdhare, Pankaj Gupta, Vikas Gupta, Thakur Dindayal Yadav, Rakesh Kochhar
Correspondence – Gaurav Muktesh - [email protected]
Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012, India, and *Department of Gastroenterology, Al Zahra Hospital, Gastroenterology, Dubai, United Arab Emirates
Background Recently large-calibre metal stents are increasingly being used, assuming higher efficacy compared to the plastic stent. However, the better efficacy of metal stents is not proven by existing studies. Treatment success was not the primary outcome of the previous randomized controlled trial (RCT), which is the major endpoint. Hence, we conducted non-inferiority RCT (plastic stents are not inferior to metal stents).
Methods This single-centre, open-label, RCT enrolled 48 patients with symptomatic WON (>20% solid debris). The primary outcome was treatment success (symptom plus radiological resolution) of WON. Secondary outcomes were technical success rate, number of procedures required, adverse event, procedure duration, and treatment failure. We assessed all outcomes three weeks after drainage with cross sectional imaging. Patients were followed up for three months to determine recurrence.
Results Twenty-four patients were randomized in each arm. The treatment success was achieved in 21(p1=87.5%) and 20 (p2=83.3%) patients in metal stent and plastic stent groups, respectively, with P1/p2 being 1.05 (95% confidence interval [CI] is 0.81 to 1.39). Assuming a 10% noninferiority margin using the Gart Nam score method, the p-value was <0.001 for non-inferiority. As noninferiority p-value was below the threshold, we conclude that plastic stent is non-inferior to the metal stent. The secondary outcomes were comparable in both groups (Table). DPDS was present in 41/48 (87.5%) patients. One asymptomatic recurrence was seen in metal stent.Variable Metal stent (n=24) Plastic stent (n=24) P-value
Volume of WON (mL)
Median, IQR (Range)
411,710 (125-2148) 370, 328 (73-1230) 0.174
Solid debris (%) 32.083 ±11.1 28.542 ±8.9 0.230
Technical success 100% 100% 1.000
Numbers of procedure 2.8±1 2.2±1 0.097
Procedure duration 12.95±5.3 29.77±6.6 0.001
Bleeding 1,4.1% 1,4.1% 1.000
Stent Migration 0 1,4.1% 1.000
Failure 1,4.1% 1,4.1% 1.000
Conclusion Plastic stents are not inferior to metal stent in terms of treatment success in transmural drainage of WON. However, a large study is needed to make definite conclusions.
Keywords Metal stents, Plastic stents, Walled off necrosis
317
Clinical profile and outcome of iatrogenic colonic perforations at a tertiary care centre in south India
Noble Mathews , Sudipta Dhar Chowdhury, Vijay Balaji, Anoop John, Ajith Thomas, Rajeeb Jaleel. Amit Dutta, Ebby Simon
Correspondence – Sudipta Dhar Chowdhury - [email protected]
Department of Gastroenterology, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Introduction Iatrogenic colonic perforations are a serious complication of colonoscopy. Although rare, identifying risk factors and optimizing treatment may reduce the occurrence of perforations and their severe complications. This study aimed to determine the frequency of iatrogenic colonic perforations and their management.
Methods A retrospective review of hospital electronic medical records of patients with iatrogenic colonic perforations following colonoscopy between April 2012 to April 2022. The demographic data, procedural information, site of perforation, and outcome were recorded.
Results A total of 42,825 endoscopic colonic procedures were performed. Sixteen colonic perforations occurred (0.037%). The most common site of perforation was at the rectosigmoid. Thirteen patients underwent laparotomy of which, the site of perforation was not localized in three patients and managed with peritoneal washout. Seven patients underwent laparotomy and primary closure, while 3 had a diversion procedure and secondary closure. Of the 3 patients managed non-surgically, one underwent needle decompression while the other 2 were handled with supportive care. Three deaths occurred among the colonic perforations, all three had a severe systemic illness and could not be salvaged following the perforation.
Conclusion Iatrogenic perforations are a rare but serious complication following colonoscopy. Early detection and management have good outcomes in otherwise well patients. Careful selection of patients for colonoscopy and preferably avoiding a full colonoscopy in patients with severe systemic illness may help reduce mortality associated with this routinely performed procedure.
Keywords Colonoscopy, Perforation
318
Rotational thrombo-elastometry reduces fresh frozen plasma transfusion in patients without liver disease undergoing therapeutic endoscopic procedures with deranged screening coagulation tests
Pegatraju Bharadwaj 1 , Ebby George Simon1, Tulasi Geevar2, Rutvi Dave2, Sukesh Chandran Nair2, Aby Abraham3, Joseph A J1, Amit Kumar Dutta1, Sudipta Dhar Chaudhury1, Rajeeb Jaleel1, Anoop John1, Ajith Thomas1
Correspondence – Pegatraju Bharadwaj - [email protected]
Departments of 1Gastroenterology, 2Transfusion Medicine, and 3Hematology, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Introduction Rotational thrombo-elastometry (ROTEM) is a viscoelastic test used in patients with liver disease for guiding blood component use. We aimed to compare the amount of blood products transfused, bleeding and survival rates in patients with and without hypocoagulable ROTEM who underwent therapeutic endoscopic procedures with deranged standard coagulation tests (prothrombin time, PT; activated partial thromboplastin time, aPTT; and platelet count) without liver disease.
Methods Clinical details of patients with deranged parameters without liver disease and who underwent therapeutic endoscopic interventions between 1st January 2020 and 31st May 2022 were retrospectively analyzed. Baseline parameters, amount of blood products transfused and outcomes like 30-day bleeding and survival rates were compared between those with and without hypocoagulable ROTEM.
Results Of the 204 patients with deranged parameters, 180 patients with liver disease were excluded. Six patients (M: F=5:1; median age: 37 years) had hypocoagulable ROTEM and 18 patients (M:F=11:7; median age:56 years) were without hypocoagulable ROTEM. Both groups were comparable in baseline characteristics except platelets (p=0.04) and aPTT levels (p=0.04). There was significant difference in total amount of fresh frozen plasma (FFP) infused and FFP infused per patient between the groups (9000 mL vs. 4500 mL; p=0.001 and 1875 mL vs. 875 mL; p=0.04). Two patients with hypocoagulable ROTEM rebled within 30 days and none in another group (p=0.05). One patient in hypocoagulable group died and none in another group (p=0.25).
Conclusions Use of ROTEM reduces FFP use in those patients without liver disease who underwent therapeutic endoscopic procedures with deranged screening coagulation tests without any increased risks of 30-day re-bleeding risk and mortality.
Keywords Fresh frozen plasma, Rotational thromboelastometry, Therapeutic endoscopic procedures
319
Can a skin disorder cause sudden onset dysphagia and melena?
Arshiya Siddiqua , Raghu D K, Sarath Chanra G, K Soma Sekhar Rao, Naveen Polavarapu
Correspondence – Arshiya Siddiqua - [email protected]
Department of Medical Gastroenterology, Apollo Hospitals, Road Number 72, Film Nagar, Hyderabad 500 033, India
Introduction Bullous pemphigoid (BP) is an autoimmune illness that primarily affects the elderly and the middle-aged. It manifests with varying degrees of mucosal involvement. However, gastrointestinal mucosal involvement is rare.
Case Report We report a 75-year-old female, recently diagnosed with BP and on treatment with steroids, presented to the hospital with a history of acute onset dysphagia and melena. After initial stabilization, endoscopy was performed, which showed hemorrhagic bullae throughout the esophagus. No other cause of bleed or dysphagia was identified. She was put on a high-dose steroid regimen along with proton pump inhibitors, as well as azathioprine. Monitored regularly, and her symptoms subsided. Steroids tapered and stopped with no recurrence of similar symptoms.
Conclusion Although GI mucosal involvement is rare in BP, it should be considered a differential of GI bleeding in patients affected by this disease. Esophageal involvement in BP usually manifests as hemorrhagic bullae involving the mucosa, which can cause esophageal luminal narrowing and dysphagia symptoms, and when ruptured manifests as GI bleed. Definitive management is with high doses of steroids along with immuno-suppression.
Keywords Bullous pemphigoid, Dysphagia, Esophageal involvement, Melena
320
Clinical spectrum of magnet ingestion in children: Experience from a single center in south India
Jayalakshmi K , Anupama Nagar, Amit G Yelsangikar, Kayal Vizhi, Raghu B M, Naresh Bhat
Correspondence – Jayalakshmi K - [email protected]
Department of Medical Gastroenterology, Aster CMI Hospital, No. 43/2, New Airport Road, NH.7, Hebbal, Sahakara Nagar, Bengaluru 560 092, India
Introduction Majority of magnet ingestions occur in children. They are accidental/unintentional. High powered magnets with neodymium are used in toys because of impressive strength (5-10 times stronger than traditional magnets). When ingested as multiple or along with a metal, they attract each other across the wall of the GI tract causing high rate of complications (75%) such as ischemia, perforation, fistula formation, obstruction, peritonitis, or death.
Methods We report 4 children (up to 18 years of age) with magnet ingestion presenting to our emergency/outpatient department from June 2020 to October 2021 and their clinical presentation including complications, management, and outcomes.
Results Four children (3 years-7 years) with accidental history of ingestion of magnets were included in the study. The clinical features were vomiting in 2 (50%), pain abdomen in 2 (50%), constipation in 1 (25%), asymptomatic in 2 (50%). The number of magnets ingested were one in 1, three in 2, ten in 1 child. Child with single magnet ingestion was managed conservatively. 2 of 4 (50%) children underwent successful endoscopic removal. One child with a bead of three magnets in the jejunum was removed using single balloon enteroscope. Child with multiple (10) magnet balls required intraop endoscopy and removal of magnets from the stomach. Two children had complications - cecal perforation in one, jejunal perforation and colonic mesenteric defect and peritonitis in the other. They were managed surgically and did well post-operatively.
Conclusion Intervention is a must when more than one or single magnet with metallic objects are ingested. Aggressive and early removal to reduce potential morbidity and mortality. The observation period and the decision for removal should not exceed 6 hours
Keywords Endoscopy, Magnets, Perforation
321
Predictors of variceal rebleeding after endoscopic variceal ligation
Kamuni Abhishek
Correspondence – Kamuni Abhishek - [email protected]
Department of Medical Gastroenterology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad 500 082, India
Background/Aims Variceal rebleeding is a life-threatening complication in patients with cirrhosis and portal hypertension and occurs within first few weeks. Mortality associated with each bleeding episode ranges from 30% to 50%. Present aim of the study is to identify the factors associated with early rebleeding after band ligation.
Methods A total of 100 patients with variceal bleeding confirmed on endoscopy were included in this study. The patients were divided into rebleeding and non-rebleeding groups. Complete history, physical examination, laboratory investigations and abdominal ultrasound (US) were performed for all patients.
Results Incidence of rebleeding within 4 weeks was around 10%. Factors significantly associated with rebleed were Child-Pugh class C, MELD-Na >24, presence of PVT and HRS.
Conclusion Predicting factors of early rebleeding after EVL will help endoscopist to plan further sessions and to pursue further lines of management such as TIPS.
Keywords Band ligation, Rebleeding
322
Underwater endoscopic mucosal resection for large sessile colorectal polyps- A tertiary care oncology center experience
Aadish Jain , Sridhar Sundaram, Prachi Patil, Shaesta Mehta
Correspondence – Sridhar Sundaram - [email protected]
Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), 1202 B Wing, Pariwar Saflya, Sewri, Mumbai 400 015, India
Background Underwater-endoscopic mucosal resection (uEMR) is a novel method for resection of sessile colorectal lesion without submucosal injection. The aim of our study was assessment of efficacy and safety of uEMR for resection of large (>10 mm) sessile colorectal lesions.
Methods Retrospective review of prospectively maintained endoscopy database was done for patients who underwent underwater endoscopic mucosal resection for colorectal polyps >10 mm, between January 2021 to July 2022. Size, location, number, morphologic appearance of the polyp were recorded. The polyp was completely inundated in water and resection was done using snare. Ablation of resection margin using snare-tip and clip application for defect closure was done as per endoscopist’s discretion. Study outcomes were complete resection (primary outcome), en-bloc resection, recurrence (on scar biopsy at 3 and 6 months), and adverse events.
Results Over 18 months, 33 patients underwent underwater EMR of whom 25 patients (mean age 53+12.1 years) were eligible for inclusion. uEMR was done for 27 lesions (mean size 21.3+8.5 mm, range 10–45 mm). Most common location was the left colon (15 [55.5%] lesions). The most common morphology was Paris type 0-Is in 18 (66.6 %) lesions, Paris IIa in 7 (25.9 %) lesions and Is+IIa in 2 (7.4%) lesions. All lesions were completely removed (100 %) by uEMR. En-bloc resection of the lesion could be done in 23 lesions (85.1%) and piecemeal in 4 (14.8%). Low grade dysplasia was seen in 16 lesions on histopathology (59.2%). Grade II deep mural injury was seen in 2 patients (7.4 %) and mild bleeding was seen in one patient (3.7%). All managed by applying haemostatic clips. Evidence of recurrence was not seen in 10 patients on follow-up.
Conclusion Underwater EMR is a safe and effective technique for resecting large sessile colorectal lesions.
Keywords Endoscopic resection, Sessile colorectal lesion, underwater EMR
323
Yoga for bowel preparation: A novel study
Manas Kumar Panigrahi , Harsh Prakash Jain, Mohd Imran Chouhan, Rajesh Manik, Ajaya Ghosh R U, Shivam Sethi, Madhav Sameer Makashir, Hemanta Kumar Nayak, Subash Chandra Samal, Mansi Chaudhary, Biswa Mohan Padhy
Correspondence – Manas Kumar Panigrahi - [email protected]
Department of Gastroenterology, All India Institute of Medical Sciences, Sijua, Patrapada, Bhubaneswar 751 019, India
Introduction Diagnostic accuracy of colonoscopy depends on the quality of bowel preparation. Despite being the most used method of bowel cleaning, polyethylene glycol (PEG) electrolyte solution is far from being the ideal agent. Shankhaprakshalana is a yogic method to cleanse the bowel. It involves the use of warm saline water and a combination of five asanas. This study was designed to assess the quality of bowel preparation by Shankhaprakshalana.
Methods A prospective observational study was conducted in the Department of Gastroenterology, All India Institute of Medical Sciences, Bhubaneswar. Patients planned for colonoscopy were screened and enrolled to undergo bowel preparation by Shakhaprakshalan (SP) on the day of colonoscopy. A low fiber diet (<10 g/day) for one day before colonoscopy. SP was done under supervision of a yoga trainer. In each cycle patients were advised to drink 400 ml of lukewarm saline water followed by five asanas (exercises) of SP (Tadasana, Tiryaka tadasana, Katichakrasana, Tiryaka bhujangasana and Udarakarshanasana), each done eight times. After completing six such cycles patients underwent colonoscopy. Boston bowel preparation score (BBPS) was used to assess the quality of bowel preparation.
Results A total of 109 patients were included. Mean age was 38 years (range 15 - 70) with a higher proportion of men (male-86, female-23). Mean BBPS was 7.87 (SD±1.24). BBPS was <6 in only two patients. Mean segmental BBPS for the 3 segments of colon (right, transverse and left) was 2.59 (SD±0.49), 2.68 (SD±0.52), 2.57 (SD±0.70), respectively. Segmental BBPS was <2 (inadequate) in 5 patients (4.5%). Adverse events in the form of nausea (n=2, 1.8%), vomiting (n=1,0.9%), abdominal pain (n=2,1.8%) and dizziness (n=1, 0.9%) were seen in a few patients.
Conclusion Findings from this study have given encouraging results on use of Shankhaprakshalana with adequate bowel preparation achieved in >95% patients with low incidence of adverse events.
Keywords Boston bowel preparation scale (BBPS), Bowel preparation, Colonoscopy, Yoga
324
Diagnostic yield and technical performance of novel motorized spiral enteroscopy compared to single-balloon enteroscopy in suspected Crohn's disease: Interim analysis of a randomized controlled study (The MOTOR-CD trial)
Partha Pal, Piyush Viswakarma, Mohan Ramchandani, Aniruddha Singh, Palle Manohar Reddy, Hardik Rughwani, Rupa Banerjee, Rajendra Patel, Anuradha Sekaran, Swathi Kanaganti, Polina Vijayalaxmi, Santosh Darisetty, Jagdeesh Rampal Singh, Pradeep Rebala, Guduru Venkat Rao, D Nageshwar Reddy, Manu Tandon
Correspondence – Partha Pal - [email protected]
Department of Gastroenterology, Asian Institute of Gastroenterology, 6-3-662, Somajiguda, Hyderabad 500 082, India
Introduction Both single balloon enteroscopy (SBE) and novel motorized spiral enteroscopy (NMSE) are effective techniques for device assisted enteroscopy (DAE). To date, no study has compared both modalities in suspected Crohn’s disease (CD) in a randomized controlled manner.
Methods Patients with suspected CD requiring DAE between May 2022 to August 2022 in a high volume tertiary center were prospectively randomized into NMSe or SBE group which were compared with regard to diagnostic yield, depth of maximal insertion (DMI), procedure time and total enteroscopy rates.
Results In this interim analysis, 77 (total target 124) suspected CD patients (25.6% female,18-73 years) underwent DAE (9-bidirectional). The diagnostic yield was 94.2% with SBE and 100% with NMSE (p=0.2). DMI was higher with antegrade NMSE (DMI [cm]: median [range]: NMSE: 500 [80-600], SBE: 150 [50-350], p<0.0001). Procedure time was not significantly different between NMSE and SBE [duration (min): median (range): NMSE: 50 (7-180), SBE: 35 (10-170), p<0.0001; retrograde: NMSE: 25 (20-60), SBE: 60 (20-180), p<0.088). To adjust for variable location of lesions, depth to time ratio was compared between NMSE and SBE which was significantly higher with NMSE (median [range], NMSE: 9.2 [2 - 27.5]; SBE: 4.1 [1-13.6], p<0.0001). Total enteroscopy rate was higher with NMSE (42.8% vs. 0% with SBE, p<0.0001). All adverse events were mild.
Conclusions Both NMSE and SBE are safe and effective for small bowel evaluation in suspected CD. NMSE scores over SBE with regards to deeper small bowel evaluation with complete small bowel coverage and shorter procedure time (NCT05363930).
Keywords Crohn’s disease, Device-assisted enteroscopy, Novel motorized spiral enteroscopy, Single-balloon enteroscopy, total enteroscopy
325
Endoscopic retrograde cholangiopancreatography related perforations:10-year experience from a tertiary care centre in south India
Ajith C Kuriak Ose, Sudipta Dhar Chaudhary
Correspondence – Sudipta Dhar Chaudhary - [email protected]
Department of Gastroenterology, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Introduction Perforation is one of the most dreaded complications of endoscopic retrograde cholangiopancreatography (ERCP). Since it is uncommon, there has been little study of incidence and outcomes of management. We aimed to study the incidence, characteristics, and outcomes of ERCP-related perforations over a 10-year period at our centre.
Methods We retrospectively analyzed prospectively collected data of patients who underwent ERCP from April 2012-June 2022. The demographic profile, indication, time of diagnosis of perforation, clinical and radiological presentation were assessed. The management, complications, length of hospital stay, and patient outcomes were also recorded.
Results A total of 6552 ERCPs were performed during the study period. Twenty-seven perforations were identified yielding a cumulative incidence of 0.41%. Majority of the procedures were done by trainee endoscopists. The mean age of patients was 53.2 years and majority (63%) were females. Most common indication was choledocholithiasis (66.7%) and others were malignant extrahepatic biliary obstruction (18.5%), biliary stricture (11.1%). Precut papillotomy was done in 7 (25%) patients. Majority of perforations were identified intraprocedure (59%). Commonest type was Stapfer type II (12,44%) followed by type I (10, 37%), type IV (3, 11%) and type III (2, 7%). Majority of patients (14, 51.8%) were managed conservatively. Seven (25.9%) were managed surgically, 4 (14.8%) endoscopically and 2 (7%) underwent percutaneous drainage. Mean hospital stay was 11.2 days (range 5–43 days). Majority (24, 88%) of the patients improved and were discharged. Three (11%) patients were sent discharge against medical advise (DAMA). There were no deaths recorded.
Conclusion We report a low incidence (0.41%) of ERCP related perforations. Majority of the patients had a good outcome with conservative management alone. Early recognition of perforation during the procedure, can help to institute appropriate therapy.
Keywords ERCP related perforations, Post ERCP complication, Stapfer classification
Motility Disorders
326
Comparison of Indian cut offs with Chicago classification v4.0-Is it really needed?
Mayank Jain
Correspondence – Mayank Jain - [email protected]
Department of Gastroenterology, Arihant Hospital and Research Centre, 297 Indrapuri, Near Bhanwarkuan, Indore 452 017, India
Background Chicago classification v 4.0 (CCv4.0) has used a database of 469 healthy volunteers (55% women, median age of 28 years, age range of 18-79 years) across 4 continents using the 3 available commercial high-resolution manometry (HREM) systems. Recent Indian data has suggested that normative data for water perfusion manometry system in Indians is different from the West.
Aim of the study To determine the change in manometry diagnosis in patients with esophageal motility disorders using CC v4.0 and Indian cut offs.
Methods This retrospective study included all patients referred for HREM study to our centre between 2019 and 2021. The analysis was done using Indian cut offs and CCv4.0 for all cases. Correlation between the two sets of final reports for concordance was done. A p value of <0.05 was considered significant.
Results A total of 105 cases were recruited. There was 100% concordance between reports using both reporting systems for normal motility and disorders of esophagogastric junction (Table 1). Ten cases (30.3%) labelled as ineffective esophageal motility were classified as normal as per Indian cut-offs. There was excellent correlation between the two reporting systems.
Conclusion CCv4.0 reporting is adequate for Indian patients with normal motility and disorders of esophagogastric junction. One third of patients with ineffective motility are classified as normal as per Indian cut offs.
Keywords Chicago, Esophageal, Indian, Motility
327
Misnomer rectal motility disorder: High volume center case series of solitary rectal ulcer syndrome
Jasmeet Singh Dhingra, Nirmaljit Singh Malhi, Rajiv Grover, Achal Garg
Correspondence – Jasmeet Singh Dhingra - [email protected]
Department of Gastroenterology, Advanced Gastroenterology Institute-The Gastrociti, Ludhiana Road Vth Floor Orison Hospital, Barewal Road, Ludhiana 141 008, India
Introduction Solitary rectal ulcer syndrome (SRUS) is an outcome of defecatory disorder with multiple presentations. This retrospective study from a high-volume center aims to identify the clinical presentation, risk factors, colonoscopic findings, pathological features and therapeutic interventions in patients presenting with SRUS.
Methods This is a retrospective study of all patients diagnosed with SRUS at Advanced Gastroenterology Institute: AGI The GASTROCITI in Ludhiana for a 30 month period from February 2020 to July 2022. Cases were identified using the Department of Endoscopy database. Data were obtained from medical records that included clinical manifestation, endoscopic findings, and histopathological features.
Results Out of total diagnostic colonoscopic procedures (Approx. 4800), 30 patients were identified. The mean age was 52.5 years (±18.5) and 70% (21) were males. 80% (24) patients had bleeding per rectum, 70% (21) had constipation and 50% (15) had straining with a mean symptom duration of 16.7 months. The most common associated factors identified were constipation (70%), digital rectal manipulation (40%), history of high-pressure water jet use to clean after defecation in 20 %, history of rectal surgery (10%), and rectal prolapse (10%). Endoscopic findings included a large single ulcer (50%) and multiple ulcers (30%); 40% had a polypoidal appearance. One patient had a proliferative mass like appearance with rectal stricture. Endoscopic finding of difficulty to obtain a good biopsy specimen had a high PPV of >90% to diagnose SRUS. On histopathology, there was surface ulceration (90%), fibrosis of the lamina propria (70%), distorted architecture (60%), and muscle hypertrophy with increased mucin production (50%). Patients were treated conservatively, and none required surgery.
Conclusion SRUS is a rare disorder with multiple presentations. High dose laxatives, counselling against digital evacuation and waterjet use, high fiber diet in addition to topical mesalamine/ sucralfate, and biofeedback are useful in treatment.
Keywords Rectal dysmotility, Rectal ulcer, SRUS
328
Efficacy of biofeedback therapy on management of functional defecatory disorder
Stephan Benny
Correspondence - Stephan Benny - [email protected]
Department of Gastroenterology, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Introduction Management of functional defecatory disorder is very challenging. We are aiming to find out the efficacy of biofeedback therapy in management of functional defecation disorder.
Method This is an interim analysis of an observational study. Adult patients who are diagnosed with functional defecation disorder by ROME IV criteria were recruited for the study. The demographic, clinical and laboratory data were documented in predesigned forms. They underwent standard biofeedback therapy of 3 sessions. Symptom severity before biofeedback therapy and after 3 months of biofeedback therapy were documented using a standard questionnaire (PAC-SYM questionnaire).
Results There were 31 patients included in the study. Twenty-four out of 31 patients were males (80.6%). The median age of the patients were 48 years with range of 16 years to 59 years. The mean duration of disease was 8.8±7.1 years. Twenty-nine out of 31 patients had type 1 anorectal dyssynergia (93.5%). Only 2 patients had type 3 anorectal dyssyneria (6.5%) and none of the patients had type 2 or type 4 anorectal dyssynergia. Among patients with type 1 anorectal dyssynergia, 16 out of 29 patients (66.8%) showed improvement after biofeedback therapy, where among the two patients with type 3 anorectal dyssynergia, only one patient showed improvement after biofeedback therapy (50%). The mean score in PAC SYM questionnaire before and after biofeedback therapy were 16.3±4.7 and 11.4±5.56 respectively which was statistically significant (p<0.05). Seventeen out of 31 patients (54.8%) had symptomatic improvement at 3 months after biofeedback therapy.
Conclusion Result from the interim analysis suggests that there is significant improvement in anorectal dyssynergia at three months with biofeedback therapy.
Keywords Anorectal dyssynergia, Biofeedback therapy, Functional defecatory disorder,
329
An observational study of esophageal manometry in patients of gastroesophageal reflux disease
Dinesh Kumar , Anil Khatri, Rajiv Baijal, Nripen Saikia
Correspondence - Dinesh Kumar - [email protected]
Department of Gastroenterology, Pushpawati Singhania Hospital and Research Institute, Press Enclave Marg, Sheikh Sarai, Phase-II, New Delhi 110 017, India
Introduction Abnormal esophageal motility and low lower esophageal pressure (LES) play an integral role among various etiologies implicated in pathogenesis and severity of gastroesophageal reflux disease (GERD). EGJ-CI in segregating GERD populations, with general agreement that this metric identifies a subset of patients with severe barrier dysfunction prone to either endoscopic oesophagitis or unequivocally abnormal reflux testing. In view of this, the Lyon Consensus concluded that the esophagogastric junction contractility integral (EGJ-CI) is a promising metric but needs further research before widespread adoption.: An observational study done in a tertiary medical care center in New Delhi from December 2019 to November 2020.
Methods An observational study was carried out among patients presenting with symptoms of GERD (heart burn and regurgitation), at least twice per week for past three months. Based on their endoscopy findings patients with GERD are grouped into two having erosive and nonerosive reflux disease. High resolution manometry was performed. Statistical methods. Chi-square test was used to analyze categorical variables and independent ’t’ test was used for continuous variables. (ROC) was used to find out cut off of EGJ-CI for predicting erosive esophasitis and. sensitivity, specificity, positive predictive value and negative predictive value of EGJ-CI for predicting erosive esophasitis.
Results Out of 76 Individuals, 56.58% individuals were male and age of patients ranged from 20 to 80 years. On esophagogastroduodenoscopy (EGD) out of 76 individuals, 60.53% had erosive esophasitis (erosive reflux disease) and 39.47% had non erosive reflux disease (normal appearing esophagus). Among 76 individuals, 31.58% shows ineffective esophageal motility and 10.53% individuals showed reduced basal lower esophageal sphincter (LES) pressure. out of 46 individuals with erosive reflux disease, 13.04% shows low basal LES pressure and ineffective esophageal motility (IEM) in 32.6%. The association of EGJ-CI with endoscopic results had low mean value for erosive reflux disease in comparison to non-erosive reflux disease; the association was not statistically significant.
Conclusions Ineffective esophageal motility, low LES pressure, low EGJ-CI and hiatus hernia were associated with GERD, but do not predict the disease with sufficient accuracy. No significant association was observed for IEM or low LES pressure to predict endoscopic esophagitis. EGJ-CI showed low sensitivity and low diagnostic accuracy with high specificity and high Positive Predictive Value (PPV) for predicting endoscopic esophagitis.
Keywords Endoscopy, Ineffective esophageal motility, Manometry
330
Epidemiology, predictors and agreement between various irritable bowel syndrome criteria among medical students in a Government Medical College in South India
Manoj Yadav, Akhil N V, Srijaya Sreesh, Ann Mary George, Minu Sajeev Kumar, Aditya Verma, Jacob Raja, Shivabrata Dhal Mohapatra, Krishnadas Devadas
Correspondence – Srijaya Sreesh - [email protected]
Department of Medical Gastroenterology, Government Medical College, Ulloor-Akkulam Road, Chalakkuzhi, Thiruvananthapuram 695 011, India
Background Irritable bowel syndrome (IBS) is found to be the most common functional gastrointestinal disorder. The prevalence of IBS among various Asian countries (ROME III) is 5% to 10%. There have been no previous studies on the epidemiology of IBS using ROME IV criteria among medical students.
Aims (1) To determine the prevalence and predictors (sociodemographic and lifestyle risk factors) of IBS by ROME IV, ROME III and Asian criteria among medical students. (2) The degree of agreement between Rome IV, ROME III, and Asian criteria.
Methods It was a cross-sectional questionnaire-based study performed on 552 medical students (138 students per batch x 4 batches) who consented for the study. Filled up questionnaires were collected, and appropriate statistical analysis was applied.
Results IBS prevalence using ROME IV, ROME III, and Asian criteria were 5.8%, 19%, 30.4% respectively. Among IBS subtypes, mixed type was the predominant one. The prevalence increases with increasing age and higher medical batch. IBS was found to have an association with lack of physical activity, high body mass index (BMI), lack of sleep, coffee, analgesic use, antibiotic intake, Caesarian birth etc. Cohen's kappa coefficient (κ) was highest (0.699) between Rome III and Asian criteria.
Conclusion The low prevalence of IBS based on Rome IV criteria was due to its stringent nature. This study demonstrated that lifestyle factors are significantly associated with IBS among medical students in a Medical College in South India. In view of its high prevalence, medical students need to be aware of IBS and stress management should be incorporated into the lifestyle.
Keywords Epidemiology, Irritable bowel syndrome, Medical. Students
331
Diagnostic yield of high-resolution esophageal manometry and its correlation with clinical presentation and impacts on management
Vikas Pemmada, Balaji Musunuri, Shiran Shetty, Ganesh Pai, Ganesh Bhat
Correspondence – Balaji Musunuri - [email protected]
Department of Gastroenterology, Kasturba Hospital Manipal, MAHE, Tiger Circle Road, Madhav Nagar, Manipal 576 104, India
Introduction High-resolution esophageal manometry (HREM) is an important test in evaluation of esophageal motility disorder. We analyzed HREM data and its correlation with symptoms and impact on management.
Methods In a single center retrospective observational study, all the patients who underwent HREM from 2017 to May 2022 were included. HREM was performed using 16 channel water perfusion system and classified according to Chicago classification v3.0. Patients were divided into Group A (with dysphagia) and Group B (without dysphagia). Groups were compared for spectrum of manometric findings.
Results Total of 422 patients (271 patients in Group A and 151 in Group B) were included, with a mean age of 43±15 years and male to female ratio was 1.63. Group B had patients with reflux symptoms (136, 32.2%) and chest pain (15, 3.55%). IRP was higher among Group A compared to Group B (19.62±7.92, 8.92±13.63, <0.001). Most common type of esophagogastric junction (EGJ) morphology was type I (A:71.6%, B:43.3%) followed by type II (A:23.5%, B:37.7%) among both the groups. Mean EGJ CI was higher among Group A compared to Group B (67.02±42.34, 46.12±29.34, <0.001). EGJ outflow obstruction was seen in 153 (56.45%) and 14 (9.27%) patients, while major peristaltic disorders were seen in 37 (13.65%) and 5 (3.31%) among Group A and B respectively. In Group A, achalasia cardia was the most common diagnosis (51.2%), followed by DES (7.3%), IEM (7%) and esophagogastric junction outflow obstruction (EGJOO) (14, 5.1%). Among group B, most of the patients (104, 68.8%) had normal study. The most common abnormality being IEM in 26 (17.2%) and EGJOO in 7(4.6%). Achalasia was seen in 7(4.6%) patients among group B.
Conclusion Achalasia cardia is the commonest finding in patient with dysphagia. Diagnostic yield of HREM in patient without dysphagia is very low and should be used only in selected patients.
Keywords Achalasia, Diagnostic yield, Dysphagia, HREM
332
Disorders of gut-brain interaction following Coronavirus disease-19: A systematic review and meta-analysis
Akash Mathur , Shikha Sahu, Uday C Ghoshal
Correspondence – Uday C Ghoshal - [email protected]
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raibareli Road, Lucknow 226 014, India
Background Persistent gastrointestinal (GI) symptoms and disorders of gut-brain interaction (DGBIs) are increasingly being recognised after Coronavirus disease-19 (COVID-19). While some studies report GI symptoms and DGBIs after COVID-19, their prevalence is highly variable.
Methods A comprehensive literature search was performed for studies reporting GI symptoms and DGBIs after COVID-19. After applying prospectively decided exclusion criteria, the eligible papers were examined using a meta-analysis approach for the prevalence of GI symptoms and irritable bowel syndrome (IBS) after COVID-19. The relative risk of development of IBS using Rome IV criteria among subjects with COVID-19 compared to healthy controls was calculated.
Results Of the available studies, 13 (5 case-control) reporting persistent GI symptoms after COVID-19 met the inclusion criteria. Among 112,674 subjects, 19.85% had persistent GI symptoms after COVID-19. Of the four studies reporting IBS using Rome IV criteria (2 case-control), patients with COVID-19 were 3.33 (95% confidence interval [CI] 0.226 to 49.061) times more likely to have post-COVID IBS as compared to healthy controls.
Conclusions A significant proportion of patients develop long-term GI consequences following COVID-19. Patients with COVID-19 are more likely to develop post-COVID IBS than healthy controls.
333
Study of subtypes of constipation and its correlation with clinical features
Ajay Jain, Sudhanshu Yadav, Shohini Sircar, Suchita Jain
Correspondence – Ajay Jain - [email protected]
Department of Gastroenterology, Choithram Hospital and Research Centre. 14, Manik Bagh Road, Indore 452 014, India
Background Chronic constipation is prevalent, with a prevalence of 12% to 17% in India. Identifying the subtypes of chronic constipation and treating them accordingly is essential to improve the patient's quality of life and decrease the economic burden.
Aims To study chronic constipation subtypes and assess their clinical characteristics in central India.
Methods This was a prospective and observational study. All patients of 18 years and above with chronic constipation as per ROME IV criteria were included in the study. All were evaluated with colonic transit study, anorectal manometry & balloon expulsion test.
Results The mean age of the patient was 50.60±15.61 years. 70.2% of patients with constipation had 7-14 bowel movements per week, with only 3.1% having bowel movements of less than 3 per week, while 2.5% had bowel movements >21/week. The most typical symptom is a sense of incomplete evacuation seen in 93.8% of patients, followed by straining in 88.8%, anorectal blockage in 13%, and manual evacuation in 14.3%. Normal transit constipation is the most common type observed in 64.0%, followed by dyssynergic defecation (DD) in 19.9% and slow transit in 14.3%. The mixed (slow transit + DD type) was seen in only 1.9%. This study suggests a significant association between type of constipation and stool frequency (p-value <.001) and time spent in the toilet (p-value < .001). There was a good correlation between digital rectal examination with manometry and balloon expulsion test (68.5% sensitivity and 96.8% specificity). The use of complementary alternative medicine (CAM) was seen in 80%.
Conclusion A sense of incomplete evacuation and not the number of bowel movements per week is the predominant symptom described by most patients with constipation in India. The use of CAM for constipation is widespread. Chronic constipation should be subclassified into its subtypes for individualized treatment.
Keywords Constipation, Dyssynergic defecation, Normal transit constipation, Slow transit constipation
334
High prevalence of sexual dysfunction among patients with irritable bowel syndrome: Data from a tertiary care center in south India
John George, Rajeeb Jaleel, Asisha Janeela, Ajith Thomas, Anoop John, A J Joseph, Amit Dutta, Ebby Simon, Sudipta Chowdhury
Correspondence – John George - [email protected]
Department of Clinical Gastroenterology and Hepatology, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Introduction Sexual dysfunction is an extraintestinal manifestation of irritable bowel syndrome (IBS) which is often neglected despite its implications on the quality of life of such patients.
Methods In this prospective observational study, we estimated the prevalence of sexual dysfunction among consecutive patients, newly diagnosed to have IBS, who were married, between the age group of 18 and 50. We used validated questionnaires -The International Index of Erectile Function-5 (IIEF-5) for erectile dysfunction (ED); the Chinese Index of premature ejaculation – 5 (CIPE-5) questionnaire for premature ejaculation (PE) in males and the Female Sexual Function Index (FSFI) for females.
Results Ninety-seven patients were recruited, of which 90 (93%) were men and 7 (7%) were women. The mean age was 37.8±6.4 years. Among men, 36 (40%) of the patients reported sexual dysfunction, while 39 (43.3%) fulfilled criteria for ED, PE, or both. Among women, 1 (14.3%) reported sexual dysfunction and 2 (28.6%) fulfilled criteria for female sexual dysfunction. Among men, a higher prevalence of sexual dysfunction- 30 (57.7%) was noted in those with moderate or severe IBS when compared with those with mild IBS - 9 (23.7%) according to IBS-Symptom Severity Score, which was statistically significant p value – 0.001, OR- 4.39 (1.74 – 11.12)
Conclusion A high prevalence of sexual dysfunction is noted among patient with IBS and addressing it may play a major role in improving the quality of life of such patients.
Keywords Female sexual dysfunction, Irritable bowel syndrome, Male sexual dysfunction
335
Unexplained vomiting in a patient with joint hypermobility syndrome
Sayan Malakar , Akash Mathur, Anshuman Elhence * , Uday C Ghoshal
Correspondence – Uday C Ghoshal - [email protected]
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raibareli Road, Lucknow 226 014, India, and *All India Institute of Medical Sciences, Gate No.1, Great Eastern Road, AIIMS Campus, Tatibandh, Raipur 492 099, India
Introduction Joint hypermobility syndrome is a common disorder as it involves four to 13% of the population. Increased incidence and prevalence of functional as well as structural gastrointestinal disorders have been reported in the literature. Here we present an interesting case of chronic nausea and vomiting in a patient with joint hypermobility syndrome.
Case Presentation A 19-year-old boy presented to us with a history of nausea, vomiting, anorexia and postprandial abdominal fullness for two years. On further questioning, he revealed that he had polyarthralgia since his childhood. An examination of the musculoskeletal system revealed joint laxity involving various small and large joints. After defining joint laxity using the Beighton score, a diagnosis of benign joint hypermobility (BJHS) was made after calculating the Brighton score. As his esophagogastroduodenoscopy was normal we kept the possibility of gastroparesis. He was already on pantoprazole, domperidone and acotiamide. After stopping the prokinetics he underwent a solid-phase gastric emptying test. After four hours, his gastric retention was 25%, which was suggestive of delayed gastric emptying (normally gastric retention should be less than 10% after four hours). As his symptoms were refractory, he was managed with an endoscopic intra-pyloric botulinum toxin-A injection. A total of 100 units of intra-pyloric botulinum toxin A was injected (25 units each quadrant). The patient’s symptoms improved following the intervention.
Conclusion BJHS is associated with gastroparesis. It can be successfully managed with intra-pyloric botulinum toxin-A injection.
Keywords Botulinum, Gastric emptying, Gastroparesis, Joint hypermobility syndrome, Vomiting
336
An observational study of pH impedance monitoring and high-resolution manometry in patients with gastroesophageal reflux diseases
Rohit Mathur, Neeraj Singla, D Nageshwar Reddy
Correspondence – Rohit Mathur - [email protected]
Department of Medical Gastroenterology, Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500 082, India
Background Gastroesophageal reflux disease (GERD) is one of the most common disorders in the west and has a negative impact on millions of people's quality of life. Now that high-resolution manometry (HRM), 24-hour ambulatory pH impedance studies, and additional novel measures are available, it is possible to assess motility disorders more accurately.
Methods Prospective observational study done at a single tertiary care hospital from November 2019 to November 2021 with classical symptoms of GERD based on Montreal classification 1.
Results Of the 79 patients, 68.4% were male, had a BMI of 25.3 kg/m2, with a mean age of 38.4 years. The most common symptoms were regurgitation (n=72, 91.2%) and heartburn (n=73, 92.4%). 89.5% of those who ate fatty foods, 34.8% alcohol user and 47.5% aerated drinks user, reported exaggeration of symptoms 4. According to the ROME and Lyon consensus 2, people were divided into four groups: those with functional heartburn (n=29, 36.7%), reflux hypersensitivity (n=11, 13.9%), and those with erosive esophagitis (n=22, 27.8%). Esophagogastroduodenoscopy (EGD) revealed grade A esophagitis in 16 (20.3%), grade B esophagitis in 6 (7.6%), and no esophagitis in 57 (72.2%) cases. A total of 30.4% of patients showed hypotensive LES pressure (HLES), while 11.3% of patients had inadequate esophageal motility (IEM) 5. The degree of esophagitis did not significantly correlate with the individual's HLES and IEM. Additionally, the degree of esophagitis and the duration of acid exposure were not correlated (AET). However, there was an inverse relationship between DCI, HLES pressure, AET, and the overall number of refluxes. AET and the contractile integral of the oesophageal junction were significantly correlated with GERD QQL (EGJ-CI).
Conclusion In individuals with GERD, lower DCI was discovered to be substantially more correlated with acid exposure time. Patients with longer acid exposure times and lower EGJ-CI had higher GERD QQL scores.
Keywords Acid exposure time, Gastroesophageal reflux disease, Motility
337
Faster small bowel transit time leads to poorer diagnostic yield in patients undergoing capsule endoscopy study
Ashiesh Khandelwal
Correspondence – Ashiesh Khandelwal - [email protected]
Department of Gastroenterology, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi 110 060, India
Shorter SBTT during VCE (<300 minutes) is associated with a poorer diagnostic yield. This may be due to a negative effect on image quality due to a faster small bowel transit. Thus, use of prokinetic agents during VCE might adversely impact the diagnostic yield and should be discouraged
Keywords Capsule endoscopy
338
Risk factors for submucosal fibrosis during per-oral endoscopic myotomy: A prospective study
Pradev Inavolu , Zaheer Nabi, Rajesh Goud, Mohan Ramchandani, Santosh Darisetty * , Nageshwar Reddy Duvvur
Correspondence – Zaheer Nabi - [email protected]
Department of Medical Gastroenterology, and *Anasthesiologist, AIG Hospitals, No 136, Plot No 2/3/4/5 Survey, 1, Mindspace Road, Gachibowli, Hyderabad 500 032, India
Background and Aim Per-oral endoscopic myotomy (POEM) is an established treatment modality for achalasia cardia. Submucosal fibrosis (SMF) is rare, but the most important reason for technical failure during POEM. Prediction of SMF may be crucial to improve technical outcomes with POEM. In this study we aim to evaluate the predictors for SMF in cases with achalasia cardia.
Methods Consecutive patients with achalasia cardia who underwent POEM (August 2021 to February 2022) were included in the study, prospectively. Various factors were analyzed for prediction of SMF including age, gender, stasis esophagitis, type of achalasia, duration of disease, lower esophageal sphincter pressure (LESP), height of barium column on barium esophagogram and severity of symptoms (Eckardt score). Esophageal mucosa was graded for the severity of stasis esophagitis (grade I to grade III) based on vascular pattern, mucosal thickening, ulceration, and nodularity. SMF was graded (I minimal, II moderate, III severe) according to mucosal lift, difficulty in entry, density of SM fibers, separation of mucosa and muscle.
Results One hundred and four patients (males 59, mean age 41.9±15.7 years) underwent POEM during the study period. Median symptom duration was 24 (2-240) months and mean pre-POEM Eckardt score was 6.9±1.7. POEM was performed via posterior route in majority of patients (95.2%). Stasis esophagitis was evident in 70 (67%) patients and majority had mild (grade I, 51.9%) stasis esophagitis. Mean duration of disease was significantly longer in those with stasis esophagitis (56.6 vs. 20.9, p=0.001). SMF and severe SMF were detected in 29 (28.2%) and 1 (1%) case, respectively. On multivariate analysis, the presence of stasis esophagitis was the only factor that predicted the presence of SMF (p=0.014). Other were not significantly associated with SMF.
Conclusion Severe SMF is rare in cases with achalasia cardia. The presence of stasis esophagitis is the only predictor for SMF during POEM.
Keywords Achalasia cardia, POEM, Submucosal fibrosis
339
Spectra and psychological profile of Rome IV disorders of gut–brain interaction among out-patients in northern India
Omesh Goyal , Arshdeep Singh, Akash Aggarwal, Prerna Goyal, Yogesh Gupta, Ajit Sood
Correspondence – Omesh Goyal - [email protected]
Department of Gastroenterology, Dayanand Medical College and Hospital, Tagore Nagar, Civil Lines, Ludhiana 141 001, India
Background Disorders of gut brain interaction (DGBI) are the most prevalent disorders in gastroenterology. They are commonly associated with psychological co-morbidities and impairment in health-related quality of life. Indian data on the prevalence of DGBIs, the overlap, and the associated psychological co-morbidities is scarce.
Aim To study the spectra and psychological profile of Rome IV DGBIs among out-patients in northern India.
Methods Consecutive patients presenting to gastroenterology out-patient department of a tertiary care institute between May 2019 to October 2019 were enrolled. Rome IV Diagnostic Questionnaire (English/Hindi) was used to diagnose DGBIs. DASS questionnaire (English/Hindi) was used to assess depression, anxiety, and stress.
Results Of the total 2547 patients screened, 1044 (40.9%) had DGBIs. Mean age was 41.8 ± 12.6 years and 51.9% were males. Most common DGBIs were functional dyspepsia (FD) (44.3%), esophageal disorders (ED) (34.9%), irritable bowel syndrome (IBS) (16.1%), functional constipation (15.6%), functional abdominal bloating/abdominal distension (7.5%), nausea and vomiting (6.3%), centrally mediated abdominal pain syndrome (4.6%), and functional diarrhea (2.8%). Co-existing DGBIs were present in 394 (37.7%) patients. Out of total FD patients (n=463), 52 (11.2%) had co-existing IBS, while 103 (22.4%) had co-existing ED. Prevalence of anxiety, depression and stress were 74.5% (n=778), 42.4% (n=443) and 31.3% (n=327) respectively.
Conclusion Rome IV DGBIs are common among out-patients in northern India, most common being functional dyspepsia, esophageal disorders, irritable bowel syndrome and functional constipation. More than one-third patients have co-existing DGBIs. Anxiety, depression, and stress are reported by majority of the patients.
Keywords Dyspepsia, Functional, Irritable bowel syndrome
Pediatric Gastroenterology
340
Microscopic colitis in adolescent population: A case series
Jasmeet Singh Dhingra, Rajiv Grover, Nirmaljit Singh Malhi, Achal Garg
Correspondence - Rajiv Grover - [email protected]
Department of Gastroenterology, Advanced Gastroenterology Institute-The Gastrociti, Opposite Grandwalk Mall, Barewal Road, BRS Nagar, Ludhiana 141 008, India
Introduction Microscopic colitis (MC) is characterized by chronic watery diarrhea, normal colonoscopy and abnormal histology. While mostly encountered in adults, pediatric or adolescent cases are rare and may show varying presentations.
Methods This is a retrospective study of all adolescent patients diagnosed with microscopic colitis at Advanced Gastroenterology Institute: AGI The GASTROCITI in Ludhiana for a 30-month period from February 2020 to July 2022. Cases were identified using the Department of Endoscopy database. Data were obtained from medical records that included clinical manifestations and histopathological features.
Results Three patients (2 females and 1 male, median age: 15 years, ranging from 14 to 16) were included. Two patients presented with non-bloody watery diarrhea and one with diarrhea associated with alternating constipation and rectal prolapse. Abdominal pain and weight loss were manifested in all patients. Two patients had celiac disease in remission and were on gluten-free diet (GFD). All patients had normal colonoscopy, but had typical histologic features of MC in colon biopsies. Two patients had clinical follow-up (12 months and 14 months duration), and both patients on follow-up had no gastrointestinal (GI) symptoms, but one patient had continued symptoms at 1 month of therapy and was lost to follow-up.
Conclusion Although rare in children and adolescents, the clinical presentation is similar to adults, with a female preponderance, presentation with diarrhea and abdominal pain, and an association with celiac disease. Adolescents are more likely to have weight loss and irritable bowel syndrome (IBS) like presentation. Active celiac disease should be ruled out and adherence to GFD is essential. Treatment is less standardized in children and adolescents with MC.
Keywords Collagenous colitis, Lymphocytic colitis, Microscopic colitis, Pediatric colitis,
341
Rectal prolapse as an unusual presentation of cystic fibrosis
Sumit Kumar Suman, Prafulla K Singh, Snehitha Nalluri, Sai Krishna Katepally, P Shravan Kumar
Correspondence – Sumit Kumar Suman - [email protected]
Department of Medical Gastroenterology, Gandhi Medical College and Hospital, Musheerabad, Padmarao Nagar, Secunderabad 500 003, India
Introduction Rectal prolapse is a common and self-limited condition in children less than 5 years of age. Various anatomical variants and medical conditions predispose a child to developing rectal prolapse .It is an unusual presentation with cystic fibrosis, accounting for only 3.6 % [1].
Case Presentation Herein we present a case of 2-year-old female child presented with complaints of increased frequency of stool since 2 months and mass per rectum since 1 month with past history of recurrent lower respiratory tract infections. Upper gastrointestinal endoscopy and colonoscopy was normal. Stool routine examination revealed presence of fat globules. Fecal elastase level was less than 15 microgram per gram of stool. Sweat chloride was 88 milliequivalent per liter and cystic fibrosis transmembrane conductance regulator (CFTR) mutation analysis revealed homozygous DF508 mutation. Patient was started on pancreatic enzyme replacement therapy. Over a follow-up of 2 months patient gained weight of 2 kg and her rectal prolapse also got resolved.
Conclusion Historical data suggests that approximately 23% of patients with cystic fibrosis experience rectal prolapse [2]. With wide spread use of new born screening for cystic fibrosis, rectal prolapse as a manifestation of disease has decreased in incidence and estimated to be as low as 3.5%. Prolapse frequently ceases with pancreatic enzyme replacement therapy and rarely surgery is required [3].
References
1. El-Chammas KI, Rumman N, Goh VL, Quintero D, Goday PS. Rectal prolapse and cystic fibrosis. J Pediatr Gastroenterol Nutr. 2015;60:110-2.
2. Kulczycki LL, Shwachman H. Studies in cystic fibrosis of the pancreas: Occurrence of rectal prolapse. N Engl J Med. 1958;259:409-12.
3. Stern RC, Izant Jr RJ, Boat TF, Wood RE, Matthews LW, Doershuk CF. Treatment and prognosis of rectal prolapse in cystic fibrosis. Gastroenterology. 1982;82:707-10.
Keywords Cystic fibrosis, Rectal prolapse
342
Pediatric gastrointestinal endoscopy by adult gastroenterologists: A retrospective study addressing the outcome and safety of performing endoscopies in resource-poor setting
Arya Suchismita , Ashish Jha, Vishwa Mohan Dayal, Jayant Prakash, Rizwan Ahmer, Anand Gupta, Rakesh Kumar
Correspondence – Ashish Jha - [email protected]
Department of Gastroenterology, Indira Gandhi Institute of Medical Sciences, Bailey Road, Sheikhpura, Patna 800 014, India
Background Pediatric endoscopic procedures are mostly performed by the pediatric gastroenterologist with pediatric endoscopes under GA or, under deep sedation in a carefully monitored unit. Data regarding the outcome and safety of pediatric endoscopy performed by an adult gastroenterologist are limited.
Methods We aimed to investigate indications, the use of sedation, endoscopic findings, and outcomes of pediatric endoscopic procedures performed by the adult gastroenterologist. We also analyzed the success rate of upper gastrointestinal endoscopy (UGIE) performed with adult gastroscopes in children weighing 7 to 10 kg. In a retrospective study, case record of pediatric patients (age up to 15 years) who underwent UGIE and lower GI endoscopy (LGIE) were reviewed.
Result Out of 391, UGIE was successfully completed in 383 (98%) patients. The mean (SD) age was 7.7 (3.3) years. 28% of the children were required mild sedation or GA for the procedure. Successful UGIE with adult gastroscopes was possible in 23 (82%) of 28 young children (weighing 7-10 kg). The endoscopic yield was 65.54%. Therapeutic UGIE were done in 39.16% patients. Out of 123, LGIE was successfully completed in 120 (97.95%) patients (sigmoidoscopy: 81.66%; colonoscopy: 18.33%). The mean (SD) age was 7.9 (3.3) years. 27% of the children were given mild sedation or GA for the procedure. The endoscopic yield was 75%. Therapeutic LGIE were performed in 44% patients.
Conclusions Pediatric GI endoscopy can be safely performed by an experienced adult gastroenterologist. Unsedated UGIE and sigmoidoscopy can be well-tolerated by children when performed by appropriate monitoring.
Keywords Colonoscopy, Lower gastrointestinal endoscopy, Pediatric endoscopic procedures, Pediatric endoscopy, Sigmoidoscopy, Upper gastrointestinal endoscopy
343
Etiology, referral pattern and role of genetics in children with neonatal cholestasis-Experience of a tertiary care centre from India
Ankit Agrawal , Anshu Srivastava
Correspondence – Anshu Srivastava - [email protected]
Department of Pediatrics Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raibareli Road, Lucknow 226 014. India
Introduction Timely and correct etiological diagnosis is the most important determinant of outcome in neonatal cholestasis (NC). This allows for administration of specific therapy including surgery in biliary atresia (BA). We determined the aetiology, age at referral and role of exome sequencing in infants with NC.
Method Retrospective observational study of infants (age <6 months) with NC admitted from 2017 to 2021. Etiological diagnosis was based on clinical profile and investigations (biochemical, radiological, histological and genetics). Clinical features and investigations were noted and analyzed.
Result Three hundred and eighty infants (66.8% boys) were analyzed. The mean age at onset of jaundice was 18.2±23.8 days and at admission was 84.2±39.2 days. The most common etiology was BA (235, 61.8%) followed by metabolic causes (62, 16.24%), idiopathic neonatal hepatitis (37, 9.7%), multifactorial (29, 7.7%), cryptogenic (12, 3.2%) and TORCH (1, 0.27%). Metabolic disorders included galactossemia, tyrosinemia, mitochondrial hepatopathy, progressive familial intrahepatic cholestasis, bile acid synthetic defect, alagille syndrome, cystic fibrosis, HNF-1B mutation and storage disorders. Among the multifactorial group, majority had a single risk factor (24, 82.6%) with sepsis (19, 65.5%) and prematurity (6, 20.7%) being most common. In BA group, the age at admission has remained at >60 days (88.7±37.3 days) over last 5 years with average delay of 75.4±36.7 days between development of jaundice and admission. One-third BA patients couldn’t be offered surgery due to advanced age (>4 months). Interval between the age of presentation and referral was longer in BA vs non-BA (88.7 vs. 76.7days; p=0.005). Among the non-BA group, yield of liver biopsy for a definitive diagnosis was lower than exome sequencing (12/43 [28%] vs. 25/33[75.7%]; p<0.0001).
Conclusion BA is the most common cause of NC followed by metabolic and multifactorial etiology. There is an urgent need for early referral of BA. Exome sequencing has better yield than liver biopsy in the non-BA group.
Keywords Biliary atresia, Genetics, Neonatal cholestasis
Surgical Gastroenterology
344
Comparative analysis of heller myotomy with dor versus toupet fundoplication for achalasia cardia
Sunita Suman 1 , Vaibhav Varshney1, Subhash Soni1, Sanjeev Sachdev2, Sabir Hussain3, Narendra Bhargava3
Correspondence – Vaibhav Varshney - [email protected]
1Department of Surgical Gastroenterology, All India Institute of Medical Sciences, Marudhar Industrial Area, 2nd Phase, M.I.A. 1st Phase, Basni, Basni, Jodhpur 342 005, India, 2Department of Gastroenterology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, 1, Jawaharlal Nehru Marg, New Delhi 110 002, India, and 3Department of Gastroenterology, Dr. S. N. Medical College, Residency Road, Sector-D, Shastri Nagar, Jodhpur 342 003, India
Background Heller myotomy with partial fundoplication is the standard of care for achalasia cardia. However, the choice of partial fundoplication is still controversial. We compared both types of fundoplication concerning subjective and objective parameters.
Methods A total of 30 consecutive patients underwent laparoscopic/robotic Heller myotomy (LHM/RHM) with either DF (n=15) or TF (n=15). Preoperative baseline characteristics, intraoperative details, and post-operative complications were recorded. Patients were followed with Eckardt score, quality of life-related scores, and 24-hour pH study and high-resolution manometry (HRM) at one year of follow-up.
Results There was no significant difference between the two groups regarding preoperative baseline parameters, length of hospital stay, and post-operative complications. The HM+DF group had 4 (27%) patients with recurrence/failure with none in the HM+TF, but it was not significant (p= 0.79). Symptom scores were similar between the groups at 6 and 12 months of follow-up. One patient in the HM+DF group and two in the HM+TF group had significant pathological acid reflux (p=0.483). On HRM, HM+TF showed a trend towards significance in terms of esophagogastric junction (EGJ) relaxation (p=0.058) with a non-significant difference in median integrated relaxation pressure (IRP) (p=0.081).
Conclusion The study showed a trend towards lower failure rates and improved EGJ relaxation with similar reflux rates in patients who underwent HM+TF compared to HM+DF. However, long-term follow-up is required to validate our findings with well-defined subjective and objective criteria.
Keywords Achalasia, Disease-specific quality, Fundoplication, Heller myotomy, pH monitoring
345
Gastrointestinal perforations during corona virus disease - 19 pandemic
Ritambhra Duseja , Ridhi Sood, Aravind Sekar, Ashwani Kumar, Rajesh Gupta
Correspondence – Ritambhra Duseja - [email protected]
Department of Histopathology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India
Introduction Gastrointestinal perforations and thromboembolic acute limb ischemia were the most common surgical specimens received during corona virus disease – 19 (COVID-19) pandemic in addition to specimens from ENT departments.
Materials There were total of 19 GIT resections from February 2020-December 2021 which were analyzed by two GIT pathologists.
Results They were mostly hemicolectomies (n-13), small intestines (5) and gastrectomy (n-1). Prevalence of GIT resections for perforations remained same as in past 10 years though general perception of increased number was due to cessation of all other non-emergency surgeries. Histopathology showed predominantly ischemic perforations with secondary infective vasculitis in 3 patients. Ischemia was mainly due venous thrombi with venulitis along with arteritis in one fourth. In addition, neo-angiogenesis not supported by any stroma was prominent finding, which generally was not seen in pre-covid perforations. Thrombotic microangiopathy was present in 3 patients. Tissue invasive candida was present in caecal perforation and gastrectomy and mucormycoses in 1 hemicholectomy.
Conclusion COVID-19 associated coagulopathy resulted vascular thrombo-emboli with compensatory neo-angiogenesis. Fungal infections were observed in some of these patients.
Keywords Ischaemia, Perforation, Thrombosis
Nutrition
346
A questionnaire survey to determine challenges in implementing practice of low FODMAP dietary intervention in India
Mayank Jain
Correspondence – Mayank Jain - [email protected]
Department of Gastroenterology, Arihant Hospital and Research Centre, 297 Indrapuri, Near Bhanwarkuan, Indore 452 017, India
Background Restriction of Fermentable Oligosaccharide, Disaccharide, Monosaccharide, and Polyols in the diet (low FODMAP diet) has been found to be effective in management of irritable bowel syndrome (IBS) and functional dyspepsia (FD). Despite good evidence regarding its benefits in Indian patients, regular use of this intervention is limited.
Aim To determine the challenges faced by gastroenterologists in implementing low FODMAP diet in daily practice.
Methods A questionnaire was circulated using Google forms. It sought information regarding place of practice, cases of FD/IBS seen per month and use of low FODMAP dietary intervention for patients at their respective centres. The data obtained were entered in Microsoft excel sheet and interpreted using number and percentages.
Results The questionnaire was circulated among 100 gastroenterologists predominantly practicing in Madhya Pradesh, Maharashtra, and Gujarat. Response rate was 51%. Nearly all (87.5%) were in private hospital setups. Majority saw >20 cases of FD (76.5%) and IBS (70.6%) per month. Rome IV criteria were used by 70.6% (36) regularly and nearly all (48, 94.1%) considered dietary intervention as necessary for management of these disorders. Dietician facility was available full time with 64.7% (33) and on call with 9 (17.6%). However, none used dietician assessment regularly for FD and IBS patients. Twenty-seven reported that dieticians at their centres were trained in administering low FODMAP diet and proper follow-up of patients. Only 9 (17.6%) used low FODMAP diet regularly. Majority (82.4%, 41) noted that patients are unable to follow low FODMAP diet due to logistic reasons (62.5%) or being too restrictive (37.5%). Use of mobile apps (100%) was considered as the best option to promote low FODMAP diet among patients.
Conclusion Low FODMAP diet is seldom used in daily practice. Lack of trained dieticians and poor acceptability by patients are the limiting factors.
Keywords Diet, Dyspepsia, Functional, Intervention, Irritable Bowel
347
Dietary intake of patients with inflammatory bowel disease: A comparison with disease phenotype subgroups and ulcerative colitis disease activity subgroups
Moni Chaudhary , Shikha Sahu, Uday C Ghoshal
Correspondence - Uday C Ghoshal - [email protected]
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raibareli Road, Lucknow 226 014, India
Background The pathogenesis of chronic and relapsing inflammatory bowel diseases (IBDs) is not fully understood. Diet is likely to play an important role in modification of the gut microbiota. The unguided dietary habits lead to nutritional deficiencies and severity of disease course. Therefore, we aimed to compare the dietary intake of IBD patients.
Methods Dietary intake of IBD patients was recorded for consecutive 3 days.
Results One hundred patients (71 ulcerative colitis [UC], 29 Crohn’s disease [CD]) were enrolled. UC patients differed in anthropometric measurement from CD patients in total body fat % (24.3±7.6% vs. 20.1±7.6%, p=0.017), and total body fluid (51.2±6.2% vs. 55.2±6.2%, p=0.005). The recommended protein and fat intake of UC disease activity subgroups (45 in remission and 26 with active disease) differed significantly (protein: 76.1±5.3 g vs. 79.8±7.3 g, p=0.017; fat 55.5±3.7 g vs. 57.7±5.3 g, p=0.05). No significant difference in fat, protein and carbohydrate intake between UC and CD patients was found (fat: 232.2 [212.4-279] kcal vs. 250.2 [215.1-283.5] kcal, p=0.494; protein: 0.5 [0.4-0.7] g vs. 0.6 [0.4-0.7]g, p=0.535; carbohydrate: 60.7 [54.6-66.7] g vs. 59.9 [53.6,63.8] g, p=0.397). No difference was seen in micronutrient intake when comparing UC and CD (potassium: 25.4 [21.7-32.3] mg vs. 24.8 [20.3-29.9] mg, p=0.646; sodium: 61.9±14.5 mg vs. 62.9±12.1 mg; p=0.772; iron: 51 [42.5-81] vs. 53.9 [38.6-94.8] mg; p=0.797; calcium: 27.3 [21.8-46.9] mg vs. 27.6 [19.3-47.5] mg, p=0.886). 91.1% (41/45) of patients in remission had protein intake below the recommended 0.8 g/kg and 92.3% (24/26) with active disease below the recommended 1.2 g/kg.
Conclusion Our study confirms recommended macronutrient differences in habitual dietary intake of UC disease activity subgroups. To be able to propose better dietary guidelines for IBD patients, more research into dietary effects on IBD disease course is needed.
Keywords Inflammatory bowel disease, Macronutrient, Micronutrient
348
Nutritional deficiencies in patients with ulcerative colitis: Prevalence… Predictors… and effect on quality of life
Anurag Sachan, Usha Dutta, Vishal Sharma, Jayanta Samanta, Arun Sharma, Kaushal Kishore
Correspondence - Anurag Sachan - [email protected]
Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012, India
Introduction Malnutrition is common in patients with ulcerative colitis (UC). To study the prevalence and predictors of nutritional deficiencies and their effect on quality of life (QOL) in patients with UC.
Subjects One hundred and twenty-six patients with UC and 57 healthy controls were analyzed.
Methods It was a cross-sectional prospective study done on patients with UC over one year (Fig. 1). Cases were defined as enrolled patients with UC and controls were healthy relatives of the cases. Short inflammatory bowel disease questionnaire (SIBDQ) score <50 denoted poor QOL.1
Results The controls and cases were well matched in their demographics. Cases as compared to controls had increased prevalence of being nutritionally poor as shown in (Table 1). Serum albumin and iron deficiency emerged as independent predictors of serum calcium-deficiency with odds ratio (OR) of 6.8 and 13.4 respectively. Serum folate-deficiency emerged as independent predictor of magnesium-deficiency with OR of 3.93. Serum calcium emerged as independent predictor of serum iron-deficiency with OR of 11.56. Serum albumin-deficiency emerged as independent predictor of vitamin D-deficiency with OR of 4.43.
Eighty-five (67.46%) of cases had poor QOL. Vitamin D (r=0.275), and albumin levels (r=0.399) positively correlated with quality of life. Vitamin D-insufficiency (<32 ng/mL) and histologically active disease by Robarts score >3 emerged as independent predictors of poor quality of life with OR of 6.0 and 4.0 respectively.2
Conclusions Micro and macro-nutrient deficiencies are more prevalent in patients with UC than healthy controls. Albumin levels correlated well with micronutrient deficiencies and QOL. Vitamin D-insufficiency and histologically active disease predict the poor QOL.
Keywords Nutrition, Quality of life, Ulcerative colitis
349
Reproductive functions and pregnancy outcome in female patients with celiac disease
Shubham Prasad 1 , Priyanka Singh 2 , Alka Singh 1 , Wajiha Mehtab 1 , Simple Rajput 1 , Sana Dang 3 , Aditya V Pasichia 1 , Shubham Mehta 1 , Ashish Chauhan 1 , Mahendra S. Rajput 1 , Garima Kachhawa 4 , Soumya Jagannath 1 , Vineet Ahuja 1 , Govind K Makharia 1
Correspondence – Shubham Prasad - [email protected]
Departments of 1Gastroenterology, and 2Obstetrics and Gynaecology, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029, India, 2Department of Medicine, Lady Harding Medical College, Shaheed Bhagat Singh Marg, Lady Hardinge Medical College, DIZ Area, Connaught Place, New Delhi 110 001, India, and 3Department of Medicine, Vardhaman Mahavir Medical College and Safdarjung Hospital, NH 48, Near AIIMS Hospital, Ansari Nagar West, New Delhi 110 029, India
Objectives: Abnormalities in the reproductive functions are often ignored while evaluating a patient with celiac disease (CeD). We evaluated the reproductive functions in female patients with CeD and effect of gluten-free diet (GFD) on them.
Methods In a case control study between 2020-2021 using detailed questionnaire, we evaluated reproductive functions (age at menarche, menstrual pattern, fertility, pregnancy outcome and menopause) in biopsy-proven female patients with CeD with age >10 years. The questionnaire was administered either in person or telephonically. Age-matched healthy female controls (twice the number) were also recruited.
Result Of 1086 CeD patients, 480 were females and 288 were included. As compared to controls (n=586), females with CeD had higher age at menarche (14.6±2.0 vs. 13.6±1.5 years; p=0.001), delayed menarche (30.8% vs. 11.4%; p=0.001), abnormal menstrual pattern (39.7% vs. 25.8%; p<0.001), involuntary delay in conception at >1 year (33.8% vs. 11.8%; p=0.01), current infertility rate (10.5% vs/ 5.2%; p=0.028) and poorer overall pregnancy outcomes (abortion (23.5% vs. 12.8%; p=0.001), pre-term birth (16.3% vs. 3.7%; p=0.001). With GFD, 69.2% patients with delayed menarche attained menarche within 0.5 to 2 years, 70.1% patients with abnormal menstruation had improvement in menstruation pattern within 6 months, 25% patients with involuntary delay in conception at >1year conceived within 1-2 years and 75% patients with poor pregnancy outcomes had improvement in pregnancy outcomes in subsequent pregnancies.
Conclusion Either one or more aspect of reproductive functions and pregnancy outcome is affected adversely in two-third female patients with CeD, and many of them do reverse with GFD.
Keywords Celiac disease, Gluten-free diet, Pregnancy outcomes, Reproductive functions
350
Comprehensive assessment of macronutrient and micronutrient deficiency in patients with ulcerative colitis: Prevalence and its effect on quality of life
Anurag Sachan 1 , M Thungapathra2, Harmandeep Kaur1, Kaushal Kishor Prasad1, Ravjeet Singh Jassal2, Vishal Sharma1, Anurag Jena1, Anupam Kumar Singh1, Kim Vaiphei3, Jayanta Samanta1, Arun Kumar Sharma1, Sanjay Bhadada4, Usha Dutta1
Correspondence – Usha Dutta - [email protected]
Departments of 1Gastroenterology, 2Biochemistry, 3Histopathology, and 4Endocrinology, Nehru Hospital, Graduate Institute of Medical Education and Research, Sector-12, Chandigarh 160 012, India
Introduction Patients with ulcerative colitis (UC) have poor nutritional intake and increased gut losses. Micronutrient and macronutrient deficiency are likely to be prevalent and may impact quality of life. Our study was designed to prospectively study the prevalence and predictors of nutritional deficiencies and their effect on quality of life (QOL) in patients with UC.
Methods A prospective study was conducted among patients with UC visiting a university teaching hospital. Cases were defined as patients with diagnosed UC and controls were healthy relatives of the cases. They were then assessed for clinical, demographic and socioeconomic characteristics. They were evaluated systematically for presence of macronutrient and micronutrient deficiency after informed consent. Further, we assessed their anthropometry, functional performance and quality of life using the Short inflammatory bowel disease questionnaire (SIBDQ) score.
Results Cases (n=126) and healthy controls (n=57) were included. Cases had poorer anthropometric parameters as compared to controls: being underweight (27.8% vs. 3.5%; p=0.000) and had lower mid-arm-circumference (45.2% vs. 12.3%; p=0.000). Cases had poorer functional status: weaker hand grip strength (66.7% vs. 45.6%; p=0.007) and weaker lower limb strength (80.2% vs. 42.1%; p=0.000). Cases had significantly higher macronutrient deficiencies than controls: protein deficiency (30.95% vs. 3.50%; p<0.000), albumin deficiency (25.39% vs. 0.00%; p=0.000) and cholesterol deficiency (62.69% vs. 28.07%; p<0.000). Micronutrient deficiencies were common in UC: Calcium deficiency (44.44%), phosphate deficiency (20.63%), magnesium deficiency (11.11%), `zinc deficiency (76.19%), iron-deficiency (87.3%), folate-deficiency (15.9%), vitamin B12 deficiency (10.3%) and vitamin D-deficiency (19.8%). Over two-thirds of cases (n=85) had poor quality of life (SIBDQ score ≤ 50). Vitamin D-insufficiency (<32 ng/mL) (OR = 6.1; 95% CI:1.9-19.7) and histologically active disease (Robarts histological score >3) (OR=4.0; 95% CI:1.6-9.9) emerged as independent predictors of poor QOL.
Conclusion Patients with UC have higher prevalence of poor functional status and macronutrient deficiencies. Patients with UC have high prevalence of poor QOL. Low serum Vitamin D levels and histologically disease are predictors of poor QOL.
Keywords Nutrition, Quality of life, Ulcerative colitis,
351
Barriers and facilitators in the adherence to gluten-free diet in adult patients with celiac disease
Wajiha Mehtab 1 , Alka Singh2, Anam Ahmed2, Ashish Chauhan3, Mahendra Singh Rajput2, Lalita Mehra2, Vikas Banyal2, Shubham Prasad2, Namrata Singh2, Vineet Ahuja2, Anita Malhotra4, Govind K Makharia2
Correspondence – Govind K Makharia - [email protected]
1Department of Home Science, University of Delhi, Ashok Vihar III – Ashok Vihar, Delhi 110 052, India, 2Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi 110 029. India 3Department of Gastroenterology, Indira Gandhi Medical College, Ridge Sanjauli Road, Lakkar Bazar, Shimla 171 001, India, and 4Department of Home Science, Lakshmibai College, University of Delhi, Ashok Vihar III – Ashok Vihar, Delhi 110 052, India
Objectives Lifelong and strict adherence to gluten-free diet (GFD) is essential for the successful treatment of celiac disease (CeD). We determined factors influencing adherence to GFD at various ecological levels of human-development and decision-making, including intra-personal, inter-personal, organizational, community and system-based levels in adult patients with CeD.
Methods A questionnaire was developed based on review of literature, group discussions and expert group meetings. The questionnaire was administered to patients with CeD attending Celiac Clinic and following GFD for >1 year.
Results Overall, 978 patients (median age 29 years, inter-quartile range: 22-46 years; females: 592) were included. We observed many barriers including intra-personal such as lack of a separate gluten-free flour mill at home in 441 (45.1%) patients and intake of gluten-containing food items due to frustration in 108 (11.1%) patients; inter-personal barrier such as inadvertent intake of gluten-containing food products either during dining-out with family/friends in 324 (33.1%) patients or due to non-supportive in-laws in 68 (9.1%) patients; organizational barrier such as non-availability and high cost of packaged GF-food products in 475 (48.6%) and 461 (47.1%) patients respectively and non-membership of celiac support group in 322 (32.9%) patients; community-based barriers such as non-awareness of complexity of eating gluten among relatives in 419 (42.8%) patients and forceful intake of gluten-containing foods due to relatives’ pressure in 78 (7.9%) patients; system-based barriers including lack of appropriate infrastructure and strategy for maintaining GF lifestyle e.g. inappropriate counselling by dietician in almost one-third of patients and irregular follow-up visit with doctor in 560 (57.2%) patients.
Conclusions In India, there are multiple barriers to the adherence of GF lifestyle at all ecological layers of human development. There is a need to create infrastructure and removal of these barriers at various levels of ecosystem.
Keywords Adherence, Barriers, Celiac disease, Facilitators, Gluten-free diet
352
Cost and nutrient comparison of gluten-free foods with their gluten containing counterparts
Wajiha Mehtab 1 , Samagra Agarwal 2 , Tamoghna Ghosh 2 , Harsh Agarwal 2 , Alka Singh 2 , Anam Ahmed 2 , Shubham Prasad 2 , Ashish Chauhan 3 , Namrata Singh 2 , Vineet Ahuja 2 , Anita Malhotra 4 , Govind K Makharia 2
Correspondence – Govind K Makharia - [email protected]
1Department of Home Science, University of Delhi, Ashok Vihar III – Ashok Vihar, Delhi 110 052, India, 2Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India, 3Department of Gastroenterology, Indira Gandhi Medical College, Ridge Sanjauli Road, Lakkar Bazar, Shimla 171 001, India, and 4Department of Home Science, Lakshmibai College, University of Delhi, Ashok Vihar III – Ashok Vihar, Delhi 110 052, India
Background A lifelong gluten-free diet (GFD) is the only available treatment for patients with celiac disease. There is paucity of data on the nutritional content and cost of gluten-free (GF) food products compared with their gluten-containing (GC) counterparts from India and Asia.
Methods After a detailed market survey, the packaged and labeled GF-food products (n=485) and their packaged gluten containing counterparts (n=790) from the supermarkets of Delhi (India) and e-commerce websites were included. Nutritional content and cost per 100-gram food (in US dollars) were calculated using the nutritional contents and prices mentioned on food label.
Results Gluten-free food products were 232% (Range: 118%-376%) more expensive than their gluten-containing counterparts. Energy content of all GF-food products was similar to their gluten-containing counterparts, except cereal-based snacks (GF:445 kcal vs. GC:510 kcal, p<0.001). The protein content was significantly lower in GF pasta and macaroni products (single-grain:GF:6.5 g vs. GC:11.5 g, p-0.002; multigrain:GF:7.6 g vs. GC:11.5 g, p-0.027), cereal flours (single-grain:GF:7.6 g vs. GC:12.3 g, p<0.001; multigrain:GF:10.9 g vs. GC:14.1 g, p-0.009) and nutritional bars (GF:21.81 g vs. GC:26 g, p-0.028) than their gluten containing counterparts. Similarly, the dietary fiber content of GF pasta and macaroni products, cereal flours, cereal premix and nutritional bars of GF-foods was significantly lower than their gluten-containing counterparts. Gluten-free bread and confectionary items, biscuits and cookies and snacks had higher total-fats and trans-fat content than their gluten-containing counterparts. Gluten-free cereal-based snack foods had higher sodium content than their gluten containing counterparts (GF:820 mg vs. GC:670 mg, p<0.001). Seventy-three percent of GF-food products were classified as ultra-processed foods.
Conclusion Gluten-free food products are significantly more expensive than their gluten containing counterparts, thus increasing the economic burden to patients and potentially acting as a barrier to adherence to GFD. Majority of packaged GF-food products are highly processed and contain less protein and dietary fiber and higher fat, trans-fat and sodium.
Keywords Celiac disease, Cost, Gluten-containing food, Gluten-free foods, Nutritional quality
Miscellaneous
353
Randomized trial of ‘Roll-over’ technique of abdominal paracentesis versus standard technique in suspected malignant ascites
Daya K Jha, Manish Rohilla, Chandan Das, Santhosh Irrinki, Harjeet Singh, Aashima Arora, Subhas C Saha, Pankaj Gupta, Harshal Mandavdhare, Usha Dutta, Aman Sharma, Vishal Sharma
Correspondence – Vishal Sharma - [email protected]
Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India
Background Single abdominal paracentesis for peritoneal carcinomatosis has a variable but low sensitivity (40% to 70%). We thought that rolling over the patient before paracentesis might improve the cytological yield because the tumor cells may settle down in the peritoneum while lying supine.
Methods We conducted a pilot, randomized cross-over study at a single center. We compared the cytological yield of fluid obtained by roll-over technique (ROG) with standard paracentesis (SPG) in suspected peritoneal carcinomatosis. In the ROG group, patients rolled side-to-side thrice, and the paracentesis was done within 1 minute. Each patient served as their own control, and the outcome assessor (cytopathologist) was blinded. The primary objective was to compare the tumor cell positivity between SPG and ROG groups.
Results Of 71 patients, 62 were analyzed. Of 53 patients with malignancy-related ascites, 39 had peritoneal carcinomatosis. Most of the tumor cells were adenocarcinoma (30, 94%) with one patient each having suspicious cytology and one having lymphoma. The sensitivity for diagnosis of peritoneal carcinomatosis was (31/39) 79.49% in SPG group and (32/39) 82.05% in ROG group (p=1.00). The cellularity was similar between both the groups (good cellularity in 58% of SPG and 60% of ROG).
Conclusion Rollover paracentesis did not improve the cytological yield of abdominal paracentesis.
Keywords Cytology, Malignant ascites, Peritoeum, Peritoneal carcinomatosis, Peritoneal tuberculosis, Tuberculous peritonitis
354
The perioperative outcome in geriatric patients undergoing major gastrointestinal surgery-A prospective observational study
Anantha Krishna V R
Correspondence - Anantha Krishna V R - [email protected]
Department of Surgical Gastroenterology, 1, Vinod Nagar Road, Anayara, Thiruvananthapuram 695 029, India
Background The surgical impact on the perioperative outcome in geriatric patients is a scarcely studied topic. The objective of this study was to identify the 30-day morbidity and mortality in geriatric patients undergoing major elective gastrointestinal (GI) surgery and the risk factors associated with the same.
Methodology Ninety-three patients above or equal to 65 years constituted this study conducted in the Department of Surgical Gastroenterology, KIMS Health, Thiruvananthapuram. The 30-day morbidity comprised of grade 2 and above Clavien Dindo complications. The preoperative risk factors for the above were analyzed. The basic ADLs i.e. skills required to manage one’s basic physical needs and the Instrumental Activities of Daily Living (IADLs) which includes more complex activities related to the ability to live independently in the community was documented preoperatively. The preoperative functional status was also assessed using the clinical frailty scale, gait speed, timed up and go test and Carlson’s comorbidity index.
Results The 30-day mortality and the 30-day overall morbidity was 3.2% and 58.06% respectively. 26.9% had grade 2 and above Clavien Dindo complications. This was more in those with prior history of falls, timed up and go test >14 seconds, significant weight loss, malignancy, and open surgeries. Age had no association with adverse postoperative outcomes.
Conclusion Age is not an independent variable in predicting postoperative outcomes. Grade 2 and above Clavien Dindo surgical complications were more in those with poor preoperative functional and nutritional status, those who were operated for malignancy and in open surgeries.
Keywords Age, Gastrointestinal, Geriatric
355
Trends and clinico-epidemological profile of patients with Giardiasis: Five-year experience from a tertiary care centre
Ujjala Ghoshal 1 , Nidhi Tejan 1 , Tasneem Siddiqui 2 , Pooja Kumari 3 , Uday C Ghoshal 4
Correspondence - Ujjala Ghoshal - [email protected]
Departments of 1Microbiology, and 4Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow 226 014, India, 2Department of Microbiology, Integral University, Kursi Road, Lucknow 226 026, India, and 3Department of Medical Microbiology, Chaudhary Charan Singh University (CCSU), Ramgarhi, Meerut 250 001, India
Introduction Giardiasis is an important cause of diarrheal disease and is associated with morbidity in children and adults worldwide [1, 2]. We aimed to study the frequency of Giardiasis, its clinical presentations, seasonal trends in detection and coinfection with other intestinal parasites. We also compared the fecal antigen and microscopy for detection of Giardia.
Methods It is a retrospective study conducted from January 2017 to December 2021 at our tertiary care center. Patients of all age groups referred to Parasitology laboratory for stool examination were included. Iodine and normal saline mounts and enzyme-linked immunosorbent assay (ELISA) were used for detection of Giardiasis in stool samples. Fisher exact test was used for analysis. Sensitivity, specificity, positive and negative predictive value, and diagnostic accuracy of tests were computed.
Results Of 8364 patients, 432 (5.2%) had Giardiasis by microscopy and/or ELISA. Giardiasis was more common in males compared to females (318/5613 [5.6%] vs. 114/2751 [4.1%]; p = 0.003) and among those ≤10-y compared to older individuals (102/560 [18.2%] vs. 330/7804 [4.2%]; 𝑃<0.0001). Most cases were detected in the month of May to October. The most common clinical presentation was diarrhea (80.1%) and abdominal pain (72.9%) followed by malnutrition (60.2%) and loss of appetite (46.8%). Stool microscopy and ELISA were comparably positive (393/864 [45.5%] and 413/864 [47.8%]; p=NS). Using microscopy as gold standard, sensitivity, specificity, positive, negative predictive values, and diagnostic accuracy of ELISA were 95%, 91%, 91%, 95% and 93%, respectively.
Conclusion 5.2% of the studied population had Giardiasis; it was commoner among male and younger individual. We observed a seasonal variation with peak during May to October. Fecal antigen was comparable to microscopy for detection of Giardiasis.
Keywords Diarrheal disease, Enzyme linked immunosorbent assay, Epidemiology, Giardiasis
References
1. Einarsson E, Maayeh S, Svärd SG. An up-date on Giardia and giardiasis. Curr Opin Microbiol. 2016; 34:47–52.
2. Painter JE, Gargano JW, Collier SA, et al . Giardiasis surveillance- united states, 2011- 2012. MMWR Surveill Summ. 2015; 64:15-25.
356
Fecal calprotectin can differentiate gastrointestinal graft versus host disease from other diarrhea in post-hematopoietic stem cell transplant patients
Santhosh Kumar 1 , Shreyas Hanmantgad2, Tintu Varghese3, A J Joseph4, Amit Kumar Dutta4, Biju George2
Correspondence – Santhosh Kumar - [email protected]
Departments of 1Hepatology, 2Hematology, 3Wellcome Research Unit, Division of GI Sciences, and 4Gastroeneterology, Christian Medical College, William Building, Ida Scudder Road, Vellore 632 004, India
Background Large number (40% to 50%) of hematopoietic stem transplant (HSCT) patients experience diarrhea in the initial post-transplant period. Gastrointestinal graft vs. host disease (GI-GVHD) has to be distinguished early from other diarrheal causes and treated. Fecal calprotectin (FC) is sensitive agent to identify bowel inflammation.
Methods We prospectively studied consecutive HSCT patients and FC levels were measured pretransplant, post-transplant day 14, day 1 of diarrhea and serially (day 3 and day 5) on treatment for GI-GVHD. We aimed to measure ability of FC to predict development of GI-GVHD and differentiate GI-GVHD from other diarrhea. Informed consent was taken and the study was Institute Review Board approved.
Results One hundred and three patients (age 18 [±14.9 years], mean [SD]) were studied, pre-transplant FC was similar among patients; GI-GVHD (11.6 ug/g [2.6-34.4] median [IQR]), no-GI-GVHD (11.3 ug/g [2.3-28.3]), p-0.93. Post-transplant day 14, FC was similar among patients; GI-GVHD (25.13 ug/g (9.9-45.2]) no-GI-GVHD (15.01 ug/g [10.4-34.1]), p-0.49. Thirty-nine patients had diarrhea (post BMT day 17 [11-26]) in the post-transplant setting, 17 patients diagnosed with GI-GVHD and 22 patients had other diarrheal illness. Day 1 of diarrhea FC levels among GI- GVHD was significantly higher (62.97 ug/g [28.3-296.7]) compared to other diarrheal illness (23.9 ug/g [19.4-48.7]), p-0.042. AUROC for day 1 diarrheal sample in a post HSCT to predict GI-GVHD was 0.7 (0.56-0.87) and FC cut-off > 50 ug/g had sensitivity (77.3%), specificity (58.8%), PPV (66.7%), NPV (70.8%) and diagnostic accuracy (69.2%). Our study numbers were small to correlate FC levels with grade of GI-GVHD and assess treatment response.
Conclusion In post HSCT patient day 1 of diarrhea FC level > 50 ug/g has good accuracy (69.2%) for diagnosing GI-GVHD. Larger post HSCT diarrhea patients need to be studied to assess correlation between FC with grade of GI-GVHD and treatment response.
Keywords Calprotectin, Graft versus host disease, Hematopoietic stem cell transplant
357
The role of fibroscan in predicting the risk of variceal bleed in patients with cirrhosis
Harinder Chhabra , Sandeep Gopal, Bailuru Vishwanath Tantry, Suresh Shenoy, Anurag Shetty
Correspondence - Harinder Chhabra - [email protected]
Department of Medical Gastroenterology, Kasturba Medical College, Mangalore MAHE, 203, Light House Hill Road, Hampankatta, Mangaluru 575 001, India
Background and Study Aim Variceal bleeding is a life-threatening event that has an incidence of 5% and 15% in patients with small and large esophageal varices respectively. Endoscopic screening for esophageal varices in cirrhotic patients is mandatory. The aim was to study the role of LSM and spleen stiffness measurement (SSM) in predicting the risk of variceal bleed in patients with cirrhosis.
Methods This is a single centre case control study conducted on chronic liver disease patients (CLD) who will undergo fibroscan over a period of 18 months from October 2020 to March 2022. A total of 70 patients have been included in this study. LSM and SSM values of cirrhotics with history of UGI bleed (cases) were compared to those without any history of UGI bleed (controls).
Results Spleen stiffness cut-off level of 47.65 kPa had 82.9% sensitivity and 74.3% specificity in determining the risk of bleeding, with a negative predictive value (NPV) of 0.81. LSM cut-off level of 25.85 kPa had 85.7% sensitivity, 65.7% specificity and NPV of 0.82 for detecting variceal bleeding. Combining the two cut-offs NPV was 0.96 (sensitivity, 97.1%; specificity, 62.85%). Only one patient had a history of variceal hemorrhage when their LSM and SSM were below their respective cut-off values.
Conclusions Our study suggests that in patients with CLD, SSM and LSM values could aid in identifying those with high risk of variceal bleed and the grades of esophageal varices. Hence majority of the patients who may never experience variceal hemorrhage, transient elastography (Fibroscan) will help to avoid invasive methods of assessment and prophylactic therapies.
Keywords CLD, Fibroscan, Liver stiffness, LSM, Spleen stiffness, SSM, Variceal bleed
358
Melioidosis presenting as splenic abscess: Case report and review of literature
Pranav Kumar 1 , Chhagan Lal Birda 2 , Yadav Suresh Chand 1 , Taruna Yadav 3 , Ashish Agarwal
Correspondence – Ashish Agarwal - [email protected]
Departments of 1Medicine, 2Gastroenterology, and 3Radiology, All India Institute of Medical Sciences, Marudhar Industrial Area, 2nd Phase, M.I.A. 1st Phase, Basni, Basni, Jodhpur 342 005, India
Introduction Melioidosis is an infectious caused by gram-negative bacilli Burkholderia pseudomallei. It has a wide variety of clinical presentations. Presentation as a splenic abscess is relatively rare and a high index of suspicion is needed for the diagnosis. In this case report, we report an interesting case of recurrent splenic abscess which was eventually diagnosed to be due to melioidosis.
Methods Melioidosis is an emerging infectious disease resulting from infection with a gram-negative bacterium. It is endemic in India but is rarely suspected and diagnosed. It has a varied presentation and is aptly called the “great mimicker”. In this case report, we have presented a case of recurrent splenic abscess which was diagnosed as Melioidosis. Although the presentation was typical, due to limited awareness and suspicion, the diagnosis was delayed.
Results Thirty-seven-year-old male patient, chronic alcoholic, presented with fever and left hypochondriac severe pain for last 3 days. He had a history of similar presentation four times in the last 1 year when he was managed with empirical antibiotics. He had also received empirical ATT 2 years back when he had presented with fever with imaging suggestive of enlarged mediastinal lymph nodes. A contrast-enhanced computed tomography (CECT) abdomen was suggestive of ruptured splenic abscess, which showed growth of B. pseudomallei on culture. A review of previous imaging showed hypoechoic lesions in the spleen in the CT done 2 years back and a ruptured splenic abscess 6 months back. The patient was treated with a prolonged course of antimicrobials specific for B. pseudomallei, with which the patient has improved.
Conclusion B. pseudomallei should be suspected in patients with deep-seated abscesses. Increased awareness and suspicion and prolonged treatment with specific antibiotics if curative in this otherwise fatal infection.
Keywords Burkholderia, Diabetes, Tuberculosis
359
Carotid intima-media thickness as a surrogate marker of cardiovascular disease in patients with inflammatory bowel disease
Jithin John, Anju Krishna K, Ravindra Pal, Avisek Chakraborty, Rushil Solanki, Devika Madhu, Vijay Narayanan, Shivabrata Dhal Mohapatra, Swetha Sattanathan, Aditya Verma, Srijaya Sreesh, Sandesh K*, Krishnadas Devadas
Correspondence- Jithin John - [email protected]
Department of Medical Gastroenterology, Government Medical College, Ulloor - Akkulam Rpad, Chalakkuzhi, Thiruvananthapuram 695 011, India and *Department of Medical Gastroenterology, Government Medical College, Gandhi Nagar, Kottayam 686 008, India
Background and Objectives There is an increased risk of cardiovascular disease in patients with inflammatory bowel disease (IBD), even without conventional risk factors. We compared the carotid intima-media thickness (CIMT), a surrogate marker for atherosclerosis, of subjects with and without IBD to study the cardiovascular risk. We also studied other factors affecting CIMT in IBD.
Methods A descriptive study on 280 subjects with and without IBD. Subjects aged more than 55 years, obese individuals, patients already diagnosed with cardio/cerebrovascular disease, and those with other chronic inflammatory conditions were excluded. Baseline data including CIMT was recorded. The quantitative data were compared using the Student’s t-test and the qualitative data by Chi-square test. Pearson and Spearman’s correlation was done to find out the factors correlating with CIMT.
Results Both groups were comparable in terms of age, sex distribution, and traditional cardiovascular risks (hypertension, diabetes, and dyslipidemia). The IBD group had 55.71% patients with ulcerative colitis (UC) and 44.28% with Crohn’s disease (CD). The CIMT was higher in patients with IBD as compared to controls (0.532±0.091 vs. 0.476±0.038, p=.000). In patients with IBD, those with n. on-alcoholic fatty liver disease (NAFLD) had an increased CIMT (0.561±0.099 vs. 0.490±0.053, p=.000). Age, CRP, and ultrasound grades of the fatty liver had positive correlations with CIMT. There was no change in CIMT with disease type (UC/CD), the extent of disease, disease activity, or severity of the disease. Multivariate regression analysis showed that age and ultrasound grading of fatty liver (R2 =0.576, p=.000) were independent predictors of higher CIMT. Fibrosis score by 2D-SWE was significantly higher in the IBD group (6.6±1.8 vs. 5.6±1.3, p=.000).
Conclusion As compared to the control group, CIMT was increased in patients with IBD. Age and NAFLD were independently associated with increased CIMT in IBD. Enhanced monitoring for cardiovascular events may be required in patients with IBD especially those with NAFLD.
Keywords Carotid intima-media thickness, Inflammatory bowel disease, Non-alcoholic fatty liver disease
360
Irritable bowel syndrome complicating asymptomatic nonrotation of midgut
Vikas Reddy, Bhashyakarla Ramesh Kumar, Malladi Uma Devi, Sahitya Reddy, Suraj Kumar, Rahul Vijay Vargiya
Correspondence - Vikas Reddy- [email protected]
Department of Medical Gastroenterology, Osmania Medical College, 5-1-876, Turrebaz Khan Road, Troop Bazaar, Koti, Hyderabad 500 095, India
Introduction Nonrotation is a part of spectrum of anatomic anomalies comprising malrotation. Most cases are symptomatic and managed surgically with a Ladd's procedure. However, incidental discovery of asymptomatic patients has also been reported. In these cases, role of surgery is debated. Malrotation is a collection of several distinct anatomic anomalies, which can be described based on the location of duodenal-jejunal junction and cecum. Most common anomaly is nonrotation of duodenum and cecum, in which both pre-arterial and post arterial midgut are mispositioned. Despite the heterogeneity of anomalies grouped under heading of malrotation, treatment is rather homogeneous as patients with all types are treated with Ladd's procedures. While the role of surgery is clear in the setting of symptomatic disease, its role in asymptomatic malrotation has been challenged by a series of publications.
Methods Twenty-one-year-old male presented with complaints of cramping abdominal pain and constipation since 3 years. Pain is in periumbilical and suprapubic regions and is non radiating. No tenderness. Computed tomography scan of abdomen showed duodenal-jejunal junction is in right side of abdomen, as is entire small bowel. Large bowel is in left side of abdomen. Cecum is in left lower quadrant. Superior mesenteric vein is left and anterior to superior mesenteric artery.
Results Patient initially treated with polyethylene glycol 3350 and fiber supplementation which resulted in daily soft bowel movements. Patient has been without abdominal complaints for more than 6 months and a Ladd's procedure has not been recommended.
Conclusion Asymptomatic nonrotation of midgut can be considered for observation alone and does not necessarily require operative intervention. Functional bowel disorders can complicate evaluation and management of patients with otherwise benign anatomy and lead to unnecessary and ultimately ineffective operations. Thorough history and physical and radiographic evaluations are critical to appropriate treatment of stable patient.
Keywords Constipation, IBS, Nonrotation
361
RS3PE and pseudo-achalasia: A rare combination and an unusual presentation of metastatic cancer
Rishi Raman, Raya Venkatesh Reddy, Shiran Shetty, Balaji Musunuri
Correspondence - Rishi Raman - [email protected]
Department of Gastroenterology and Hepatology, Kasturba Medical College, Tiger Circle Road, Madhav Nagar, Manipal 576 104, India
Introduction Although Remitting Seronegative Symmetrical Synovitis with Pitting Edema (RS3PE) syndrome has been reported in malignancies including lung cancer, prostatic carcinoma, bladder cancer, myelodysplastic syndrome and adenosquamous lung carcinoma literature is sparse related to hepatic and luminal cancers. To our knowledge, pseudo-achalasia and RS3PE both occurring together in a patient with metastatic cancer is a rare occurrence.
Case Report A 60-year-old lady presented to us with history of progressive dysphagia since 4 months associated with progressive weight loss, symmetrical joint swelling involving both upper limbs for one month duration. She had bilateral pitting pedal edema. Evaluation revealed anemia (Hb of 9 g/dL), elevation of inflammatory markers (CRP 63 mg/L). The inflammatory polyarthritis was seronegative with rheumatoid factor and anti-CCP being normal. Upper GI endoscopy revealed a significantly dilated tortuous esophagus with food residue, with significant narrowing at GE junction, normal mucosa, with suspicion of achalasia. Esophageal manometry revealed findings of Achalasia (high IRP and aperistalsis in all the swallows). CT scan revealed a 3 cms lymph nodal lesion compressing the gastroesophageal (GE) junction, with multiple liver metastatic lesions. Biopsy done from the liver lesion was confirmative of malignancy. She was diagnosed as RS3PE with metastatic malignancy with lymph nodal compression at GE junction causing pseudoachalasia.
Discussion RS3PE is a distinct clinical syndrome, initially by McCarty et al. (1985), which was described as a distinct form of late-onset rheumatoid arthritis. It has been found to coexist with various rheumatic diseases, such as Sjogren's syndrome, polyarteritis nodosa, ankylosing spondylitis, sarcoidosis, amyloidosis, relapsing polychondritis and bronchiolitis obliterans organizing pneumonia. It is also found to be associated with various malignancies including hematological and solid tumors and represents a form of paraneoplastic syndrome. Pathogenesis is unknown but it has been hypothesised that VEGF promotes synovial inflammation and vascular permeability in patients with RS3PE syndrome causing pitting edema and synovitis.
Conclusion Pseudoachalasia and RS3PE presenting together as a first presentation of metastatic cancer is a rare occurrence.
Keywords Metastatic carcinoma, Pseudoachalasia, RS3PE
362
Serological response to vaccination against coronavirus disease-19 in patients with inflammatory bowel disease
Akash Mathur, Shikha Sahu, Uday C Ghoshal
Correspondence - Uday C Ghoshal - [email protected]
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raibareli Road, Lucknow 226 014, India
Background Vaccination against coronavirus disease-19 (COVID-19) is effective to prevent the occurrence or reduction in the severity of the infection. Patients with inflammatory bowel disease (IBD) are on long-term immunomodulator therapy, which may alter the serological response to vaccination against COVID-19. Accordingly, we studied, (i) serological response to vaccination against COVID-19 in IBD patients, and (ii) comparison of serological response in IBD patients with that in healthy controls.
Method A prospective study was undertaken during a 6-month period (July 2021 to January 2022). Blood samples were collected from vaccinated, unvaccinated IBD patients and vaccinated healthy controls. Seroconversion was assessed using COVID Kawachanti-SARS-CoV-2 IgG antibody detection ELISA kit (J. Mitra and Co. Pvt. Ltd., New Delhi, India) and optical density (OD) was measured at 450 nm. OD is directly proportional to the antibody concentration.
Result One hundred and thirty-two blood samples were collected from 97 IBD patients (85 [87.6%] ulcerative colitis and 12 [12.4%] Crohn’s disease). 41/71 (57.7%) unvaccinated and 60/61 (98.4%) vaccinated IBD patients tested positive (OD >0.3) for SARS-CoV-2 IgG antibodies. OD values were significantly higher in vaccinated IBD patients than unvaccinated IBD patients (1.31 [1.09-1.70] vs. 0.53 [0.19-1.32], p<0.001) and 16 vaccinated healthy controls (1.31 [1.09-1.70] vs. 0.64 [0.43-0.78], p<0.001). OD values of vaccinated healthy controls and unvaccinated IBD patients were comparable (0.64 [0.43-0.78] vs. 0.53 [0.19-1.32], p=0.882). 3/71 (4.22%) of the unvaccinated IBD patients reported to have recovered from COVID-19.
Conclusion Most IBD patients seroconvert after vaccination against SARS-CoV-2, similar to a healthy population in spite of being on drugs used to treat IBD. A large proportion of IBD patients had anti-SARS-CoV-2 antibodies even before vaccination despite a low frequency of occurrence of clinically recognized COVID-19 in the past suggesting occurrence of herd immunity.
Keywords Coronavirus disease-19, Inflammatory bowel disease, Vaccination
363
Hyperammonemic encephalopathy following sleeve gastrectomy: First report from India
Jitendra Mohan Jha , Avnish Kumar Seth
Correspondence - Jitendra Mohan Jha - [email protected]
Department of Medical Gastroenterology, Manipal Hospital, Sector 6, Dwarka, Delhi 110 075, India
Introduction Hyperammonemic encephalopathy (HAE) related to liver disease or shunt surgery is frequent. Rarely, HAE may occur in the absence of liver disease due to inborn errors of metabolism, drugs, parenteral nutrition, or infections by urease producing bacteria. We present a patient with HAE following bariatric surgery.
Case Report Forty-nine—year-old female who underwent sleeve gastrectomy for morbid obesity eight years ago, presented with insidious onset of altered sensorium over three days. There was no history of fever or seizure. She was on Thyroxine 100 mcg daily for primary hypothyroidism. On examination GCS was E2V3M5, weight 82 Kg with BMI of 28 Kg/m2. She was afebrile, BP 134/80, pulse 88/minute. There was no focal neurological deficit or signs of meningeal irritation. Investigations revealed Hb 9.1G/dL, WBC 5500 and platelets 1,52,00/c.mm. INR 1.3, sodium 140 mEq/L, creatinine 0.5 mg/dL, random blood sugar 110 mg/dL, bilirubin 1.3.g/dL, AST 42 and ALT 27 U/L. albumin 2.9 G/dL. X-ray chest was normal and NCCT head was normal. Plasma ammonia level was 345 mcg/dL. Ultrasound abdomen showed grade two fatty liver. Fibroscan showed F0-F1 fibrosis. She was started on L-Ornithine L-Aspartate, Lactulose and Rifaximin but sensorium continued to deteriorate, requiring intubation. Peak ammonia was 649 mcg/dL. CECT head showed marked cerebral edema with loss of demarcation of grey and white matter, loss of sulci and compression of lateral ventricles. She developed evidence of sepsis and multiorgan failure and died after six days.
Discussion Previous reports of HAE following Bariatric surgery describe the syndrome in females, up to 28 years following surgery, usually Roux-en-Y gastric bypass. Mechanism remains obscure but nutritional deficiency of Arginine and Zinc leading to unmasking of subclinical urea cycle defects and bacterial overgrowth have been proposed.
Conclusion HAE is a rare but potentially fatal complication of bariatric surgery.
Keywords Bariatric surgery, Hyperammonemic encephalopathy
364
Irritable bowel syndrome patients diagnosed by Rome IV criteria have greater symptom severity, worse quality of life and sleep disorder compared to those diagnosed by Rome III criteria
Anshika Varshney , Moni Chaudhary, Vamika Mansi Saigal, Uday C Ghoshal
Correspondence - Uday C Ghoshal - [email protected]
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raibareli Road, Lucknow 226 014. India
Background The changes in the diagnostic criteria for irritable bowel syndrome (IBS) from Rome III to Rome IV might have led to the selection of a group of patients with more severe symptoms and higher level of psychological co-morbidity. The relative paucity of data with some conflicting findings, demands further studies to examine the impact of change in IBS diagnostic criteria on symptom severity, sleep quality and quality of life.
Methods A total of 57 IBS patients were categorized as having IBS using Rome III and Rome IV questionnaires. The symptom severity was assessed using IBS-symptom severity score (SSS), quality of life by world health organization quality of life-BREF (WHOQOL-BREF) and sleep quality by Pittsburgh sleep quality index score (PSQI).
Results Of 57 IBS patients, 51 (89.5%) fulfilled the Rome III IBS criteria and 40 (70.2%) fulfilled the Rome IV criteria. Overall, 59.6% of Rome III IBS patients fulfilled the Rome IV criteria for IBS, but 40.4% did not. Rome IV-positive subjects were significantly more likely to have greater pain severity (4 [10%] vs. 0 [0%], p=0.041) and pain frequency (12 [30%] vs. 0 [0%], p<0.001); higher IBS-SSS score (median scores, 260 [187.5, 306.2] vs. 190 [150,215], p=0.005), and symptom severity than Rome IV-negative subjects. For the psychosocial alarm status, work impairment and abuse were higher in Rome IV-positive than the other patients.
Conclusion IBS patients positive by Rome IV criteria have more severe symptoms, pain frequency, work impairment and history of abuse than the Rome IV negative patients. Forty percent of Rome III-positive IBS patients fulfilled the Rome IV IBS criteria.
Keywords Irritable bowel syndrome, Sleeps disorders, symptom severity
365
Comparing the psychosocial health and quality of life in patients with ulcerative colitis and functional gastrointestinal disorders
Shikha Sahu, Moni Chaudhary, Sushmita Rai, Uday C Ghoshal
Correspondence - Uday C Ghoshal - [email protected]
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raibareli Road, Lucknow 226 014. India
Background Inflammatory bowel disease (IBD) patients after control of their disease activity may continue to have symptoms of functional gastrointestinal disorders (FGID), which may be associated with poorer quality of life. Moreover, patients with active IBD may have poor quality of life (QOL) because of their severe symptoms. Accordingly, we studied the psychological issues and QOL of patients with ulcerative colitis, those with FGID and healthy control.
Method Quality of life and psychological issues were assessed using World Health Organization quality of life-BREF (WHOQOL-BREF) and Rome III psychosocial alarm questionnaire, respectively. Data were obtained from 225 participants (100 UC patients, 100 FGID patients and 25 healthy controls). Severity of UC was assessed using ulcerative colitis disease activity index (UCDAI) and Truelove and Witt’s severity index.
Result Of 225 subjects, 100 UC patients (median age 36 years, range [28.0-48.7]; 47 [47%] male), 100 FGID patients (median age 38 years [range 29.0-51.0]; 44 [44%] male), and 25 controls (median age 29 years, [range 27-41], 15 [60%] male) had significant differences in all the four domains of WHOQOL-BREF: physical domain score (53.57 [42.85-53.57] vs. 53.57 [43.7-64.2] vs. 53.75 [50.0-62.5]; p=0.026), psychological domain score (54.16 [45.8-54.1] vs. 50.0 [37.5-62.5] vs. 66.87 [64.6-70.6]; p<0.001), social relationship domain score (66.6 [58.3-75.0] vs. 75.0 [66.0-75.0] vs. 75.0 [50.0-87.5]; p<0.001) and environment scores (median scores and range, 50.0 [46.8-59.3] vs. 59.37 [56.2-65.6] vs. 65.6 (53.1-78.1); p<0.001). The psychological QOL scores of FGID and IBD patients were comparable, whereas the parameters of Rome III psychosocial alarm questionnaire: depression, severity of body pain, impairment and impaired coping were lower in FGID patients. Suicidal tendency was higher in FGID as compared to IBD.
Conclusion UC patients in relapse have poorer social relationship and environment domain of QOL than FGID. Psychosocial alarm parameters are also greater in UC patients than FGID.
Keywords Functional gastrointestinal disorders, Quality of life, Ulcerative colitis
366
Case of primary disseminated intraabdominal hydatidosis
Sumit Suman, Harish Kulkarni, Prafulla K Singh, Sai Krishna Katepally, P Shravan Kumar
Correspondence - Sumit Suman - [email protected]
Department of Medical Gastroenterology, Gandhi Medical College and Hospital, Musheerabad, Padmarao Nagar, Secunderabad 500 003, India
Introduction Hydatidosis, a zoonotic disease caused by echinococcus granulosus sensu lato, can be primary or secondary. However primary disseminated intraabdominal hydatidosis is a rare form of the disease accounting for 2% of all intraabdominal cysts [1].
Case Presentation We report a case of primary disseminated intraabdominal hydatidosis with multiple organ involvement in a 40 year old man presenting with abdominal pain with abdominal distension for 2 weeks. Ultrasound and computed tomography revealed one cystic lesion of size 4.9*4.2*6.2 cm in segment VII of liver and a 10*9.7*12 cm sized cystic lesion in spleen, two cystic lesions adjacent to gallbladder fossa, one cystic lesion posterolateral to left kidney. Endoscopic ultrasound revealed a daughter cyst in hepatic cystic lesion. Enzyme linked immunosorbent assay for IgG Echinococcus was also positive. The patient was started on albendazole 400 mg twice daily and praziquantel 600 mg thrice daily. There was regression in cyst size at 2 months of follow-up.
Conclusion Although hydatidosis usually affect liver and lung, it can involve other organs, albeit less frequently. The cystic lesion of the disease can be primary or secondary [2], while a rare form of primary hydatidosis, Disseminated intraabdominal hydatidosis accounts for 2%. Such dissemination occurs through lymphatic or systemic circulation.
While surgical excision is the mainstay of treatment for localized hydatid cysts or cysts with infection and multiple septae, management of disseminated disease is medical therapy in the form of albendazole [3].
References
1. Anandpara KM, Aswani Y, Hira P. Disseminated hydatidosis. BMJ Case Rep. 2015;2015: bcr2014208839.
2. Meera M, Vrushali T, Tanaya LK. Primary multiple intraventricular hydatid cysts in a child. Trop Parasitol. 2018; 8:47–9.
3.Brunetti E, Kern P, Vuitton DA; Writing Panel for the WHO-IWGE. Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans. Acta Trop 2010; 114:1-16.
Keywords Echinococcus granulosus sensu lato, Hydatidosis
367
Strongyloides hyperinfection causing refractory gastrointestinal bleed in an immunocompromised patient - A rare presentation
Chitikeshwarapu Sai Kumar , Chandragiri Praneeth
Correspondence – Chandragiri Praneeth - [email protected]
Department of Gastroenterology, Asian Institute of Gastroeneterology, 6-3-661, Somajiguda, Hyderabad 500 082, India
A 34-year-old male with diffuse motor and sensory demyelinating poly radiculoneuropathy (post rabies vaccine) on azathioprine and steroids presented with fever, abdominal pain, bilious vomiting and black, tarry stools since 15 days. On examination abdomen showed mild epigastric tenderness. His hemoglobin was 7 gm%. Contrast-enhanced computed tomography (CECT) abdomen revealed circumferential wall thickening of the pylorus and D1, D2 segments with active bleed in duodenum. Upper GI endoscopy showed multiple large deep ulcerations with nodular and edematous mucosa with active bleeding in stomach, D1, D2 duodenum and proximal jejunum.
Biopsies revealed active gastritis and chronic active duodenitis, with associated strongyloides infection. Steroids were stopped and the patient was started on oral ivermectin and albendazole. With a continued drop in hemoglobin, empirically underwent coil embolization of GDA and SPDA initially and later Whipple’s pancreaticoduodenectomy procedure after a multidisciplinary meet. Histopathology showed numerous eggs, rhabditiform larvae and adult worms of strongyloides in the glands, crypts and the muscularis propria from gastric and duodenal sections. Ivermectin and albendazole were continued.
Conclusion This rare diagnosis displays the importance of screening patients at a high risk of Strongyloides infection before starting glucocorticoids.
Keywords Immunocompromised, Strongyloides hyperinfection, upper gastrointestinal bleed
368
Interesting case of ascites
Nitin Pai , Sahil Rasane, Chaitanya Lodha
Correspondence – Sahil Rasane - [email protected]
Department of Gastroenterology, Ruby Hall Clinics, 40, Sasoon Road, Sangamvadi, Pune 411 001, India
Introduction Eosinophilic gastroenteritis is a rare and heterogeneous gastrointestinal disorder. Definitive diagnoses requires histological demonstrations of eosinophilic infiltration of the gastrointestinal wall or high eosinophil count in ascitic fluid, absence of extragastrointestinal eosinophilic infiltration and exclusion of other diseases. The Klein classification, where patients are arbitrarily divided into those with predominantly mucosal, muscle layer or subserosal disease, is widely used. We report a case of eosinophilic ascites and how we managed our patient.
Case Report A 35-year-old gentleman came with complaints of insidious onset abdominal distension for 3 weeks which was progressively increasing. Abdominal examination revealed free fluid in abdomen. On evaluation, complete blood count showed eiosinophilia, gastroscopy and ileocolonoscopic mucosal biopsies were normal, ascitic fluid analysis showed low SAAG high protein ascites with 55% eosinophils which led to the diagnosis of eosinophilic ascites. The patient was treated with dietary modifications and oral steroids. Ascites was resolved within 1 week of starting treatment.
Conclusion Eosinophilic gastroenteritis is a rare cause of ascites. The pathogenesis of this disease remains obscure, but the diagnosis should not be missed. Steroids remain the mainstay of therapy for eosinophilic gastroenteritis with good symptomatic response as also seen in our case.
Keywords Ascites, Eosiniphilic ascites, Eosinophilic gastroenteritis, Steroids, Unexplained ascites
369
Chronic recurrent multifocal osteomyelitis of the ribs associated with ulcerative colitis : A case report
Aradya H V, Ganesh Koppad, Nandeesh H P, Deepak Suvarna, Vijaykumar T R, Sharathchandra K K, Devansh Bajaj, Abhishek Kabra
Correspondence - Ganesh Koppad - [email protected]
Department of Medical Gastroenterology, J S S Hospital, Mahatma Gandhi Road, Fort Mohalla, Mysuru 570 004, India
Introduction Chronic recurrent multifocal osteomyelitis (CRMO) is a condition characterized by sterile bone inflammation of unknown etiology. Most cases of CRMO are associated with Crohn’s disease; very few are associated with ulcerative colitis; We report a case of CRMO associated with inflammatory bowel disease-ulcerative (IBD-UC).
Methods and Results A 31-year-old male patient known case of IBD–UC on tab mesalamine presented with fever, right sided chest wall pain and swelling, melena since 3 days, O/e multiple subcutaneous swellings were seen over the right chest wall which were tender and there was local rise of temperature. Hb was 6.1 g%, platelets 10.02 lacs, TLC 20410 cells/cumm, CRP 58.13 mg/L, ESR 60 mm, serum procalcitonin 6.83. There was no growth on blood culture, USG thorax showed an ill-defined hetroechoic collection/phlegmon measuring 7.4 × 5.2 × 4.4 cms encasing right 5th and 6th ribs with its destruction and cortical irregularity. CECT thorax confirmed the same, aspiration of the pus was done, grams stain was negative, pus culture was negative, AFB staining and CBNAAT from pus sample was negative. He was treated empirically with IV antibiotics and supportive treatment, However, pain and fever persisted till day 10. UGI endoscopy showed multiple clean based ulcers in D1, colonoscopy revealed multiple pseudopolyps.
Conclusion On the basis of patient’s clinical course, diagnosis of CRMO associated with UC was confirmed, Treatment with mesalamine was continued and Tab Prednisolone /Azathioprine were initiated, there was improvement in the symptoms and resolution in the chest wall abscess after intensifying immunosuppression in the form of steroids / Azathioprine, To conclude the association of IBD–UC with CRMO is rare, physicians should be aware of the possibility of CRMO associated with UC when bone related symptoms are encountered in cases of IBD.
Keywords Azathioprine, CRMO, Osteomyelitis, Steroids, Ulcerative colitis
370
Eosinophilic disorders of gastrointestinal tract - A case series
Dandi Kranthi, Suhas Udgirkar, Amol Dahale
Correspondence – Amol Dahale - [email protected]
Department of Medical Gastroenterology, Dr D Y Patil Medical College, Hospital and Research Centre, Pune 411 018, India
Introduction Eosinophilic gastrointestinal (GI) disorders are chronic, immune mediated disorders characterized histologically by a pathological increase in eosinophilic predominant tissue inflammation and clinically by GI symptoms Primary eosinophilic GI diseases include five variants according to their localization on their GI tract : Esophagitis, gastritis, gastroenteritis, enteritis, colitis. Eosinophilic gastroenteritis is classified according to the most infiltrated layer of intestinal wall in the form of mucosal, muscular and serosal involvement.
Methods Twelve patients in the study of which 8 patient had eosinophilic eosophagitis, 4 patient had eosinophilic gastroenteritis were analyzed from June 2021 to May 2022 based on review of biopsy results from previous endoscopies and colonscopies. All the patients with eosinophilic esophagitis defined as 15 eosinophils/HPF. Biopsy sample were taken from mid and distal esophagus, stomach, duodenum and jejunum.
Results The mean age in the study population was 32 yrs, males effected were 91.63%, females were 8.37%. Most common presentation was dysphagia (50%), intermittent food impaction was seen in 16.6%, abdominal pain in 33.3%. Mean duration of follow-up was 6months, 1 patient was treated with elimination diet, 3 patients with local (inhalational steroids) and 8 patients with systemic steroids. All patients responded well and on regular follow-up.
Conclusion Eosinophilic disorders of GI tract were uncommon but not rare, high degree of suspicion is required and are easily treatable.
Keywords Elimination diet, Eosinophilic esophagitis, Eosinophilic gastroenteritis, Steroids
371
An interesting case of celiac crisis in adulthood
Nitin Pai, Sahil Rasane, Chaitanya Lodha
Correspondence – Sahil Rasane - [email protected]
Department of Gastroenterology, Ruby Hall Clinics, 40, Sasoon Road, Sangamvadi, Pune 411 001, India
Introduction Celiac crisis is rare in adults. It is life threatening syndrome with high mortality thus the need to identify early. The prevalence of celiac crisis is adults is less than 1% in India and only 12 reported cases in literature. Here we present a case of celiac crisis in an adult female and how we managed our patient.
Case Report Thirty-two-year-old female came with diarrhea of large volume, watery stools since more than 2 weeks with no blood, 8 to 10 per day with nocturnal episodes as well associated with colicky abdominal pain, nausea and vomiting for 7 days, myalgia and generalized weakness. She was initially treated by a local physician with IV antibiotics, IV fluid and supportive care. Patient then developed hypotension and was shifted to our centre. Her routine workup revealed anemia, deranged electrolytes, metabolic acidosis and hypoproteinemia. contrast-enhanced computed tomography (CECT) abdomen was suggestive of mild hepatomegaly. Patient was admitted to the intensive care unit (ICU) and started with supportive management, IV empirical antibiotics and IV fluids. Even after 4 days there was no improvement in the patient’s overall condition and hence endoscopy was performed which was suggestive of celiac crisis, confirmed on histopathology. Patient was managed with steroids, strict gluten-free diet, and supportive correction nutritional deficiencies, with good response to therapy and discharged on day 10 of steroids.
Conclusion The need for early identification is crucial in patient with celiac crisis because of high mortality index, but the management remain conservative with control of immune system activation and bowel inflammation.
Keywords Celiac crisis, Celiac disease in adults, Uncontrolled dirrhea
372
Lead as an unusual cause of acute pain abdomen: Case report
Manish Kak, Charu Agarwal, Rajesh Bhardwaj, Vinca Kaulkak
Correspondence – Manish Kak - [email protected]
Department of Gastroenterology, Manipal Hospital, Ghaziabad, NH-24, Hapur Road, Pandav Nagar, Ghaziabad 201 002, India
Acute pain abdomen is a common day to day symptom in GI practice; usual diagnosis is achieved by history taking, blood tests, imaging, and endoscopy; however, at times we have a patient who does not fit in any clinical syndrome; usually such patients are labelled as IBS; we present once such case that presented with acute, unrelenting pain abdomen, his routine workup was negative, finally diagnosed as lead toxicity.
Keywords Acute abdomen, Blood lead levels, Lead toxicity
373
Role of tofacitinib as an adjunct to intravenous corticosteroids in the management of acute severe ulcerative colitis: An interim analysis
Manjeet Goyal , Arshdeep Singh, Shivam Kalra, Ajit Sood
Correspondence – Manjeet Goyal - [email protected]
Department of Medical Gastroenterology, Dayanand Medical College and Hospital Tagore Nagar Civil Lines, Ludhiana 141 001, India
Acute severe ulcerative colitis (ASUC) is a medical emergency and a potentially life-threatening condition requiring hospitalization. Intravenous steroids are the mainstay of therapy, but 30; 40% of patients will fail to respond to steroids and require progression to rescue therapy. The current study aimed to evaluate the role of tofacitinib in reducing steroid refractoriness when used as an adjunct to intravenous corticosteroids.
Keywords Inflammatory bowel disease, Tofacitinib, Ulcerative collitis
374
Etiological spectrum of mediastinal and intra-abdominal lymphadenopathy diagnosed by endoscopic ultrasound guided fine needle aspiration
Sagar G
Correspondence – Sagar G - [email protected]
Department of Medical Gastroenterology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad 500 082, India
Introduction Evaluation of mediastinal and abdominal lymphadenopathy is a great diagnostic challenge considering the myriad of causes. Tuberculosis is reported as the commonest etiology but the diagnosis still remains a challenge due to inaccessibility to these sites. In recent years, the role of endoscopic ultrasound (EUS) has been greatly extended in evaluation of lymphadenopathy due to its safety, and accuracy. There is a scarcity of data from India about the etiology of intra-abdominal and mediastinal lymphadenopathy and hence the present study was conducted.
Methods A retrospective study was conducted after reviewing hospital records from July 2021 to July 2022 who underwent EUS-guided fine needle aspiration (FNA). A total of 80 patients with mediastinal and/or intra-abdominal lymphadenopathy detected by cross-sectional imaging were examined for clinical features, EUS, and histopathology records.
Results A total of 70 patients (68% male, n=47) were identified with mean age of 43.5 years. Fifty-four patients (77.1%) had mediastinal lymphadenopathy and 16 (22.8%) had abdominal lymphadenopathy. The median number of needle passes was 2 (range: 1–4). The majority of patients in the mediastinal EUS group had tubercular etiology 31% (n=17) followed by metastases 24% (n=13). Other etiologies were reactive-12% (n=7), lymphoma-5% (n=3), sarcoidosis-1 and Aspergillosis-1. The diagnosis was inconclusive in 22% (n=12) of patients.
In the abdominal group, metastasis 43% (n=7) was the most common etiology followed by TB (n=3), lymphoma (n=1) and reactive (n=1). 25% (n=4) had inconclusive report. There was no significant difference between the two groups with respect to the proportion of patients with tubercular and malignant etiology. Seven patients underwent repeat procedure. There were no complications related directly to the procedure.
Conclusion Tuberculosis was the most common cause of mediastinal lymphadenopathy and metastasis was the most common etiology of abdominal lymphadenopathy. EUS FNA is an important modality for the diagnosis of mediastinal and intra-abdominal lymphadenopathy.
Keywords Abdominal lymphadenopathy, EUS-FNA, Mediastinal lymphadenopathy
375
Mastocytic enterocolitis as a rare cause of recurrent abdominal pain
Vamshi A, Adarsh C K, Bhuvan Shetty, Pooja K
Correspondence – Vamshi A - [email protected]
Department of Medical Gastroenterology, B G S Gleneagles Global Hospitals, 67, Uttarahalli Main Road, Sunkalpalya, Bengaluru 560 060, India
Introduction Abdominal pain is a frequent complaint that causes patients to visit an emergency department. In most cases, a cause can be identified during initial work-up, however there are few cases where the diagnosis may not be straight forward. Mastocytic enterocolitis is a rare disorder characterized by an increased number of gut mucosal mast cells (>20 per high power field) that are revealed by immunohistochemical demonstration of mast cell tryptase. This disorder can be easily missed if immunohistochemical staining for mast cells is not done.
Case Report A 26-year-old female patient presented with complaints of recurrent pain abdomen since 20 days in the epigastric and periumbilical region, severe in intensity, associated with multiple episodes of non-bilious vomitings. No history of radiation of pain, no aggravating or relieving factors. On examination HR-120 bpm, BP-110/70 mmHg. Mild epigastric tenderness was present. Baseline investigations done were normal. Amylase, lipase were normal. CRP was 12. Contrast-enhanced computed tomography (CECT) abdomen showed few prominent mesenteric lymph nodes in the epigastric region. On day 2, she had severe abdominal pain and tachycardia. She was shifted to ICU and managed with analgesic infusions. Urine porphobilinogen and serum lead levels were normal. Upper GI endoscopy showed few superficial gastroduodenal erosions. and colonoscopy was normal. Duodenal, ileal and colonic biopsies showed increased cellularity of lamina propria composed of lymphocytes and plasma cells and also spindle to plasmacytoid cells with fine granular cytoplasm, mast cells (30/HPF) . Immunohistochemistry staining with CD117 showed increased mast cells.
Conclusion It is important to consider mastocytic enterocolitis in the differential diagnosis when evaluating patients with unexplained abdominal pain as these patients typically respond well to histamine receptor antagonists, antileukotrienes and inhibitor of mast cell degradation.
Keywords Abdominal pain, Mast cells, Mastocytic enterocolitis
376
Acute intermittent porphyria- Commonly missed well known entity: Case series report
Ajay Jain, Amber Mittal, Shohini Sircar
Correspondence – Amber Mittal - [email protected]
Department of Gastroenterology, Choithram Hospital and Research Centre. 14, Manik Bagh Road, Indore 452 014, India
Introduction Acute intermittent porphyria (AIP) is an autosomal dominant disorder resulting from partial deficiency of porphobilinogen deaminase enzyme in haem biosynthetic pathway. The presentation of AIP as an acute abdomen is well known but a short duration of gastrointestinal symptoms followed by rapidly progressive neuropsychiatric manifestations may also occur thereby misleading the diagnosis.
Report of the Cases A 14-year-old female presented in emergency with sudden onset diffuse, severe excruciating abdominal pain for 5 days, vomiting multiple episodes since 4 days. There was no history of fever, weight loss, altered bowel habit, abdominal distension. She had similar episode 4 months back requiring hospitalization. Family history for AIP was positive. On examination vitals were stable. Abdominal examination revealed non distended diffusely tender abdomen with sluggish bowel sounds. Blood investigations revealed anaemia, sodium-116 mEQ/L, urine PBG: Positive. Next day patient developed generalized tonic clonic seizures with vision loss. Magnetic resonance imaging (MRI) brain s/o posterior reversible encephalopathy (PRES).
Another case of 15-year-old female presented to emergency with severe excruciating diffuse abdominal pain since 7 days with absolute constipation since 3 days. On examination vitals were stable, on per abdomen examination abdomen was diffusely tender. Investigations revealed hyponatremia and urine for PBG: Positive. During hospital stay she had a episode of generalized tonic clonic seizure. MRI brain s/o PRES. Both patients were managed conservatively with IV fluids, antiepileptics along with correction of hyponatremia.
Conclusion Diagnosis of AIP requires high degree of clinical suspicion. Diagnosis of AIP is difficult due to constellation of diverse symptoms involving multiple systems AIP is a life threatening disease, so correct diagnosis and proper management plan regarding abortive and preventive therapies, treatment of acute crisis are crucial to save life of the patient. The patient should be referred to genetic specialist for family screening.
Keywords Acute abdomen, Hyponatremia, Seizures
377
Gastrointestinal and hepatic manifestations in Corona virus disease-19 - A data from western India
Dhaval Gupta, Nilesh Pandav, Palak Shah
Correspondence – Dhaval Gupta - [email protected]
Department of Medical Gastroenterology, G C S Medical College, Hospital and Research Center, Naroda Road, Ahmedabad 380 025, India
Background An increasing number of studies have reported gastrointestinal (GI) symptoms and liver injury in patients with Corona virus disease-18 (COVID-19). Early identification of GI manifestations is not only crucial in management but also of public health importance.
Aims and Objectives. We aim to study relationship between COVID-19 and GI and hepatic manifestations focusing on both clinical findings and their impact on outcomes.
Methods We retrospectively analyzed the data from 630 patients admitted in GCS Medical College, Hospital and Research Center, Ahmedabad during May 2020 till December 2021.
Results and Discussion Among patients with GI manifestations 30.8% had vomiting and 29% had diarrhea. In patients with GI manifestations 64.4% of cases had mild covid infection, 15.5%, 12.8% and 7.3% of cases had moderate, severe and critical covid respectively (p value < 0.005). Among patients with mild COVID, 38 % had exclusive GI manifestation, 30 % had both GI and respiratory, 24% had only respiratory manifestations, 8% had neither of them (p<0.005). Sixteen percent of cases with GI manifestations required oxygen support compared to that of patients with respiratory manifestations who required oxygen support in 48.6% of the cases. Twelve percent of patients with GI manifestations required ventilatory support. Patients with exclusive GI manifestations had 1.2% mortality whereas those with combined GI and respiratory manifestations had a mortality of 18.6%. 23.5% of the patients had deranged liver function tests. Amongst patients with deranged LFTs, bilirubin, AST, ALT, ALP and GGT were elevated in 37.5%, 32.1%, 22.2%, 3% and 12% of cases respectively. Abnormal LFTs were associated with higher mortality.
Conclusion COVID patients with GI manifestations has favorable outcomes with reduced severity, shorter hospital stay, reduced need for O2 support, lesser mortality whereas abnormal LFT favoured severe covid, longer hospital stay, increased need for O2 support and higher mortality.
Keywords COVID-19, Gastrointestinal, Hepatic
378
A rare case of drug induced badycardia in inflammatory bowel disease
Devamsh G N, Mallikarjun
Correspondence – Devamsh G N - [email protected]
Department of Medical Gastroenterology, St. John's Medical College, Sarjapur - Marathahalli Road, John Nagar, Koramangala, Bengaluru 560 034, India
A 45-year-old female presented to the hospital with bloody diarrhea and weight loss since 1 month. On evaluation, patient was diagnosed to have acute flare of ulcerative colitis. She was started on prednisone and mesalamine. Within 24 hours of initiation of mesalamine, patient developed giddiness and chest discomfort. She was found to have sinus bradycardia on ECG. After withdrawing mesalamine, the heart rate returned to normal within 24 hours. This is a rare case report of severe symptomatic sinus bradycardia due to mesalamine therapy. To our knowledge, only four cases of mesalamine induced bradycardia have been reported so far in literature. Clinicians should be aware of this serious adverse effect of mesalamine and keep a look out for bradycardia in patients on mesalamine. Further research is required to establish the mechanism, natural history and prognosis of bradycardia in patients receiving mesalamine.
Keywords Bradycardia, IBD, Mesalamine
379
Utility of MGIT culture and Xpert MTB RIF assay in diagnosing extraintestinal intraabdominal tuberculosis
Polavarapu Jagadish 1 , Hemanth Chinthala1, Joy Sarojini Michael2, Lalji Patel1, Shaleen Dass1, Ajith Thomas1, Anoop John1, Reuben Thomas Kurian1, Rajeeb Jaleel1, Sudipta Dhar Chaudhury1, Ebby George Simon1, Joseph A J1, Anna Pulimood3, Amit Kumar Dutta1
Correspondence – Polavarapu Jagadish - [email protected]
Departments of 1Gastroenterology, 2Microbiology, and 3Pathology, Christian Medical College, Ida Scudder Road, Vellore 632 004, India
Introduction Diagnosis of abdominal tuberculosis relies on microbiological tests to detect M tuberculosis and histopathology. Newer microbiological tests like MGIT (culture test for M tb) and Xpert (PCR test for M tb) have an established role in diagnosing pulmonary TB. This study aimed at assessing the diagnostic accuracy of these tests in extra-intestinal intraabdominal tuberculosis (EIATB).
Methods We conducted a retrospective study among patients diagnosed with EIATB. The clinical and investigation details were recorded on a data sheet. This included nature and duration of symptoms and site of lesion. The sample was acquired under radiological guidance and sent for histopathology, MGIT culture and Xpert test. Final diagnosis of EIATB was based on the presence of histopathology findings suggestive of tuberculosis or positive microbiological test for tuberculosis or response to ATT. Yield of MGIT and Xpert tests were calculated for diagnosis of EIATB.
Results We included twenty-eight patients with EIATB. Their mean age was 47.8+13.6 years and 16 (57.1%) were males. Fever was present in 60.7% and abdominal pain in 35.7% cases. Tissue sample for diagnosis of TB was obtained from omentum in 16 (57.1%), intraabdominal lymph node in 7 (25%) and other sites in 5 (17.9%) patients. Histopathology supported a diagnosis of TB in 67.9% cases. Xpert test was positive in eight (28.6%) cases. MGIT culture was positive in 3 (10.7%) of whom two also had a positive Xpert test. The combined sensitivity of the two tests together was 32.1%. Six of the seven intra-abdominal lymph node tissue had a positive Xpert test while none of the omental tissue sample showed a positive result for this test.
Conclusion Microbiological tests can help in the diagnosis of EIATB in about one-third of cases, especially when the tissue is obtained from intra-abdominal lymph nodes.
Keywords Intraabdominal tuberculosis, MGIT culture, Xpert TB
380
Kikuchi fujimoto disease rare presentation
Dattatray Patki
Correspondence – Dattatray Patki - [email protected]
Department of Medicine, Poona Hospital, Sadashiv Peth, Pune 400 030, India
Patients with Kikuchi disease have been misdiagnosed as having lymphoma and treated with cytotoxic agents. Other conditions that have been confused with Kikuchi disease are tuberculous adenitis, lymphogranuloma venereum, and Kawasaki disease. Neurologic symptoms are increasingly reported, including aseptic meningitis, meningoencephalitis, acute cerebellar symptoms with tremor and ataxia, and optic neuritis. Aseptic meningitis is the most common neurological complication, usually at the time of the lymphadenopathy. Given that lymphadenopathy is a common presentation, it is important for physicians to be cognizant of Kikuchi disease in the differential diagnosis of lymphadenopathy to prevent misdiagnoses and unnecessary treatments.
Keywords Kikuchis disease
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| 36512172 | PMC9745698 | NO-CC CODE | 2022-12-15 00:02:40 | no | Indian J Gastroenterol. 2022 Dec 13;:1-124 | utf-8 | Indian J Gastroenterol | 2,022 | 10.1007/s12664-022-01305-9 | oa_other |
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Article
Clinical efficacy and safety of intravitreal fluocinolone acetonide implant for the treatment of chronic diabetic macular oedema: five-year real-world results
http://orcid.org/0000-0003-3984-6014
Dobler Emilie [email protected]
Mohammed Bashar Raouf
Chavan Randhir
Lip Peck Lin
Mitra Arijit
Mushtaq Bushra
grid.414513.6 0000 0004 0399 8996 Birmingham and Midland Eye Centre, Birmingham, UK
13 12 2022
16
13 6 2022
24 10 2022
28 11 2022
© The Author(s), under exclusive licence to The Royal College of Ophthalmologists 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Background/Aim
To report 5-year real-world efficacy and safety data following the treatment of chronic diabetic macular oedema (DMO) with the intravitreal 0.19 mg fluocinolone acetonide implant(ILUVIEN).
Methods
Retrospective cohort study of 31 eyes treated with ILUVIEN for chronic DMO at a tertiary centre in Birmingham (UK). Best corrected visual acuity (BCVA) and central retinal thickness (CRT) were recorded at baseline, and then at 1-,2-,3-, and 5-years. Safety was assessed based on intraocular pressure (IOP) -lowering medication, surgery, and other complications.
Results
BCVA significantly improved 1-year post-ILUVIEN (+4.2 letters, p < 0.05) and gradually reverted to baseline levels over the 5-year period of follow-up (+0.2 letters at year-5). A significant and sustained CRT reduction was observed throughout the 5-years. The proportion of eyes on IOP-lowering medication increased from 16% at baseline, to 70% at 5-years (p < 0.001) with eyes on a mean of 1.3 medications. Laser trabeculoplasty (n = 2), cyclodiode laser (n = 1), and trabeculoplasty and trabeculotomy (n = 1, in the same eye; 3.2%) were required for uncontrolled IOP. Other complications included endophthalmitis (n = 1) and vitreous haemorrhage (n = 1). 58% of eyes required additional intravitreal injections, with a mean 29.2 months to first injection. We observed a 69% reduction in treatment burden following treatment with ILUVIEN implant.
Conclusions
Our real-world results confirm the efficacy of the ILUVIEN implant over 5 years, with two-thirds of eyes having improved or stable visual acuity 5 years after ILUVIEN, and an overall sustained improvement in anatomical outcome. Although the rate of IOP-lowering medications use was higher than previously reported, the rate of incisional IOP-lowering surgery and other complications remained low and in keeping with rates reported in larger studies.
Subject terms
Diabetes complications
Drug therapy
Retinal diseases
==== Body
pmcIntroduction
Diabetic macular oedema (DMO) is a leading cause of visual loss in young adults in developed countries. It is a multifactorial condition, which directly impairs central vision, affecting 12% of Type 1 and 28% of Type 2 diabetics within 9 years of diagnosis [1]. Its treatment used to be limited to focal/grid macular laser photocoagulation and sub-Tenon or intravitreal short-acting corticosteroid injections, such as the off-label use of triamcinolone acetonide [2, 3]. In recent years, anti-VEGF agents, such as Ranibizumab and Aflibercept, have transformed the treatment of DMO and become first-line options [4]. Nevertheless, for an estimated 40% of patients, response to anti-VEGF remains sub-optimal [5]. In such cases, intravitreal corticosteroids remain a valuable alternative pharmacological option by targeting alternative pathways to VEGF, in particular sustained-release implants of dexamethasone (Ozurdex®, Allergan Inc., Irvine, California) and fluocinolone acetonide (ILUVIEN®, Alimera Sciences Ltd.; Alpharetta GA, USA) [6–9].
ILUVIEN provides a slow-release preparation of fluocinolone acetonide 0.19 mg and is approved by regulators in the UK for the treatment of chronic DMO that is insufficiently responsive to alternative therapies in eyes with a pseudophakic lens and it offers the advantage of prolonged clinical effects lasting for up to three years [10, 11]. Its effectiveness and safety have been well established in several clinical trials, with the most common adverse effect reported being cataract formation and elevated intraocular pressure (IOP) [12, 13]. Several reports of real-world outcomes of chronic DMO treatment with ILUVIEN have been published with 3 years of follow-up reported [14–17]. To our knowledge, this is the first long-term report of real-world safety and efficacy of intravitreal ILUVIEN implant over a 5-year follow-up period in a cohort of 31 eyes at a tertiary ophthalmology centre in Birmingham, United Kingdom.
Materials and Methods
Study design
This a retrospective study of a cohort of patients who have been treated for chronic DMO with an intravitreal ILUVIEN implant (fluocinolone acetonide 0.19 mg) over a three-year period (2014–2016) at the Birmingham and Midland Eye Centre (UK). Clinical records were used to identify patients meeting these criteria and n = 60 treated eyes were identified as part of this real-world cohort. No ethics committee approval was required, as this data was collected retrospectively for departmental clinical effectiveness purposes. This analysis was conducted in accordance with the Declaration of Helsinki and the UK’s Data Protection Act. Patients gave informed consent for all investigations and treatments.
Due to the retrospective nature of this study, the COVID-19 pandemic caused some disruption to the timing of 5-year follow-up visits for patient treated in 2015. Eyes were included in the analysis only if they had documented Best-Corrected Visual Acuity (BCVA) and an Optical Coherence Tomography (OCT) scan both at baseline and at the 5-year follow-up visit (accepted from a minimum of 4.5 years following ILUVIEN implant). Data was collected from case notes, clinical letters, and Topcon OCT (3D OCT-2000; Topcon Corporation, Tokyo, Japan). BCVA was measured at the last clinic visit prior to ILUVIEN implant injection, and patients were excluded if there was any other intravitreal injection or macular laser in the interval between the last measured BCVA and ILUVIEN implant.
In order to observe the safety profile of ILUVIEN in a real-world setting, patients were included in this study regardless of any prior history of IOP steroid response, past or current IOP-lowering medication, or any diagnosis of OHT. The clinical decision to use ILUVIEN in those situations rested with the treating clinician and the patient. ILUVIEN product characteristics specify that it is contraindicated in the presence of pre-existing glaucoma.
Individual clinical decisions regarding the use and timing of any rescue intravitreal injections, macular laser, and IOP-lowering therapy following ILUVIEN rested with the clinician’s judgement and the patient’s informed choices.
Twenty-nine eyes were excluded as they missed 5-year follow-up data due to death (n = 21), discharge from clinic (n = 2), and loss to follow-up (n = 6). Therefore, 31 eyes were included in this analysis, which belonged to 25 individual patients (6 patients had both eyes included in this analysis).
BCVA was converted from Snellen visual acuity score to Early Treatment Diabetic Retinopathy Study letter score using the formula described by Gregori et al., in order to facilitate statistical analyses [18].
Study endpoints
Baseline demographic data was collected, including age, sex, ethnicity, diabetes mellitus type, duration of DMO, prior treatment (macular laser, vitrectomy, intravitreal corticosteroids, intravitreal anti-VEGF), and baseline IOP-lowering medication.
Primary outcome measures were the change from baseline in BCVA and Central Retinal Thickness (CRT) five years after starting treatment with the ILUVIEN implant.
Secondary outcome measures included the change in BCVA and CRT at 1-, 2- and 3-years post-ILUVIEN, number and type of complications following ILUVIEN, IOP-lowering treatments (number of IOP-lowering medications at 5-year follow-up visit, selective laser trabeculoplasty or cyclodiode laser treatment, incisional surgery), number and type of intravitreal injections or implants within 5 years post-ILUVIEN, and number of retinal laser photocoagulation treatments.
Statistical analyses
Statistical analyses were performed using Wilcox’s signed rank paired t-test, with a level of p < 0.05 being accepted as statistically significant. Centre values are reported as mean ± standard deviation.
Results
The mean follow-up period was 1867 ( ±122) days, which is equivalent to 5 years and 6 weeks. Two eyes (from a single patient) were missing 2- and 3- year follow-up data, and one eye was missing 1-year BCVA measurement, but as they all had adequate baseline and 5-year follow-up data, they were included in this analysis.
Baseline characteristics
Baseline characteristics are presented in Table 1. As per the UK national guidelines for treatment with ILUVIEN, all eyes were pseudophakic and had some form of prior treatment for DMO at baseline, with 97% having received prior anti-VEGF therapy, 58% having received prior intravitreal corticosteroids (intravitreal triamcinolone or intravitreal Ozurdex implant) and 68% having received prior macular laser photocoagulation. The mean interval between the last intravitreal injection and/or macular laser and ILUVIEN implant was 213 ( ± 289) days, with the shortest recorded interval being 54 days. No eye received Ozurdex within 6 months prior to ILUVIEN. No eye had a pre-existing diagnosis of glaucoma at baseline. Five eyes were on IOP-lowering medication at baseline, due to a diagnosis of ocular hypertension (n = 3) or previous steroid-related IOP elevation (n = 2).Table 1 Baseline characteristics of 31 eyes included in this analysis.
Baseline characteristics Eyes (n = 31 from 25 patients)
Age in years, mean ± SD 67 ± 8.0
Gender, n (%) Male 12 (39%)
Female 19 (61%)
Ethnicity, n (%) Asian 13 (42%)
White 9 (29%)
Afro-caribbean 7 (23 %)
Mixed 2 (6%)
Diabetes type, n (%) Type 1 3 (10%)
Type 2 28 (90%)
DMO duration in years, mean ± SD 5.9 ± 3.5
BCVA (ETDRS letters) BCVA mean ± SD 48.1 ± 16.2
Patients with <60 letters, n (%) 22 (71%)
Patients with ≥60 letters, n (%) 9 (29%)
Central retinal thickness, μm (mean ± SD) 477.1 ± 159.5
Prior treatment, n (%) Vitrectomy 4 (13%)
Macular/focal/grid laser 21 (68%)
Any intravitreal therapy 30 (97%)
Mean number of treatments ± SD 9.7 ± 6.3
Any anti-VEGF 30 (97%)
Mean number of treatments ± SD 8.2 ± 5.6
Bevacizumab 24 (77%)
Mean number of treatments ± SD 4.3 ± 2.5
Ranibizumab 24 (77%)
Mean number of treatments ± SD 6.0 ± 3.4
Any intravitreal corticosteroid 18 (58%)
Mean number of treatments ± SD 3.0 ± 2.8
Ozurdex intravitreal implant 2 (6%)
Mean number of treatments ± SD 1.0 ± 0.0
Triamcinolone acetonide intravitreal injection 16 (52%)
Mean number of treatments ± SD 3.3 ± 2.9
On IOP-lowering medication, n (%) 5 (16%)
BCVA
BCVA at baseline ranged from 0 to 76 letters, with a mean of 48.1 ( ±16) letters, which improved to 52.3 ( ±17) letters after one-year (a gain of +4.2 letters) before gradually reducing back down to 48.3 ( ±23) letters at 5 years. Compared to baseline, the difference in BCVA at 1-year was statistically significant (p < 0.05), but it was not statistically significant at 2-, 3-, and 5-year follow-up.
The change in BCVA at baseline and at one, two, three, and five-year follow-up visits is shown in Fig. 1.Fig. 1 Functional and anatomical outcomes over five years following ILUVIEN.
Change in BCVA (ETDRS letters) and CRT (μm) over 5 years following treatment with Fluocinolone Acetonide (FAc) ILUVIEN implant. *p < 0.05.
Five years after treatment with ILUVIEN, 13 eyes had an improved BCVA of 5 letters or more compared to baseline, 8 eyes had a similar BCVA as baseline (+/− 4 letters from baseline), and 10 eyes had a worse BCVA with a loss of 5 letters or more compared to baseline. This means that 68% of eyes had a similar or improved BCVA after 5 years when compared to baseline.
The proportion of eyes achieving a BCVA of 60 letters or more (6/18 Snellen equivalent) increased from 29% at baseline to 42% at 1-year, before reducing to 39% at 2- and 3-year, and 35% at 5-year post-ILUVIEN.
CRT
Baseline CRT ranged from 222 μm to 835 μm, with a mean of 477.1 μm ( ±160), which improved to 323.7 μm ( ±117) after 1 year (a 32% reduction), and remained stable thereafter, with a mean CRT of 310.2 μm ( ±116) after 5 years. The difference in CRT compared to baseline was statistically significant (p < 0.001) for all time points. Changes in CRT over 5 years following ILUVIEN are shown in Fig. 1.
Patients with a thicker baseline CRT (≥400 μm) had a more pronounced decrease in CRT after 1 year (−234.7 μm), which was maintained after 5 years (−257 μm), whereas there was no significant change in CRT in the group with thinner baseline CRT (<400 μm) at any timepoint. However, this was not reflected in the BCVA changes in those two groups. The group with thin baseline CRT had a statistically significant increase in BCVA at 2-years (+10.3 letters, p < 0.05), and the group with thick baseline CRT had a statistically significant increase in BCVA at 1-year (+5.7 letters, p < 0.05), although both groups had no significant change in BCVA at 5 years compared to baseline. Results are summarised in Table 2.Table 2 Change in CRT (μm) compared to baseline for two categories of baseline CRT (<400 μm and ≥400 μm).
Number of eyes Change from baseline (in um) after
1 year 2 years 3 years 5 years
CRT ≥ 400 um CRT 20 −234.7* −225.4* −239.5* −257*
BCVA 5.7* 1.4 2 0.3
CRT < 400 um CRT 11 −5.5 39.9 52 −2.9
BCVA 2 10.3* 3.3 0.2
*p < 0.05.
Rescue therapy
After 5 years post-ILUVIEN, 42% of patients remained free of any rescue intravitreal injection. Eighteen eyes required rescue intravitreal therapy over 5 years, with a mean time to first rescue injection of 29.2 ± 14 months. Sixteen eyes received rescue anti-VEGF therapy (mean 6.4 ± 4.8 injections over 5 years), two eyes received an Ozurdex implant (mean 1.0 ± 0.0 implants over 5 years) and five eyes received a repeat ILUVIEN implant. Two eyes received intravitreal triamcinolone injections, which were given peri-operatively for epiretinal membrane surgery and retinal detachment surgery.
Eyes that did not require any rescue intravitreal injections were found to have received less macular laser at baseline than eyes that received rescue intravitreal injections (46% vs. 83%, respectively).
Two eyes received PRP laser and three eyes received macular laser over 5 years post-ILUVIEN.
Repeat ILUVIEN implant
Five eyes received one repeat ILUVIEN implant, with a mean time to repeat ILUVIEN of 38 ± 4 months. One of these five eyes suffered a rhegmatogenous retinal detachment affecting the macula 20 months after the initial ILUVIEN implant (eye number 18), which was surgically repaired, and ILUVIEN implant was removed during the vitrectomy, before receiving a second implant 41 months after the first one. This eye had a predictably poorer outcome. Mean change in BCVA from baseline is summarised in Table 3. No eye received more than one repeat ILUVIEN during this study’s 5-year follow-up period.Table 3 Change in BCVA (ETDRS letters) compared to baseline in eyes receiving no further intravitreal injections, eyes receiving repeat ILUVIEN implant (results shown including and excluding one eye which had a retinal detachment 20 months post-ILUVIEN), and eyes receiving other rescue intravitreal injections (anti-VEGF and/or Ozurdex implant).
Rescue intravitreal injection Number of eyes Mean change in BCVA compared to baseline (ETDRS letters)
1 year 2 years 3 years 5 years
None 13 +6 +5.1 +2 +3.8
ILUVIEN Including all eyes 5 +4.6 +6.4 +4.2 −5.8
Excluding 1 eye with retinal detachment at 20 months 4 +5.8 +14.5 +8 +1.5
Anti-VEGF and/or Ozurdex implant 13 +2.5 +1.1 +0.9 −1
Treatment burden
Eyes required a mean of 2.5 intravitreal injections per year prior to ILUVIEN, vs. 0.78 intravitreal injections per year in the 5 years post-ILUVIEN, representing a reduction in treatment burden of 69%.
Safety
IOP-related events
Five eyes (16%) were on IOP-lowering drops at baseline, versus 22 eyes (70%) on IOP-lowering drops at the 5-year follow-up visit. Eyes received an average of 0.2 ( ± 0.6) IOP-lowering topical medications at baseline, versus 1.3 ( ±1.1) IOP-lowering medications at the 5-year follow-up visit.
No eye had a prior diagnosis of glaucoma. The 5 eyes on IOP-lowering medication at baseline had either a diagnosis of OHT (n = 3) or prior steroid-response (n = 2). One of these eyes had poorly controlled IOP following ILUVIEN and required SLT and incisional surgery; the other four eyes continued to have well-controlled IOP on topical medication following ILUVIEN.
Over the five years following ILUVIEN, two eyes had selective laser trabeculoplasty (SLT) only, one eye had cyclodiode laser, and one eye had both SLT and incisional glaucoma surgery. As detailed above, the eye requiring SLT and incisional surgery had a prior history of ocular hypertension (OHT). The other three eyes requiring SLT or cyclodiode laser had no prior history of OHT or glaucoma, and one received a diagnosis of steroid-induced OHT, while the other two were diagnosed with OHT and glaucoma in both eyes several years after ILUVIEN and were not deemed to be steroid-induced by their glaucoma specialist.
Eyes receiving repeat ILUVIEN (n = 5) were not found to be at any significantly increased risk of IOP-related complications, with eyes receiving a mean of 1.5 IOP-lowering medications after year-5 and 1 eye receiving SLT.
Other complications
One eye developed rubeotic glaucoma (unilateral, occurred 4 years and 2 months after treatment with ILIUVIEN), which was managed with panretinal photocoagulation and topical IOP-lowering medication.
Other significant complications included one case of endophthalmitis presenting 3 days post-ILUVIEN implant (confirmed by vitreous tap), which was treated with intensive intravitreal antibiotic therapy and made a good recovery, with a 5-year BCVA of 61 letters (vs. 55 letters at baseline); one case of vitreous haemorrhage presenting 6 days post-ILUVIEN; and one case of rhegmatogenous retinal detachment 20 months post-ILUVIEN. One patient required epiretinal membrane surgery and vitrectomy 32 months post-ILUVIEN.
Safety-related outcomes are summarised in Table 4.Table 4 Summary of IOP-related outcomes and other significant complications occurring within 5 years following ILUVIEN.
Adverse events Eyes (n = 31) Further details
IOP-related events On IOP-lowering medication at baseline, n (%) 5 (16%)
On IOP-lowering medication after 5 years, n (%) 22 (70%)
Number of IOP-lowering agents after 5 years, mean ± SD 1.3 ± 1.1
SLT laser only, n (%) 2 (6.5%)
Cyclodiode laser only, n (%) 1 (3%)
Incisional glaucoma surgery, n (%) 1 (3%) Trabeculotomy
Other complications Endophthalmitis 1 (3%) 3 days post-ILUVIEN
Vitreous haemorrhage 1 (3%) 6 days post-ILUVIEN
Rhegmatogenous retinal detachment 1 (3%) 20 months post-ILUVIEN
Epiretinal membrane surgery 1 (3%) 32 months post-ILUVIEN
Rubeotic glaucoma 1 (3%) 49 months post-ILUVIEN
Discussion
This is the first report of real-world outcomes of patients over 5 years following treatment with intravitreal ILUVIEN implant for chronic DMO and it confirms the safety and efficacy of ILUVIEN demonstrated in FAME and PALADIN trials, as well as other real-world studies. Although our cohort had a lower baseline BCVA than in FAME and PALADIN studies (48.1 vs. 53.3 and 61.3 respectively), we still observed a statistically significant BCVA gain of +4.2 letters one year after ILUVIEN, which is in keeping with BCVA gains reported those studies (+4.4 letters in FAME study low-dose group after 2 years, and +3.71 in PALADIN study after 1 year), as well as in real-life studies such as the Medisoft audit study and IRISS study (+3.6 letters and +3.7 letters respectively after 1 year) [12–15]. Gains in BCVA were observed over 3 years post-ILUVIEN, although there was a gradual return to baseline BCVA at year 5, which is in keeping with the estimated duration of action of ILUVIEN of up to 3 years. The FAME, PALADIN, and Medisoft audit studies all demonstrated a sustained improvement in BCVA over three years, whereas in our small cohort we observed a peak improvement at 1-year, followed by a gradual decline towards baseline [13, 15, 19]. This could be in part due to the fact that our cohort had a higher mean baseline CRT than in FAME and Paladin studies (477 μm vs. 461 μm and 386 μm, respectively), a factor which has been shown to be associated with DMO persistence or earlier recurrence [20]. Anatomically, there was a significant improvement in CRT observed after 1 year and sustained throughout the 5-year follow-up period. Interestingly, this did not translate into sustained BCVA gains, a phenomenon which has been reported in several studies and may be attributable to other factors, such as neural and glial cell loss, disorganisation of the inner retinal layers, and macular ischaemia associated with DMO [21–23]. Further studies investigating different anatomical characteristics on OCT other than CRT and their predictive value on functional outcomes would be required, in order to better understand the differing functional responses to treatment and to better tailor individual treatment plans for different patients.
The proportion of eyes on topical IOP-lowering medication at the 5-year endpoint (70% after 5 years vs. 16% at baseline) was significantly higher than that reported in other studies: in the PALADIN study 22% of eyes were on IOP-lowering medication at year-3; in the FAME study 23.9% of eyes required treatment-emergent IOP-lowering medication over 3 years; in the IRISS study 23.3% of eyes required treatment-emergent IOP-lowering medication over 3 years; and in the Medisoft Audit study 29.7% of eye required treatment-emergent IOP-lowering medication over 2 years [13–15, 19]. Nevertheless, most eyes had well-controlled IOP on topical treatment alone, with the proportion of eyes receiving trabeculoplasty alone (6.5%) and incisional IOP-lowering surgery (3.2%) over 5 years post-ILUVIEN being in keeping with rates reported in other studies (1.3% and 4.8%, respectively in FAME study over 3 years) [19]. This suggests that the majority of eyes have well-controlled IOP on topical medication alone [19]. Therefore, the higher proportion of patients we observed on IOP-lowering eye drops may not be an accurate surrogate measure for the true rate of persistent OHT and glaucoma. In a real-world busy clinical practice, patients may not be as closely monitored as in clinical trials, particularly during the covid-19 pandemic period, which limited face-to-face assessments and may have impacted the regular monitoring required for patients receiving sustained-release intravitreal corticosteroids. Clinicians may therefore have a more cautious approach, using a lower threshold to start IOP-lowering therapy than in clinical trials. We can also hypothesise that there may be less of an emphasis in real-world practice to stop IOP-lowering drops in a timely manner, even when IOP has been well-controlled for several months, and while collecting the data for this study we did observe patients remaining on IOP-lowering treatment with well-controlled IOP for several years, without an attempt to stop treatment. This may represent sub-optimal clinical practice and, moving forward will be the object of an internal departmental review to improve the care of patients receiving sustained-release corticosteroid implants. The high proportion of patients already on IOP-lowering eye drops at baseline (16%) also sets this real-world study apart from the FAME (patients with any history of glaucoma or OHT were excluded) and PALADIN studies (9.6% of patients were on IOP-lowering medication at baseline) and may have an impact on the proportion of patients on IOP-lowering drops after 5 years [13]. Nevertheless, our findings reinforce the idea that patients receiving sustained-release intravitreal corticosteroid preparations require ongoing regular monitoring of IOP. Further research would be required to investigate the true impact of ILUVIEN on IOP and data on serial IOP measurements, optic disc cupping, and visual fields may be more informative in establishing the true adverse effects of ILUVIEN.
This study demonstrates a significant reduction in the number of intravitreal treatments required following ILUVIEN, with a remarkable 69% reduction in treatment burden and nearly half of eyes remaining free of intravitreal injections for 5 years. This is comparable with the 70.5% reduction in treatment frequency reported in the PALADIN study over 3 years following treatment with ILUVIEN [13]. The reduction in treatment burden we observed translates to nearly 9 fewer injections per eye on average over the 5 years following treatment with ILUVIEN; a very positive outcome for both patients, with a reduced risk of possible injection-related infection and discomfort, and providers, with a reduction in the ever-growing demand for intravitreal injections. This may be an important consideration for ophthalmology service providers proactively planning the delivery of diabetic eye disease care, which includes the use of long-term therapies, in accordance with the Royal College of Ophthalmologists Way Forward report. Further research would be needed to establish the optimum type and timing of rescue interventions following treatment with ILUVIEN.
Our study’s main strength is its long duration of follow-up in a real-world setting, including patients with previous OHT, previous vitrectomy, and where patients were reinjected with a second ILUVIEN. Potential limitations of this study include a small sample size, its retrospective nature, the lack of comparator arm, and use of IOP-lowering medication and laser/surgical intervention as a surrogate measure for IOP-related adverse events. The use of rescue treatments following ILUVIEN is also a potential confounding factor, but this study shows the long-term outcomes of real-life patients treated with ILUVIEN, for whom rescue intravitreal injections and laser treatment are commonly used adjunctive treatments.
Conclusion
This real-life study suggests that intravitreal ILUVIEN fluocinolone acetonide 0.19 mg sustained-release implant is a safe and effective treatment option for the treatment of chronic DMO in patients with a pseudophakic lens. We observed a significant improvement in both functional and anatomical outcomes one year after treatment, and after 5 years around two-thirds of eyes had the same or better visual acuity than at baseline, with a sustained reduction in CRT. The most commonly observed adverse effect was IOP elevation, which we found was higher than reported in other studies, although this may be due to confounding factors and the rate of serious adverse events remains low and in keeping with published literature. Larger studies are required to corroborate these findings.
Summary
What was known before
ILUVIEN is effective for the treatment of chronic diabetic macular oedema in pseudophakic eyes with effects lasting up to 3 years.
Main adverse effects include cataract formation in phakic eyes and intraocular pressure elevation.
What this study adds
This real-world study confirms the efficacy of the ILUVIEN implant over 5 years, with two-thirds of eyes having improved or stable visual acuity 5 years after ILUVIEN, and an overall sustained improvement in anatomical outcome.
Intraocular pressure elevation is a common adverse effect of ILUVIEN, but appears to be well controlled on topical therapy in this real-world setting, which includes a variety of patients, and also after repeated treatment with the ILUVIEN implant. Over 5 years following treatment with the ILUVIEN implant, the rate of serious adverse events, such as incisional IOP-lowering surgery, remains low and in keeping with rates reported in clinical trials.
This study demonstrates a 69% reduction in intravitreal treatment frequency following treatment with the ILUVIEN implant in a real-world setting.
Author contributions
ED contributed to the study’s planning, data collection, data analysis, creation of tables and figures, and writing of the manuscript. BM contributed to the study’s conceptualisation and planning, data analysis, and critically reviewing and editing the manuscript. BRM, RC, PLL, and AM critically reviewed and edited the manuscript.
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests
E Dobler—none. BR Mohammed—received educational travel sponsorship from Bayer and Novartis and attended educational meeting sponsored by Alimera. R Chavan–received speaker fees and travel grants from Novartis, Bayer, and Allergan. PL Lip—none. A Mitra—consultant for Roche, Novartis, Alimera Sciences, and Allergan. B Mushtaq - advisory board member and consultant for Novartis, Bayer, Allergan, and Alimera sciences.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
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| 36513858 | PMC9745701 | NO-CC CODE | 2022-12-15 00:02:40 | no | Eye (Lond). 2022 Dec 13;:1-6 | utf-8 | Eye (Lond) | 2,022 | 10.1038/s41433-022-02338-2 | oa_other |
==== Front
Rev Relig Res
Rev Relig Res
Review of Religious Research
0034-673X
2211-4866
Springer US New York
518
10.1007/s13644-022-00518-w
Original Research
Eating Your Cake and Having it Too: US Megachurches and Factors Associated with Attending Multiple Congregations
http://orcid.org/0000-0002-7948-5877
Corcoran Katie E. [email protected]
1
House-Niamke Stephanie M. 1
Bird Warren 2
Thumma Scott L. 3
1 grid.268154.c 0000 0001 2156 6140 Department of Sociology & Anthropology, West Virginia University, PO Box 6326, 26506-6326 Morgantown, WV USA
2 Evangelical Council for Financial Accountability, Winchester, VA USA
3 Hartford Institute for Religion Research, Hartford International University, Hartford, CT USA
13 12 2022
122
30 1 2021
30 11 2022
1 12 2022
© The Author(s) under exclusive license to Religious Research Association, Inc. 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Background
It is typically assumed in the social scientific study of religion that individuals attend one congregation or none. As such, there is scarce research on individuals who attend more than one congregation yet doing so may affect congregational participation.
Purpose
This study theorizes factors affecting whether someone attends multiple congregations and how this might influence congregational volunteering and giving in the context of megachurches. It hypothesizes that parents, those who are single, those of lower socioeconomic status, those who are racially and ethnically minoritized, and those who are not socially embedded in a congregation will be more likely to attend a megachurch and other congregations. It also theorizes competing hypotheses regarding the association between attending multiple congregations and congregational volunteering and giving.
Methods
This study draws on survey data from 12 representative megachurches to test the proposed hypotheses using logistic and ordinal logistic regression models.
Results
Those who are single, those of lower socioeconomic status, those who are racially and ethnically minoritized, and those who are not socially embedded in the megachurch are more likely to attend multiple congregations simultaneously. Attending multiple congregations is negatively associated with congregational volunteering and giving.
Conclusions and Implications
The results demonstrate the need to reconceptualize congregational attendance to recognize that individuals may attend more than one congregation. Accordingly, future surveys should allow respondents to identify attending multiple congregations. The results also highlight how congregations may be negatively impacted by non-exclusive attendees who are less likely to volunteer and give money.
Keywords
Multiple congregational attendance
Megachurch
Volunteer
Tithe
==== Body
pmcThe religious landscape of the US has in many ways changed over the past 30 years and a core factor in that has been the emergence and proliferation of megachurches (Bird and Thumma 2021; Chaves 2006)—Protestant churches with an average weekly attendance of 2,000 or more members. The majority of US churchgoers attend churches in the 90th percentile for size even though 65 people is the median size of US congregations (Thumma and Travis 2007). Megachurches have large impacts on their local religious markets in which they influence attendance at other congregations (Eiesland 1997; Wollschleger and Porter 2011). While this research suggests that megachurches may ‘steal’ attendees of other congregations, it fails to recognize that individuals may both attend a megachurch and another congregation (Thumma and Bird 2009). Yet, other than Thumma and Bird’s (2009) work, we know little about this phenomenon.
This is likely due to the influence of Western Christian assumptions on the study of religion in which religious affiliations have historically been treated as “mutually exclusive, indeed antagonistic, categories” (McGuire 2008:12). Ideas about how one “ought to be committed” (McGuire 2008:12) (e.g., that people ‘should’ only attend one congregation) appear to affect how data on congregational attendance are collected. Surveys typically only ask questions about the respondent’s “church” or “congregation” singular without allowing a respondent to identify more than one congregation. Lived religion, how religion is actually practiced in real-life, does not always conform to categories created by organized religion and/or scholars of religion (McGuire 2008). For example, while religious identities have often been treated as mutually exclusive, people can simultaneously hold multiple religious and non-religious identities (Corcoran et al. 2021). Likewise, people can attend multiple congregations.
There are only a handful of studies that address attending multiple congregations. In a U.S. nationally representative survey of adults, Pew (2009) found that 35% of respondents attend more than one congregation and 24% of all respondents attend congregations of different faiths. Thumma and Bird (2009) found that around 12% of megachurch attendees in their survey considered the megachurch their “home church” but also attended another congregation. These studies suggest that attending multiple congregations is not a rare phenomenon in the US, which has important theoretical and methodological implications. Methodologically, congregational membership and participation counts are taken to be independent of each other, but if 35% of the population attend more than one congregation (Pew Forum on Religion & Public Life 2009), then the numbers reported may overlap and not represent independent populations, thereby affecting counts of the number of religiously affiliated individuals.
Numerous studies indicate a trend in the US toward individualism in religious choices in which individuals ‘shop’ in a religious or spiritual marketplace for the congregation or spiritual practice that best fulfills their needs and beliefs (Bellah et al. 2007; Dougherty and Mulder 2020; Hammond 1992; Roof 1989; Sikkink and Emerson 2020; Stark and Finke 2000; Turner 2004; Twitchell 2007; Wellman Jr, Corcoran, and Stockly 2020; Wolfe 2003). They may even choose to switch congregations in order to attend one that better satisfies their social and spiritual needs (Sikkink and Emerson 2020). What has yet to be considered is that individuals may choose to attend more than one congregation in order to have more of their needs met, perhaps the ultimate expression of religious individualism. Multiple attendance also has possible organizational ramifications. As voluntary associations, congregations need members who are willing to donate their time and money (Ammerman 1997; Chaves 2004; Stark and Finke 2000). In the US context—in which religion and spirituality are mostly unregulated—congregations and other organizations compete for members/practitioners (Stark and Finke 2000). But this logic largely depends on conceptualizing congregational participation as exclusive—if you attend one, you cannot attend another. Given that some individuals do attend multiple congregations (Pew Forum on Religion & Public Life 2009; Thumma and Bird 2009), understanding the factors associated with it can aid congregations in their recruitment and retention efforts. If multiple attendance affects measures of differential participation or congregational commitment (e.g., monetary donations and volunteering) (Thumma and Bird 2009), it also has important implications for congregational vitality and livelihood.
This study extends the research of Thumma and Bird (2009) and theorizes factors affecting whether megachurch attendees attend more than one congregation and whether this is associated with congregational volunteering and giving. We draw on qualitative and quantitative data on megachurch attendees; we use qualitative interview data to empirically ground our hypotheses and a large-N survey of megachurch attendees to test our hypotheses.
Data
Thumma and Bird (2011) have been tracking and compiling data on US megachurches since 1992. They created the Database of Megachurches in the United States from that data, which provides an approximate census of US megachurches. There were 1,250 megachurches in the database in 2007. Using this as their sampling frame, Thumma and Bird (2011) specifically selected 12 megachurches to reflect the US megachurch landscape in terms of region, attendance, dominant race, church age, denomination, and other characteristics. The sample has an average size that is somewhat larger than the typical megachurch and slightly underrepresents the western region of the US, otherwise it is fairly representative of the megachurch population in 2007 (Thumma and Bird 2009). In 2008, Thumma and Bird distributed surveys to all adult attendees during church services on a given Sunday at each church, conducted focus groups, interviews, and also observed services. The survey responses were coded into a data set and the interviews were transcribed. Leadership Network, a nonprofit research group and consultancy, funded and, together with the Hartford Institute for Religion Research, collected these data. Two hundred eighty-two attendees (132 males and 150 females) were interviewed in focus groups lasting roughly 1.5 h. Interviewees were asked questions about how they started attending the megachurch and became involved in it. Respondents were not specifically asked about multiple church attendance but, after reading and coding the transcribed interviews, it emerged as a topic in several focus groups across congregations in which many respondents provided their reasons for doing so. We use this data to empirically ground our theoretical hypotheses and suggest their feasibility. We test them with the attendee survey data, which we will describe after presenting the hypotheses.
Multiple Congregational Attendance
There is little research on attending multiple congregations. Pew’s (2009) nationally representative sample of US adults is one of the first major studies on the topic. They found that 35% of respondents regularly/occasionally attend religious services at more than one congregation, the majority of which reported that sometimes the services are at congregations of different faiths. While 37% of White evangelicals, 31% of White mainline, and 40% of Catholics reported attending multiple congregations, 57% of Black Protestants identified attending more than one congregation. Black Protestants also had the largest percentage of individuals reporting attending other places regularly (12%) compared to 6% for White evangelicals and White mainline Protestants and 9% of Catholics. Black Protestants also have higher percentages of attending “two other faiths” (14%) and “three or more” other faiths (9%), the next largest percentage for “two other faiths” was among White evangelicals (9%) and for “three or more” mainline Protestants (5%).
Using the 2008 megachurch attendee survey data from the 12 megachurches described above, Thumma and Bird (2009) found that roughly 12% of respondents identified attending other congregations while considering the megachurch their “home” church. They note: “There was a time when church participants were members of only one congregation. Switching, when it occurred, happened serially […] This may no longer be true for all congregations’ attenders but it is certainly no longer descriptive of many megachurch attenders.” We extend the work of Thumma and Bird (2009) and hypothesize factors that affect whether respondents attend multiple congregations.
There is considerable research identifying that many church-goers in the US shop around for congregations and choose one that best satisfies their needs and may switch congregations looking for the right one (Bellah et al. 2007; Hammond 1992; Roof 1989; Sikkink and Emerson 2020; Stark and Finke 2000; Twitchell 2007; Wolfe 2003). The same logic applies in the context of multiple congregational attendance. Given that many individuals are seeking to satisfy a wide variety of needs (e.g., spiritual, religious, social, emotional, and material), to the extent that one congregation cannot satisfy all their needs, they may choose to attend multiple congregations each of which satisfy certain needs that the others do not. In this environment, it benefits congregations to be inimitable, such that they serve a particular niche in a religious market and may thereby satisfy particular needs that other congregations do not or cannot (Miller 2002). We draw on the unique features of megachurches to derive hypotheses regarding what factors should affect someone’s likelihood of attending a megachurch and another church(es).
Megachurches are known for being distinct from smaller Protestants churches in several ways. Megachurches are intentional about meeting the spiritual and personal needs of attendees and even go as far as polling their members to determine their interests and needs (Thumma and Travis 2007; Wellman Jr et al. 2020). Economies of scale allow megachurches to offer a wide variety of ministries, small groups, and programs for attendees to meet a diverse array of interests and the size of the church ensures that there will be a sufficient number of participants in these activities. In comparing US megachurches to non-megachurches, von der Ruhr and Daniels (2012) found that a higher percent of megachurches offer small groups across all categories. Wellman and colleagues (2020:164) note the many types of small groups and ministries that megachurches offer: “prenatal care, newborn care, childcare, schools, youth sports leagues, afterschool tutoring, college prep help, college-age activities, singles groups, marriage classes, car maintenance facilities, hair salons, job search help, dance classes, fitness classes, recovery resources, medical care, Senior living facilities, even a columbarium.”
Many of the programs listed are social welfare services. A congregation’s ability to provide social support to its congregants is often tied to their desire to participate in the congregation. Previous studies show social supports such as assistance in the housing and job market, presence of relevant ministries, and social networks available to congregants impacted attendance and commitment to their church. In Tsang’s study (2015), Chinese immigrants consistently mentioned that their church offered help in finding jobs, housing, and visa paperwork for employment. An important consideration for social support is how the congregant’s race and ethnicity informs their social needs. Many Black church congregants have less need for assistance with visa paperwork and language interpretation and more need for support in managing racism in daily life (Fitzgerald and Spohn 2005). For working class and married, young adult congregants, the presence of a children’s ministry is vital (Gurrentz 2017).
Using a representative sample of US megachurches, Bird and Thumma (2011) found that community service was identified as a program of “strong emphasis” in their congregation by 74% of megachurches, which was the second most prevalent program listed as a “strong emphasis” of the congregation, following youth activities. In terms of types of welfare services: 98% identified cash assistance, 94% financial counseling, 80% food pantry/soup kitchen, 60% daycare/pre-school, 59% job training, 55% elder care, 54% tutoring, and 52% literacy. This emphasis on community service is not surprising as larger congregations participate in more social service activities likely due to their increased financial and human resources (Chaves and Tsitsos 2001). This could mean that those who need social service programs the most (i.e., those of lower-socioeconomic status) would be more likely to attend megachurches. Yet, larger congregations, including megachurches, have larger percentages of higher-socioeconomic status (SES) attendees (i.e., college degrees and high incomes) and higher-SES individuals are more likely to attend larger congregations (Eagle 2012). Thus, it seems that, overall, megachurches do not generally appeal to those of low SES. Given this, we hypothesize that those with low SES who attend megachurches will be more likely to also attend other congregations that satisfy their non-material needs.H1: Lower-SES megachurch attendees will be more likely to attend another congregation(s) than higher-SES megachurch attendees.
Youth groups and ministries are a core emphasis of the majority of megachurches. 91% of megachurches identified “youth activities” as a “strong emphasis” of their congregation. The size of megachurches allows them to offer large youth programs specifically tailored to varying ages. For example, a megachurch could “have roughly five hundred fifty children from birth to eleven years old and around three hundred youth in the twelve-to-seventeen age range” (Thumma and Travis 2007:104). Megachurches offer “high-quality, relevant, and safe” programs for children, youth, and young adults including “special-purpose spaces” specifically for those ministries (Thumma and Travis 2007:176). 75% of attendees of the largest Protestant churches identify being satisfied with the children and youth ministries of their churches (Thumma and Travis 2007). One megachurch church attendee from the interview data noted that the youth ministries was the main draw of the megachurch: “Because my son will be coming to live with me to go to high school […] I was looking for […] a congregation, a community that is youth based.” Individuals who attend primarily for their children may have other unmet needs. We expect that megachurch attendees with children will be more likely to attend another congregation(s).H2: Megachurch attendees with children will be more likely to attend another congregation(s) than megachurch attendees without children.
Akin to their youth ministries, megachurches are also typically able to offer larger singles groups as they generally have a higher number of singles in their congregations. Several interviewees noted this as a reason for joining the megachurch:I was really wanting to get back into a church and get more involved, and I figured a larger church would have more opportunities for getting connected with other people […] I’d been to both [small and large churches], but I know that from going to larger churches before, they have singles groups. They have outings. They have other stuff that a lot of the smaller churches don’t have the organization.
A focus group of longtime megachurch attendees noted that their post-graduate small group attracted many new attendees because it was one of the best places to meet other single young adults:Well, I think when I came back here, it was probably primarily to come into what they called the grad group then. It was like a singles group of post grads […] And it had the largest singles group around. Sometimes it sort of veered between either [other place] or here, but then it was definitely here. (emphasis added).
Yeah, I would say there are a lot of people that go to [group name], which is our 20’s group that go to [group name] first and then go to church. And that’s mainly been written up in several magazines in the last five years being one of the in places to meet singles. […] we figured out about […] 25 to 30% of the people that were involved in [group name] didn’t go to [megachurch’s name]. (emphasis added).
This last quote identifies that a large percentage of attendees of that small group didn’t attend the megachurch and thus were obviously attracted to the church due to the singles/young adult group. We predict that singles will be more likely to attend multiple congregations as they may attend the megachurch for the large singles groups that other congregations do not have.H3: Singles who attend megachurches will be more likely to attend another congregation(s) than megachurch attendees who are not single.
Congregational choice in the US is increasingly an individualistic and voluntary choice in which individuals choose a congregation(s) that meets their needs. This reflects an understanding of congregational choice and religious identities as achieved or chosen, rather than ascribed. Even though there is a move toward religion as an achieved status with less connection to race, ethnicity, or nationality (Davidman 1991; Sikkink and Emerson 2020), there are still many individuals for which it is ascribed or both ascribed and achieved (Cadge and Davidman 2006; Chafetz and Ebaugh 2000; Ebaugh and Chafetz 2000; Ebaugh and Curry 2000; Ecklund 2006; Hartman and Kaufman 2006). Hartman and Kaufman (2006:384) describe how distinguishing between religious and ethnic identities rarely captures lived religious experiences, which suggests that “religious, ethnic, racial, and secular identities are intertwined.” Religious identities and commitments can simultaneously be both achieved and ascribed. Ethnic congregations serve many functions for their communities including incorporating attendees into civic life, social integration, cultural preservation, supporting ethnic identity, and providing social services, social status, organizational resources for civic engagement, and an extended fictive family/kinship network (Chafetz and Ebaugh 2000; Chong 1998; Ebaugh and Chafetz 2000; Ebaugh and Curry 2000; Ecklund 2006; Ellison and Sherkat 1990; Fitzgerald and Spohn 2005; Kurien 2013; Tsang 2015). Some research on second generation Christians has found that they are drawn to evangelical Protestant values and practices including a nondenominational, individualistic, anti-liturgical focus in which evangelism, ministry, and outreach to those outside of one’s immigrant community is important (Ecklund 2006; Kim 2010; Kurien 2012, 2013; Min and Kim 2005). In fact, “many Western-born children of immigrants no longer see religious identity and ethnicity as linked. Instead, they embrace a religion that is purified of the cultural traditions and observances of their parents” (Kurien 2012:448). While some second-generation Korean Christians have created their own congregations (Kim 2010), other second-generation Christians do not have the numbers to do so and often must choose between attending an ethnic congregation and a non-immigrant congregation that satisfies their spiritual/religious needs (Kurien 2012). Yet, there are reasons other than religion to attend ethnic congregations including familial obligation, ethnic community and culture, and familial and fictive kinship relationships (Ebaugh and Curry 2000; Kurien 2012, 2013).
Some individuals may resolve the tension between attending an ethnic congregation versus a congregation that satisfies their spirituality by attending both congregations. Kurien (2012:461), in her study of second generation Indian Christians, notes that “the community orientation and familial nature of the [ethnic] church was the primary factor motivating some second-generation members to continue to attend the services (sometimes in addition to a nondenominational church), to return to serve the youth, or to want to raise their children in the church.” Here she indicates that some members attended both a nondenominational church and Mar Thoma (i.e., ethnic church). For example, one respondent in the study indicated that he attended both a nondenominational church and Mar Thoma because “while he liked attending the Mar Thoma church because of the community there, he attended the nondenominational church to address his spiritual needs” (Kurien 2012:459). Another respondent “who attended a nondenominational church and only came to the Mar Thoma church once a month with her husband, said that the reason she continued to attend the Mar Thoma church was to keep in touch with Indian culture, the Malayalam language, and their friends” (Kurien 2012:461).
These findings may be applicable outside of immigrant congregations to ethnic congregations more broadly. Ethnic community and extended fictive kinship relationships are also present in Black churches (Chatters et al. 1994). In addition to the spiritual/religious reasons for viewing the Black church favorably, Black Americans also indicated its historical importance and its role in providing social ties and community (Taylor, Thornton, and Chatters 1987). McRoberts (2003) found that, after moving to a different neighborhood, some Black Americans chose to continue to attend the congregation in the neighborhood in which they previously lived. Our qualitative data from a Black megachurch further suggests this. We provide an extensive back-and-forth conversation within one focus group to illustrate this:“Because we have a lot of people that come to this church that are still members of other churches. So I know when I first started coming, […] I’d come to the 7:30 service and attend and then go back to my church and teach Sunday school, you know. […]”
“We have a lot of people that come over for 8:30 service that actually goes to another church that’ll come over and hear the Word and then they’ll go out to their church and do their duties at their church. […]”
"Because a lot of people and I know this happens a lot of places, but I know it happens a lot within the African-American community, where you are tied to a church because like, I’m here because I’ve been here all my life.” “All my life, I grew up here.” “I can’t stand it, I hate it, but I’ve been here all my life.” “For my family.” “Exactly.” “My family’s here, yeah.” “Family ties and so on.”
“And so a lot of folks in this church, […] probably grew up in churches here, probably have family here. And to switch from one church to another means turning your back on family ties.” “Huge!” “Ostracized by the whole family!” […]
These respondents indicated that, in their experience, ties to a family church made it more difficult for Black Christians to leave that church to exclusively attend the megachurch even if they wanted to and instead, many would attend both. We expect that because ethnic congregations and megachurches may meet different needs, racial and ethnic minorities will be more likely to attend a megachurch and another congregation(s) compared to White megachurch attendees.H4: Racially and ethnically minoritized megachurch attendees will be more likely to attend another congregation(s) than White megachurch attendees.
Many individuals participate and remain in congregations in part for friendship and feelings of belonging and community (Ferguson et al. 2017; Gallagher 2020; Sikkink and Emerson 2020; Stark and Finke 2000; Tsang 2015). Given the large size of megachurches, it may be harder for some people to make friends and feel a strong sense of belonging. One megachurch attendee noted: “I have not gotten any friends yet through this church. I’ve been kind of at this other church, you know, where I have lifetime friends and I’m going to gain from that previous church. And I’m looking at gaining more here.” We hypothesize that attendees who are not socially embedded (i.e., have fewer friends in the megachurch and feel like they do not belong) will be more likely to attend other congregations:H5: Megachurch attendees who are less socially embedded will be more likely to attend another congregation(s) than megachurch attendees who are more socially embedded.
Multiple Attendance and Congregational Volunteering and Donating Money
In order to survive and thrive congregations need attendees to donate time and money (Ammerman 1997; Chaves 2004; Finke et al. 2006; Stark and Finke 2000). The average American congregation receives 91% of its total income from member contributions (Corcoran 2015). It’s thus important that congregations “strive to convert affiliates with tepid commitments into constituents willing to sacrifice resources’’ both time and money (Scheitle and Finke 2008:815; Stark and Finke 2000).
There has been considerable research identifying predictors of religious or congregational giving and volunteering including socio-demographic (e.g., education, marital status, age, and income) (Bekkers and Wiepking 2011; Chaves 2002; Finke et al. 2006; Iannaccone 1997), religious beliefs (Corcoran 2013; Finke et al. 2006; Luidens and Nemeth 1994; Peifer 2010; Scheitle and Finke 2008; Smith et al. 2008; Vaidyanathan and Snell 2011; Whitehead 2010), religious behaviors (Bekkers and Wiepking 2011; Chaves 2002; Lam 2002; Lewis et al. 2013; Loveland et al. 2005; Smith et al. 2008; Yeung 2017), religious social ties (Bekkers and Wiepking 2011; Corcoran 2013, 2020; Finke et al. 2006; Polson 2016; Scheitle and Finke 2008; Whitehead 2010; Whitehead and Stroope 2015), and religious emotions (Corcoran 2015, 2020). Yet, there are no studies testing the association between attending multiple congregations and congregational giving and volunteering. Thumma and Bird (2009) identified that those who attend megachurches and another congregation(s) tend to volunteer and give less; this paper extends their work in a multivariate context.
One line of research on religious giving and volunteering identifies these behaviors as zero-sum—one only has a certain amount of time and money to give, so the more one gives to one organization the less they should give to other organizations (Hill and Vaidyanathan 2011). As Kitts (1999:556) notes “It seems obvious that a person who donates some time or money to one organization cannot, by definition, donate those same resources to another organization. This implies that organizations are competing for essential resources from a finite pool.” Much of the research on giving focuses on whether those who are religious, in addition to donating to their own religious organizations, also donate more money to secular or out-group organizations than the non-religious. In Yasin, Adams, and King (2020) review of the literature on the relationship between religiosity and giving to out-groups, they identified that most studies found a positive relationship between religiosity and charitable giving to out-group organizations. Numerous studies of social movements have found positive associations between external organizational affiliations and participation in a social movement or protest (Corcoran et al. 2011, 2015; Kitts 1999; McAdam 1986; Passy and Giugni 2001; Schussman and Soule 2005; Somma 2010; Walsh and Warland 1983) even when the external organizational affiliations are other social movement organizations (Kitts 1999). Thus, “involvement in voluntary associations tends to generally breed more involvement” (Kitts 1999:571). This is contrary to a purely zero-sum interpretation of commitment. This could be because participation in voluntary associations increases civic skills and knowledge of other organizations (Almond and Verba 2015; Kitts 1999; Klandermans et al. 2008; McClurg 2003), which facilitates further participation, or because prosocial values or identities may encourage volunteering and donating money to multiple organizations. This leads to the following hypothesis:H6a: Attending multiple congregations will be positively associated with donating time and money to the megachurch.
Yet, Kitts (1999:557) found that participation in “parallel groups”, those that promote “equivalent goals”, decreases involvement in the focal social movement organization. Since many congregations promote similar goals, we expect that attending multiple congregations may be associated with less money and time donated to the megachurch. Given this, we also specify a competing hypothesis:H6b: Attending multiple congregations will be negatively associated with donating time and money to the megachurch.
Quantitative Data and Method
Surveys were distributed by Bird and Thumma in 2008 to adults (18 years or older) during all religious services over a given weekend at all 12 megachurches. 58% was the average survey response rate, which was calculated based on the percentage of adults in attendance who submitted a survey. We exclude first-time attendees and those who say they are visiting from the sample as their experiences are likely different from those of other attendees. After listwise deletion, we have a sample of 17,986 attendees.
Dependent Variables
To measure attending multiple congregations, we use the following question: “Do you consider this church your home church?” Respondents could answer “yes (this church only), yes (but I also attend other churches), and no. We are only interested in comparing individuals who consider the megachurch their home church as those who do not may be fundamentally different from those that do. Home church identification denotes church membership, whether officially or unofficially, and allows us to predict attending multiple congregations among those who consider the megachurch their home. Additionally, the question doesn’t allow us to distinguish between those for whom the megachurch is not their “home church” and they do not attend other congregations and those for whom the megachurch is not their “home church” and they do attend other congregations. Given these reasons, we drop those who answered “no” from the sample.
To capture congregational volunteering, we use the question: “How often do you typically volunteer in any capacity at this church?” With the following response categories, 1 = never, 2 = occasionally (a few times a year), 3 = regularly (once or twice a month), and 4 = three times a month or more. We measure congregational giving with the question “About how much do you give financially to this church?” Respondents were provided with the following response categories: 1 = I do not contribute financially here, 2 = I give a small amount whenever I am here, 3 = I give less than 5% of net income regularly, 4 = I give about 5–9% of net income regularly, and 5 = I give about 10% or more of net income regularly.
Predictor Variables
Respondents were asked their marital status with the following response choices: single, never married; married, first marriage; remarried; separated or divorced; widowed; and other. We created a single binary indicator (1 = single, never married and 0 = otherwise). To measure having children in one’s household, we used the question “Which statement best describes the people who currently live in your household?” Respondents were given the following options: I live alone; a couple without children; one adult with child/children; two or more adults with child/children; some adults living in the same household. We used these categories to create a binary has children in the household measure (1 = adult with child/children and two or more adults with child/children; 0 = otherwise).
To measure SES, we use household income and education. Respondents were asked for their total household income before taxes and were given the following response choices: under $25,000; $25,000- $49,999; $50,000-$74,999; $75,000-$99,999; $100,000-$149,999; and $150,000 or more. We took the midpoints of these categories, used $150,000 for the highest category, and then logarithmically transformed the variable.1 For education, respondents were asked “What level of education have you finished?” 1 = some high school; 2 = High school Diploma; 3 = Some college, trade, or vocational school; 4 = College degree; and 5 = post-graduate work/degree.
Respondents were asked “How do you describe yourself?” White/Caucasian/Anglo; Black/African/African American; Hispanic/Latino; Asian/Pacific Islander; Native American; and Other. We created binary indicator variables for each of these categories and set White/Caucasian/Anglo as the reference category. Respondents were asked whether they agreed that: “I have a strong sense of belonging to this church” and “I have very few close friends at this church” (1 = strongly disagree to 5 = strongly agree). These variables measure social embeddedness within the megachurch.
Control Variables
We control for frequency of attending worship services at the megachurch (0 = hardly ever or on special occasions; 1 = less than once a month; 2 = once a month; 3 = two or three times a month; 4 = usually every week or more), how long the person has been attending church services at the megachurch (0 = less than one year; 1 = 1–2 years; 2 = 3–5 years; 3 = 6–10 years; and 4 = more than 10 years), gender (1 = female; 0 = male), and age in years. We also include binary indicators for 11 congregations (the number of congregations – 1) but do not present them in the tables to conserve space.
Method
We use logistic regressions to predict the multiple congregational attendance variable as it is binary. The congregational volunteering and giving variables are ordinal but measure a latent continuous concept. We first estimated models using ordinal logistic regression. The Brant test identified that the multiple congregational attendance variable passed the parallel lines assumption for models predicting both dependent variables, though several control variables failed the test. We then estimated generalized logistic regression models, which relax the assumption of parallel lines. The multiple congregational attendance coefficient mirrored the results from the ordinal logistic regression model. Finally, we also estimated Ordinary Least Squares (OLS) models and again the results for the multiple congregational attendance variable remained the same. As such, we present the results for the ordinal logistic regression models but note that the associations between the multiple congregational attendance variable and the dependent variables are robust to varying model specifications.
Results
Table 1 Descriptive Statistics
Variable Obs Mean or % Std. Dev. Min Max
Multiple Attendance 17,986 13% --- 0 1
Cong. Volunteer 17,986 2.126 1.111 1 4
Cong. Giving 17,986 3.684 1.288 1 5
Female 17,986 60.5% --- 0 1
Attendance 17,986 3.704 0.631 0 4
Tenure 17,986 4.742 3.531 0 10
Age 17,986 40.827 14.379 18 99
Log Income 17,986 10.966 0.799 9.433 11.998
Education 17,986 3.551 1.029 1 5
Children in Household 17,986 49% --- 0 1
Single 17,986 27.8% --- 0 1
Race/Ethnicity
White 17,986 69.7% --- 0 1
Black/African American 17,986 22.2% --- 0 1
Hispanic/Latino 17,986 3.2% --- 0 1
Asian/Pacific Islander 17,986 3.4% --- 0 1
Native American 17,986 0.4% --- 0 1
Other Race 17,986 1.1% --- 0 1
Few Cong. Friends 17,986 2.981 1.487 1 5
Belonging 17,986 4.021 1.061 1 5
Table 2 Logistic Regression Predicting Multiple Attendance and Ordinal Logistic Regression Predicting Volunteering and Giving, Odds Ratios Displayed (SE)
Logistic Ordinal Logistic
Multiple Attendance Volunteer Giving
Model 1 Model 2 Model 3 Model 4
Constant 5.433*** 135.833** --- ---
(0.754) (56.599)
Female 0.879** 0.831*** 1.01 1.092***
(0.042) (0.041) (0.03) (0.031)
Attendance 0.471*** 0.52*** 2.21*** 1.975***
(0.014) (0.016) (0.068) (0.046)
Tenure 0.858*** 0.888*** 1.147*** 1.091***
(0.007) (0.008) (0.006) (0.005)
Age 0.997 1.01*** 1.003** 1.011***
(0.002) (0.002) (0.001) (0.001)
Log Income --- 0.805*** 1 1.306***
(0.027) (0.022) (0.028)
Education --- 0.935** 1.303*** 1.251***
(0.024) (0.02) (0.019)
Children in Household --- 0.808*** 0.972 0.786***
(0.044) -0.031 (0.025)
Single --- 1.618*** 0.910* 0.683***
(0.112) (0.040) (0.029)
Black/African American --- 1.324* 0.812** 0.88
(0.151) -0.065 (0.065)
Hispanic/Latino --- 0.974 0.738** 0.954
(0.126) (0.066) (0.078)
Asian/Pacific Islander --- 2.13*** 0.721*** 0.871
(0.227) (0.063) (0.070)
Native American --- 2.227* 1.354 1.248
(0.739) -0.31 (0.296)
Other Race --- 1.246 1.072 1.108
(0.254) -0.147 (0.152)
Few Cong. Friends --- 1.022 0.743*** 0.911***
(0.018) -0.008 (0.009)
Belonging --- 0.626*** 1.345*** 1.170***
(0.014) (0.021) (0.017)
Multiple Attendance --- --- 0.656*** 0.574***
(0.032) (0.025)
N 17,986 17,986 17,986 17,986
Pseudo R2 0.124 0.158 0.124 0.099
Table 3 Predicted Probabilities1
Model 2 Predicting Multiple Attendance Models 3 & 4 Predicting Volunteering & Giving
Log Income Only Attend Mega. Multiple Attend.
9.433 0.124 Cong. Volunteering
10.532 0.1 Never 0.346 0.446
11.043 0.091 Occasionally 0.372 0.349
11.736 0.085 Regularly 0.149 0.113
11.736 0.079 3 Times a Month + 0.133 0.092
11.998 0.075
Cong. Giving
Education None 0.033 0.055
Some HS 0.107 Some 0.152 0.227
HS Degree 0.1 Less than 5% 0.196 0.235
Some College 0.095 5–9% 0.275 0.252
College Degree 0.089 10% or more 0.344 0.232
Post Graduate 0.084
Marital Status
Not Single 0.081
Single 0.125
Race
White 0.084
Black/African American 0.109
Hispanic/Latino 0.082
Asian/Pacific Islander 0.164
Native American 0.173
Other Race 0.103
Belonging
Strongly Disagree 0.294
2 0.207
3 0.14
4 0.092
Strongly Agree 0.06
1 All other variables are set at their means
Table 1 presents the descriptive statistics for the variables. The typical megachurch attendee is white, not single, has a college education, is female and 41 years old. Females comprise approximately 60% of our sample, which mirrors their disproportionate share of American megachurch attendees and American Protestant church attendees (Thumma and Bird 2009). Almost 50% of attendees have children in their household. 13% of the sample considers the megachurch their home church but also attends other congregations. The average megachurch attendee identifies volunteering occasionally and contributing between the categories less than 5% and between 5 and 9% of net income regularly.
Table 2 presents the logistic and ordinal logistic regression models. Models 1 and 2 predict multiple congregational attendance. Model 1 presents the baseline model with control variables only. Compared to males, females are significantly less likely to attend multiple congregations. Those who attend the megachurch frequently and have been attending the megachurch for longer periods of time are also significantly less likely to attend multiple congregations. Age is not significantly related to multiple congregational attendance. Model 2 adds the predictors to the baseline model and Table 3 presents the predicted probabilities for select variables from this model with all other variables set to their means. Looking at SES, both log household income and education are significantly and negatively associated with the odds of attending multiple congregations. This supports hypothesis 1, which predicts that those with lower SES will be more likely to attend multiple congregations. The predicted probability for attending multiple congregations is roughly 12% for those reporting the lowest income category and 7.5% for those reporting the highest income category. The predicted probability for attending multiple congregations is approximately 11% for those with some high school and 8% for those with post graduate education. Having children in the household is also significantly and negatively associated with the odds of attending multiple congregations, which fails to support hypothesis 2. Megachurch attendees who are single are significantly more likely to attend multiple congregations compared to all other marital statuses. The predicted probability of attending other congregations is 12.5% for single megachurch attendees compared to 8% for all other marital statuses. This supports hypothesis 3. African American, Asian, Pacific Islander, and Native American megachurch attendees are significantly more likely to attend multiple congregations compared to White attendees. While the coefficient for Other Race is in the predicted direction it does not reach statistical significance. Hispanic and Latino attendees do not significantly differ from White congregants in their likelihood of attending multiple congregations net of the control variables. The predicted probability of attending multiple congregations for White and Hispanic/Latino attendees is roughly 8% compared to Black attendees at roughly 11%, Asian/Pacific Islander congregants at roughly 16%, Native American attendees at roughly 17%, and Other Race at roughly 10%. This provides partial support for Hypothesis 4. Having few friends in the megachurch is not significantly associated with multiple congregational attendance. Belonging is significantly and negatively associated with the likelihood of attending multiple congregations. When belonging is at its lowest value (1), the predicted probability of attending multiple congregations is approximately 30% compared to 6% when belonging is at its highest value (5). These results provide some support for hypothesis 5.
Models 3 and 4 report ordinal logistic regression models predicting congregational volunteering and giving respectively. Multiple congregational attendance is significantly and negatively associated with volunteering for the congregation and giving to the congregation. Table 3 provides the predicted probabilities for volunteering by whether someone attends multiple congregations with all other variable set to their means. The predicted probability for never volunteering is roughly 45% for those who attend multiple congregations compared to 35% for those who only attend the megachurch. The predicted probability for volunteering 3 times a month or more is 9% for those who attend multiple congregations compared to 13% for those who don’t. Looking at Table 3, the predicted probability for those who attend multiple congregations of giving 10% or more of their income is 23% compared to 34% for those who only attend the megachurch. The predicted probability of giving some money when they attend is roughly 23% for those who attend multiple congregations and 15% for those who only attend the megachurch. This supports hypothesis 6b, but fails to support hypothesis 6a.
Discussion
Studies of lived religion encourage scholars to rethink ingrained assumptions of how people practice religion based on actual lived religious experience (McGuire 2008). The social scientific study of religion has generally viewed congregational attendance as only occurring at one congregation. Yet the current paper and past research cast doubt on this viewpoint (Pew Forum on Religion & Public Life 2009; Thumma and Bird 2009). 13% of megachurch attendees in the sample attend the megachurch and one or more other congregations. That is not a small percentage. Understanding the factors that affect multiple congregational attendance is thus important. This study theorized predictors of multiple congregational attendance and found support for all but one of them.
Megachurch attendees with higher SES are significantly less likely to attend multiple congregations, whereas those who are single are significantly more likely to attend multiple congregations. Megachurches provide a wealth of resources and services for attendees. Those with lower SES may especially need those resources and services and yet megachurches generally tend to appeal more to those with higher SES (Eagle 2012). Those with lower SES may choose to attend the megachurch for these resources but also attend other churches that fit their class niche. Singles may also attend megachurches because of the singles ministries they offer, which generally have a larger number of people than what a smaller congregation can provide. Thus, for some individuals the draw of the megachurch may be less due to its theology but specifically the services and goods it offers. Qualitative research is needed to identify the reasons why some lower SES and single megachurch participants attend multiple congregations.
Black, Asian/Pacific Islander, and Native American megachurch attendees are significantly more likely than White megachurch attendees to attend multiple congregations. This further problematizes how the social scientific study of religion measures congregational attendance, since assuming individuals only attend one congregation will disproportionately undercount Black, Asian/Pacific Islander, and Native American attendees and even more so fail to reflect their lived experience. While research on immigrant congregations and the megachurch qualitative data suggest possible reasons why certain racial and ethnic groups may be more likely to attend multiple congregations, more research is needed that focuses specifically on this issue.
Contrary to hypothesis 2, we found that having children in one’s household decreases the likelihood of attending multiple congregations. This may be because those with children do not want to put in the effort or the extra time to take children to multiple congregations. Thus, congregations interested in having attendees exclusively attend their congregation may find it beneficial to attract those with children.
Finally, the results show that those with a higher sense of belonging within the megachurch are less likely to attend more than one congregation. Those who feel less belonging within the megachurch may attend other congregations in which they do feel like they belong or in order to find a congregation where they can experience this. While having few friends in the megachurch was not significantly associated with attending multiple congregations, this was due to controlling for belonging. With belonging excluded from the model, having few friends in the megachurch is significantly and positively associated with multiple congregational attendance, which suggests that having few friends in the megachurch is only related to multiple congregational attendance if it makes one feel like they do not belong.
This study also theorized and found that multiple attendance was significantly and negatively associated with congregational volunteering and giving. This is in line with viewing congregational volunteering and giving as zero sum—individuals only have so much time and money to give, so if they are giving to more than one congregation, they may give less to one or more of them. This has important implications for congregations because it suggests that they may receive less time and money from those who do not exclusively attend their congregation. Megachurches are likely less affected by this than smaller congregations due to their size, though they may also be more likely to experience it because of their size and unique features.
This study has some limitations. First, we used cross-sectional data and reverse causality is possible. It may be the case that those who attend multiple congregations are less likely to feel like they belong to the megachurch because they attend other congregations. Congregational volunteering and giving are measures of one’s commitment to the congregation, which could affect whether one attends multiple congregations. We expect that these relationships are likely reciprocal and dynamic, rather than one-directional. Future research would benefit from asking multiple congregational attendance questions on a longitudinal survey that would better pinpoint causal direction. Second, the survey did not ask any questions about the other congregations participants attend. Thus, we do not know what affiliation they are or their size. These are important questions to add to future surveys. Third, we use megachurches as a case study to examine multiple congregational attendance. Future research is needed to determine if the factors that affect multiple congregational attendance among megachurch attendees also affects those who attend smaller congregations. Finally, it is not possible to test congregational-level factors that might affect multiple congregational attendance as the survey only collected data from 12 megachurches. In all models we controlled for congregation and some were significantly more likely to have attendees who attend multiple congregations. Examining congregational-level factors associated with attending multiple congregations is a fruitful avenue for future research.
Conclusions and Implications
This is the first study to theorize and test predictors of attending multiple congregations and its association with congregational volunteering and giving using the case of megachurch attendees. It contributes to literature on lived religion by identifying the need for religion scholars to revise how they think about attendance to allow for the possibility that individuals may attend multiple congregations. Attending multiple congregations has important methodological implications for how religion is studied. For those who attend multiple congregations, what does it mean to be asked on a survey how frequently they attend religious services or how much they give to their congregation? Which congregation would the respondents use as the reference or would they average the answers they would give had they been asked the same questions for multiple congregations? These answers affect whether survey responses to congregational questions are undercounting congregational activities. Additionally, the congregations one attends may not be within the same affiliation (Pew Forum on Religion & Public Life 2009). Since surveys only ask individuals to report one affiliation, this would undercount affiliations and may fail to accurately represent the religious affiliations of people who are more likely to attend multiple congregations, which, in this study, were Black, Asian/Pacific Islander, and Native American attendees. The results demonstrate the need for future surveys to incorporate the ability to identify attending multiple congregations in order to fully represent lived religious experience.
The findings also suggest that social location (e.g., lower SES, single, and certain racially minoritized groups) affects multiple congregational attendance. This may reflect the broader US trend of ‘shopping’ for the congregation that best meets one’s needs (Bellah et al. 2007; Dougherty and Mulder 2020; Hammond 1992; Roof 1989; Sikkink and Emerson 2020; Stark and Finke 2000; Turner 2004; Twitchell 2007; Wellman Jr et al. 2020; Wolfe 2003). The current study extends this research by indicating that some people may feel they need to attend multiple congregations in order to fully meet their needs. Due to the COVID-19 pandemic, more congregations are offering remote services (Hartford Institute for Religion Research 2021), which makes attending services at multiple congregations easier. Further research is needed on how people ‘shop’ for multiple congregations to attend and how remote options affect this. Moreover, the findings suggest that those who attend multiple congregations may volunteer and give less money, which directly impacts congregations. Additional research is needed to determine if these results are generalizable to non-megachurches.
Acknowledgements
The data used in this article were generously funded and collected by Leadership Network, Dallas, Texas (www.leadnet.org) and Hartford Institute for Religion Research, Hartford, Connecticut. The lead author also thanks the Department of Sociology & Anthropology at West Virginia University for the research support to carry out this project.
1 Using the original ordinal scale does not alter the results.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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| 0 | PMC9745703 | NO-CC CODE | 2022-12-15 00:02:40 | no | Rev Relig Res. 2022 Dec 13;:1-22 | utf-8 | Rev Relig Res | 2,022 | 10.1007/s13644-022-00518-w | oa_other |
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J Antibiot (Tokyo)
J Antibiot (Tokyo)
The Journal of Antibiotics
0021-8820
1881-1469
Nature Publishing Group UK London
585
10.1038/s41429-022-00585-9
Article
Isolation, structural determination, and antiviral activities of metabolites from vanitaracin A-producing Talaromyces sp.
http://orcid.org/0000-0001-8773-3909
Kamisuki Shinji [email protected]
12
Shibasaki Hisanobu 1
Murakami Hironobu 12
Fujino Kan 12
Tsukuda Senko 3
Kojima Ikumi 4
Ashikawa Koudai 1
Kanno Kazuki 1
Ishikawa Tomohiro 5
Saito Tatsuo 5
Sugawara Fumio 4
Watashi Koichi 346
http://orcid.org/0000-0003-0571-9703
Kuramochi Kouji 4
1 grid.252643.4 0000 0001 0029 6233 School of Veterinary Medicine, Azabu University, Kanagawa, Japan
2 grid.252643.4 0000 0001 0029 6233 Center for Human and Animal Symbiosis Science, Azabu University, Kanagawa, Japan
3 grid.410795.e 0000 0001 2220 1880 Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
4 grid.143643.7 0000 0001 0660 6861 Department of Applied Biological Science, Tokyo University of Science, Chiba, Japan
5 grid.410772.7 0000 0001 0807 3368 Department of Chemistry for Life Sciences and Agriculture, Faculty of Life Sciences, Tokyo University of Agriculture, Tokyo, Japan
6 grid.410795.e 0000 0001 2220 1880 Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, Japan
13 12 2022
18
28 12 2021
2 11 2022
24 11 2022
© The Author(s), under exclusive licence to the Japan Antibiotics Research Association 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Vanitaracin A, an anti-hepatitis B virus polyketide, has been previously isolated from Talaromyces sp. In the present study, we searched for novel compounds in the culture broth obtained from a vanitaracin A-producing fungus under various conditions. Three novel compounds (vanitaracin C, vanitaraphilone A, and 2-hydroxy-4-(hydroxymethyl)-6-methylbenzaldehyde) were isolated, and their structures were determined using spectroscopic methods (1D/2D NMR and MS). In addition, the antiviral spectrum of vanitaracin A was examined by measuring its antiviral activities against rabies virus, Borna disease virus 1, and bovine leukemia virus. This compound exhibited antiviral activity against bovine leukemia virus, which is the causative agent of enzootic bovine leukosis. The anti-bovine leukemia virus effects of other compounds isolated from the vanitaracin A-producing fungus, namely, vanitaracins B and C, vanitaraphilone A, and 2-hydroxy-4-(hydroxymethyl)-6-methylbenzaldehyde, were also evaluated. Vanitaracin B, vanitaraphilone A and 2-hydroxy-4-(hydroxymethyl)-6-methylbenzaldehyde were also found to exhibit activity against bovine leukemia virus. These findings reveal the broad-spectrum antiviral activity of the vanitaracin scaffold and suggest several candidates for the development of anti-bovine leukemia virus drugs.
Subject terms
Natural products
Small molecules
https://doi.org/10.13039/501100001691 MEXT | Japan Society for the Promotion of Science (JSPS) KAKENHI 18K05343 KAKENHI 21K05299 KAKENHI 20H03499 22K05467 Kamisuki Shinji Saito Tatsuo Watashi Koichi https://doi.org/10.13039/100009619 Japan Agency for Medical Research and Development (AMED) JP20fk0210036 JP22fk0310504 JP22fk0310511 JP21fk0108589 JP22jm0210068 JP20fk0210036 JP20wm0325007 JP20fk0210036 Kamisuki Shinji Watashi Koichi Kuramochi Kouji https://doi.org/10.13039/501100001700 Ministry of Education, Culture, Sports, Science and Technology (MEXT) Private University Research Branding Project Private University Research Branding Project Private University Research Branding Project Kamisuki Shinji Murakami Hironobu Fujino Kan
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pmcIntroduction
Among antivirals isolated from natural sources, several exhibit activities against multiple virus types by targeting host cellular pathways that are exploited by different viruses [1, 2]. For example, fungus-derived cyclosporine A inhibits the replication of hepatitis C virus (HCV), influenza virus, and corona virus by binding to cyclophilin A2. Lipid-lowering statins, such as lovastatin isolated from the fungus Aspergillus terreus, inhibit HMG-CoA reductase and attenuate the replication of some enveloped viruses [1]. Ivermectin, an antiparasitic drug that inhibits the replication of HIV-1 and dengue virus by blocking importin α/β-mediated nuclear import [3], has also recently been found to inhibit the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [4]. Such host-targeting antivirals (HTAs) are generally expected to possess a much higher genetic barrier to drug resistance than direct-acting antivirals (DAAs) [2]. Furthermore, HTAs with broad-spectrum antiviral activities may provide treatment options for rapidly growing infectious diseases caused by new viral pathogens [1, 2, 5, 6].
In addition to viral infectious diseases that are a serious threat to human health, animal viral infectious diseases, including zoonosis such as rabies, are also a major concern in pet and livestock animals. Previously, by screening for antiviral compounds against human or animal viruses from the culture broth of fungi, we found anti-hepatitis B virus (HBV) [7], anti-HCV [8–10], and anti-bovine leukemia virus (BLV) compounds [11]. HBV and HCV cause chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. In contrast, BLV is a retrovirus that causes enzootic bovine leukosis, a lethal infectious disease of cattle. BLV infection also reduces lifetime milk production, reproductive efficiency, and lifespan, thus causing major economic losses in the cattle industry [12–15]. In addition, BLV is closely related to human T-cell leukemia virus (HTLV), a human retrovirus that is the etiological agent of adult T-cell leukemia.
Previously, we isolated vanitaracin A (1, Fig. 1), an anti-HBV tricyclic polyketide, from a fungus of the genus Talaromyces [7, 16]. Compound 1 inhibits viral entry by binding to sodium taurocholate cotransporting polypeptide, an HBV entry receptor on the cell surface [17]. This compound, which is an HTA, represents a novel class of anti-HBV agents with a different mechanism of action than existing DAAs, such as nucleos(t)ide analogs. In addition, the structure of 1 seems to be uncommon, comprising a tricyclic skeleton, which, to the best of our knowledge, is only found in penijanthinone A and dothideomycetide A [18, 19].Fig. 1 Structures of vanitaracins A–C (1–3), vanitaraphilone A (4), and 2-hydroxy-4-(hydroxymethyl)-6-methylbenzaldehyde (5)
In the present study, we cultured 1-producing fungus of the genus Talaromyces under various conditions to isolate novel vanitaracin derivatives. The structures of the obtained compounds were determined using spectroscopic methods (1D/2D NMR, MS, and IR spectroscopy), and their anti-HBV activities were assessed. Furthermore, 1 was subjected to antiviral assays against zoonotic viruses, such as rabies virus, Borna disease virus 1, and BLV to examine its antiviral spectrum. In addition to anti-HBV activity, 1 was found to be effective against BLV, suggesting that this compound has broad-spectrum antiviral activity. We also found that various compounds isolated from the 1-producing fungus exhibited anti-BLV activity. Our data suggest that vanitaracins have potential for controlling BLV infection and that the vanitaracin scaffold shows potent broad-spectrum antiviral activity.
Results and discussion
Our previous study demonstrated that the cultivation of a fungus of the genus Talaromyces in potato dextrose broth (PDB) yielded 1, vanitaracin B (2), 3,5-dihydroxy-2-(2-(2-hydroxy-6-methylphenyl)-2-oxoethyl)-4-methylbenzaldehyde, 7-hydroxy-5-methyl-2-(2-oxobutyl)-4H-chromen-4-one, and 2,7-dihydroxy-5-methyl-2-(2-oxobutyl)chroman-4-one [7]. To isolate further novel compounds related to 1, we cultured the fungus under various conditions. First, procaine, a DNA methyltransferase inhibitor, which reportedly enhances secondary metabolite production in fungi [20], was added to the PDB culture medium. The crude extract from this fungal culture broth was subjected to TLC-guided fractionation using silica gel chromatography and HPLC. Under these culture conditions, 1 was obtained together with unknown compound 3. The molecular formula of compound 3 (C24H34O6) was determined using HRMS (FAB). 1H NMR spectroscopy suggested that the structure of compound 3 was similar to that of 2, except for the presence of a methine proton signal (δ 5.36) and the absence of a ketone signal at C-10 (Fig. 1 and Table 1). Based on the correlation between H2-9 and H-10 in the 1H–1H COSY spectrum of 3, the methine proton signal was assigned to H-10, which was supported by HMBC correlations of H3-16 with C-10, C-11, and C-12 (Fig. 2). The consecutive 1H–1H COSY correlations of H-2′–H-8′, and the HMBC correlations of H-3′ and H-7′ with C-1′ (δ 176.5) revealed the presence of a 2,4-dimethylhexanoate unit, which is also present in 1 and 2. The HMBC correlation of H-10 with the ester carbon (δ 176.5) for 3 suggested that the 2,4-dimethyl hexanoate side chain was connected to C-10, whereas this side chain was connected to C-11 in the structures of 1 and 2. The differences in the molecular formulas of 2 and 3 indicated the presence of a hydroxy group at the C-11 position in 3. The remaining proton and carbon signals were assigned using 1H–1H COSY, HMQC, and HMBC experiments (Table 1). Thus, the structure of 3 was determined, as shown in Fig. 1, and this compound was named vanitaracin C. A NOESY correlation between H-2 and H-4 was observed, which indicated a syn relationship between OH-2 and H3-15 (Fig. 2). The NOESY correlation between H3-16 and H-9 (δ 3.34) suggested that these two protons were on the same face of the ring. Cross peaks were observed between H-9 (δ 3.34) and H-10 but not between H-9 (δ 3.09) and H-10, indicating that H-10 was also on the same face. Thus, the relative configuration of the tricyclic moiety was determined, as shown in Fig. 2.Table 1 1H NMR (400 MHz, CDCl3) and 13C NMR (100 MHz, CDCl3) data for compound 3
3
Pos. δC type δH mult (J in Hz)
1 37.3 CH2 3.76 dd (4.4, 18.5)
3.02 dd (5.3, 18.5)
2 66.2 CH 4.29 m
3 36.8 CH2 2.16 m
1.80 m
4 26.9 CH 3.20 m
5 127.9 C
6 158.1 C
7 113.4 CH 6.44 s
8 140.2 C
9 33.1 CH2 3.34 dd (3.3, 18.4)
3.09 dd (2.3, 18.4)
10 75.7 CH 5.36 dd (2.3, 3.3)
11 75.2 C
12 199.9 C
13 121.4 C
14 140.2 C
15 22.3 CH3 1.45 d (7.1)
16 23.6 CH3 1.41 s
1′ 176.5 C
2′ 37.7 CH 2.42 m
3′ 41.0 CH2 1.57 m
0.97 m
4′ 32.3 CH 1.20 m
5′ 29.7 CH2 1.06 m
6′ 11.0 CH3 0.70 t (7.4)
7′ 18.1 CH3 1.02 d (6.9)
8′ 18.8 CH3 0.78 d (6.5)
Fig. 2 Key 1H–1H COSY, HMBC, and NOESY correlations for 3
The relative configurations of the 2,4-dimethyl hexanoate moiety in 2 and 3 were determined using Schmidt’s method, which we previously applied to determine the configuration of the moiety in 1 (refs. 16, 21). The differences in the chemical shifts (Δδ) of the C-3′ geminal protons of compounds 2 and 3 were calculated to be 0.64 and 0.60 ppm, respectively (Figure S17). These Δδ values were all greater than 0.4 ppm, suggesting a syn relationship between C-2′ and C-4′ in 2 and 3, similar to that in 1 (refs. 16).
Because the conformational characteristics between the tricyclic skeleton and the side chain of 3 is still unclear, we employed computational methods to predict the absolute configuration of the stereogenic centers in 3. Based on the data described above, we set four possible diastereomers, (10S,11S,2′S,4′S)-3a, (10S,11S,2′R,4′R)-3b, (10R,11R,2′S,4′S)-3c, and (10R,11R,2′R,4′R)-3d, which were analyzed using the DP4 analysis program [22, 23] (Figure S18). Initially, all the diastereomers were submitted to a conformational search using the MMFF94s conformer research algorithm. Thereafter, all the conformers with relative differences within 5 kcal/mol were optimized via DFT calculations at the B3LYP/6-31G(d,p) level based on the solvent effect for PCM (CHCl3) in the Gaussian 16 package [24]. The optimized conformers were identified using the GIAO method at the mPW1PW91/6-31G(d,p) level, and the NMR spectra of the resultant conformers within 5 kcal/mol were averaged based on the Boltzmann populations to give the estimated chemical shifts. The 1H and 13C chemical shifts of all diastereomers with the statistical DP4+ value resulted in agreement with (10S,11S,2′S,4′S)-3a, which suggested that compound 3 has the structure of 3a or its enantiomer. Furthermore, we calculated CD spectra of each diastereomer using TD-DFT at the cam-B3LYP/6-311++G(2d,p) level. The calculated ECD spectrum of 3a matched the experimental data well as shown in Figure S19. Thus, the absolute and relative stereo configurations were determined as (2S,4R,10S,11S,2′S,4′S)-3a.
Next, we cultured the fungus in a malt extract broth. Purification of the crude extract via silica gel chromatography yielded 1 as well as unknown compounds 4 and 5. The molecular formula of compound 4 (C25H32O7) was determined by HRMS (FAB). The 1H NMR spectrum implied that the scaffold of 4 differed from that of vanitaracin. The 13C NMR and HMQC spectra revealed the presence of 25 carbons, including 3 ketone carbons, 1 ester carbon, 4 quaternary carbons, 8 methine carbons, 4 methylene carbons, and 5 methyl carbons (Table 2). The 1H–1H COSY and HMBC correlations revealed the presence of a 2,4-dimethylhexanoate unit, which is present in all the vanitaracins (Fig. 3). The 1H and 13C NMR data, the HMBC correlations of the methyl protons (H-17) with ketone carbons C-12 (δ 192.9) and C-14 (δ 193.0) as well as oxygenated quaternary carbon C-13 (δ 83.9), and the HMBC correlations of olefinic protons H-9, H-11, and H-16 with C-8, C-10, C-14, and C-15 indicated the presence of an azaphilone skeleton. The presence of a 3-hydroxy-5-methylcyclohexanone moiety was established based on the consecutive 1H–1H COSY correlations for H-2–H-7 and the HMBC correlation of H-2 with C-1 (δ 202.3). The HMBC correlation between H-9 and C-6 indicated that the cyclohexanone moiety was connected to the azaphilone skeleton. Thus, the planer structure of 4 was determined, as shown in Fig. 3, and this compound was named vanitaraphilone A. The relative configuration of the 3-hydroxy-5-methylcyclohexanone moiety in 4 was determined based on NOESY correlations (Fig. 3). The NOESY correlation between H-3 and H-5 suggested a syn relationship between OH-3 and H3-7. The relative configurations of C-5 and C-6 were defined based on the typical trans-diaxial coupling constant (JH-5/H-6 = 12.2 Hz), as supported by the NOESY correlation between H-2α (δ 2.44) and H-6. Compound 4 is structurally related to azaphilones, cohaerin B isolated from the stromata of the xylariaceous ascomycete Hypoxylon cohaerens [25], and penicilone A isolated from the marine-derived fungus Penicillium janthinellum HK1‑6 (ref. 26). The difference between the chemical shifts (Δδ) of the C-3′ geminal protons of 4 was 0.64 ppm (Figure S17), suggesting a syn relationship between C-2′ and C-4′ (ref. 21). Given that the stereochemistry of the C-13 positions of several azaphilones, including cohaerins and penicilones, have been established via ECD spectroscopy [25, 26], we measured ECD spectrum of 4. Compound 4 showed a negative Cotton effect at 354 nm, which clearly indicated (R)-configuration for C-13 (Figure S20). However, due to shortage of materials, the absolute configurations of other stereogenic centers in 4 were not determined.Table 2 1H NMR (400 MHz, CDCl3) and 13C NMR (100 MHz, CDCl3) data for compound 4
4
Pos. δC type δH mult (J in Hz)
1 202.3 C
2 50.5 CH2 2.88 ddd (2.1, 4.8, 13.0)
2.44 dd (11.6, 13.0)
3 67.9 CH 4.02 m
4 42.6 CH2 2.32 m
1.60 m
5 31.0 CH 2.08 m
6 61.1 CH 2.95 d (12.2)
7 20.5 CH3 1.12 d (6.4)
8 156.9 C
9 112.4 CH 6.09 s
10 141.7 C
11 107.7 CH 5.53 d (1.1)
12 192.9 C
13 83.9 C
14 193.0 C
15 115.3 C
16 153.7 CH 7.84 d (1.1)
17 22.0 CH3 1.54 s
1′ 176.4 C
2′ 36.2 CH 2.70 m
3′ 40.8 CH2 1.77 m
1.13 m
4′ 31.8 CH 1.52 m
5′ 29.5 CH2 1.34 m
1.15 m
6′ 11.1 CH3 0.89 t (7.4)
7′ 17.6 CH3 1.19 d (7.0)
8′ 19.1 CH3 0.92 d (6.6)
Fig. 3 Key 1H–1H COSY, HMBC, and NOESY correlations for 4
The molecular formula of compound 5 (C9H10O3) was determined using HRMS (FAB). The 1H NMR and 13C NMR data suggested the presence of one aldehyde carbon, six aromatic carbons, one oxymethylene carbon, and one methyl carbon. All the proton and carbon signals were assigned based on the HMBC correlations of H-7 with C-1 and C-2, H2-8 with C-3, C-4, and C-5, and H3-9 with C-1, C-5, and C-6 (Figure S21). Thus, compound 5 was determined to be 2-hydroxy-4-(hydroxymethyl)-6-methylbenzaldehyde (Fig. 1).
None of the newly identified compounds (3–5) exhibited anti-HBV activity (Figures S22 and S23). Our previous study demonstrated that 2 has much lower anti-HBV activity than 1 (ref. 7). These observations suggested that the overall structure of 1, especially the methyl and hydroxy groups at the C-9 position, is essential for anti-HBV activity. Additionally, we examined the antiviral spectrum of 1 by evaluating its antiviral activities against zoonotic viruses such as rabies virus, Borna disease virus 1, and BLV. Compound 1 had no significant effect on rabies virus or Borna disease virus 1 (Figure S24), but displayed dose-dependent anti-BLV activity without cytotoxicity (Fig. 4a, b). Compound 1 inhibited syncytia formation, a typical cellular morphology caused by BLV infection. We also evaluated the anti-BLV activities of all the other metabolites obtained from a 1-producing fungus. At a concentration of 10 µM, 2 and 5 exhibited significant anti-BLV activities. However, vanitaracin C (3) and vanitaraphilone A (4) did not show any such behavior (Fig. 5a and b). Compound 4 only exhibited significant anti-BLV activity at a concentration of 30 µM (Fig. 5c). Our results also indicated that at concentrations in the range 30–100 µM, 3 significantly decreased the viability of CC81 cells. Further, 4 showed cytotoxicity at high concentration (50 and 100 µM) (Figure S25).Fig. 4 Cytotoxicity and anti-BLV activity of 1. a Cell viability of CC81 cells treated with various concentrations of 1. b Anti-BLV activity measured via syncytium assays. CC81 cells were cultivated with FLK-BLV supernatant supplemented with various concentrations of 1. The counts of the infectious virus are shown as relative syncytium-forming units (SFU). Data are presented as mean ± SE (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001: ANOVA with post-hoc Tukey test
Fig. 5 Anti-BLV activities of compounds 2–5. CC81 cells were treated with FLK-BLV supernatant containing BLV and compounds 2–5 (10 μM) (a, b) and compound 4 at 30 μM (c). Cells containing more than five nuclei were defined as syncytia. *P < 0.05: ANOVA with post-hoc Tukey test (a) and Student’s t-test (b, c). Data are presented mean ± SE (n = 3)
In conclusion, the cultivation of 1-producing fungus in PDB containing DNA methyltransferase inhibitor or malt extract broth revealed three novel metabolites. The structures of vanitaracin derivative 3, azaphilone derivative 4, and benzaldehyde derivative 5 were established based on spectroscopic data. Notably, compounds 1, 2, 4, and 5 showed anti-BLV activity. Although BLV infection is prevalent worldwide and causes significant economic losses, no anti-BLV drugs have yet been developed. Thus, compounds 1, 2, 4, and 5 could be useful for controlling BLV infection. In future, we will evaluate the antiviral activities of these compounds against HTLV, a human retrovirus that is closely related to BLV, and other viruses. Zoonotic diseases caused by the emergence of new viral pathogens, which are a serious global public health problem, could potentially be treated using such broad-spectrum antiviral small molecules [5]. Among the antiviral compounds that we previously identified via chemical library screening, only 1 exhibited both anti-HBV and anti-BLV activities. This observation indicated that the vanitaracin scaffold shows potent broad-spectrum antiviral activity. Further studies on the antiviral spectrum of vanitaracins and their mechanisms of action are currently underway.
Materials and methods
General experimental procedures
Optical rotations were recorded using a JASCO P-2200 digital polarimeter (Jasco Corp., Tokyo, Japan) at room temperature. UV spectra were obtained using a UVmini-1240 spectrophotometer (Shimadzu Corp., Kyoto, Japan). ECD spectra were recorded in MeOH at a concentration of 2.0 × 10−4 M and at 23 °C using a JASCO J-725 CD spectrometer with 10-mm path-length cuvettes.
IR spectra were recorded using a JASCO FT/IR-4600 spectrophotometer (Jasco Corp.). 1H and 13C NMR spectra were recorded in CDCl3 using a Bruker 400 MHz spectrometer (Avance DRX-400 or Avance III-400; Bruker, Billerica, MA, USA) with TMS and CDCl3 as internal references for 1H and 13C NMR measurements, respectively. Chemical shifts are expressed in δ (ppm) relative to the TMS or residual solvent resonance, and coupling constants (J) are expressed in Hz. Mass spectra were obtained using a JEOL mass spectrometer (JMS-700; JEOL, Tokyo, Japan). Analytical TLC was performed on precoated silica gel 60 F254 plates (Merck, Darmstadt, Germany). Silica gel 60N (Kanto Chemical, Tokyo, Japan) was used for silica gel column chromatography.
Extraction and purification of compound 3
The vanitaracin A-producing fungus [7] was cultured in 4 l of PDB containing 0.5 mM procaine hydrochloride under static conditions at room temperature in the dark for 39 days. The culture broth was extracted using CH2Cl2, and the organic layer was evaporated in vacuo to obtain a crude extract (179 mg). This crude extract was then separated via silica gel column chromatography using CHCl3–MeOH (100:0–95:5) to obtain fractions 1–6. Fraction 4 was further separated via silica gel column chromatography using toluene–EtOAc (20:1–1:1) to give fractions 4-1–4-5. Fraction 4-5 was then purified via HPLC (Shiseido Capcell Pak C18, 5 μm, 20 × 250 mm, with 50%–100% MeOH–H2O gradient elution and at a flow rate of 5 ml min−1) to afford compound 3 (1.4 mg).
Vanitaracin C (3)
Pale pink oil; [α]26D + 59 (c 0.070, CHCl3); UV λMeOH max nm (ε) 284 (11,800), 235 (13,500), 215 (14,000); ECD (c 2.0 × 10−4, MeOH) Δε (nm) −0.68 (280), +0.29 (234); IR νmax (film) cm−1 3425, 2960, 2926, 1726, 1712, 1666, 1583, 1259, 1121; HRMS (FAB) m/z 441.2255 [M + Na]+ (calcd for C24H34O6Na, 441.2253); 13C and 1H data, see Table 1.
Extraction and purification of compounds 4 and 5
The fungal strain was cultured in 10 l of malt extract broth under static conditions at room temperature in the dark for 21 days. The culture broth was extracted using CH2Cl2, and the organic layer was evaporated in vacuo to obtain a crude extract (220 mg). This crude extract was separated via silica gel column chromatography using CHCl3–MeOH (99:1–95:5) to obtain fractions 1–12. Fraction 8 was separated by silica gel column chromatography using hexane–EtOAc (4:1–0:1) to yield compound 4 (2.8 mg). Fraction 5 was separated by silica gel column chromatography using hexane–EtOAc (4:1–0:1) to yield compound 5 (0.4 mg).
Vanitaraphilone A (4)
Brown oil; [α]22D –163 (c 0.065, CHCl3); UV λMeOHmax nm (ε) 331 (29,200), 219 (23,500); ECD (c 2.0 × 10−4, MeOH) Δε (nm) −0.34 (354), +0.21 (272), +0.20 (240), −0.23 (220); IR νmax (film) cm−1 3431, 3020, 2966, 1718, 1641, 1216; HRMS (FAB) m/z 445.2225 [M + H]+ (calcd for C25H33O7, 445.2226); 13C and 1H data, see Table 2.
2-Hydroxy-4-(hydroxymethyl)-6-methylbenzaldehyde (5)
Pale yellow oil; UV λMeOH max nm (ε) 338 (1,100), 271 (3,800), 216 (5,400); IR νmax (KBr) cm−1 3335, 2928, 1644, 1067; HRMS (FAB) m/z 167.0708 [M + H]+ (calcd for C9H11O3, 167.0708); 1H NMR (400 MHz, CDCl3) δ 11.97 (1H, s, OH-2), 10.29 (1H, s, H-7), 6.82 (1H, s, H-3), 6.73 (1H, s, H-5), 4.68 (2H, s, H-8), 2.61 (3H, s, H-9); 13C NMR (100 MHz, CDCl3) δ 194.8 (C-7), 163.6 (C-2), 151.2 (C-4), 142.4 (C-6), 119.6 (C-5), 117.7 (C-1), 113.3 (C-3), 64.5 (C-8), 18.2 (C-9).
Anti-BLV assay
To evaluate the anti-BLV activities of the compounds, a syncytium assay was conducted as previously described [11]. In brief, CC81 cells were cultivated in growth medium containing supernatant from persistently BLV-infected FLK-BLV cells and the compound of interest or DMSO, supplemented with 100 ng ml−1 polybrene. When the cells reached confluence, the formation of syncytia were visualized by Giemsa staining and light microscopy. Cells containing more than five nuclei were defined as syncytia.
Supplementary information
Supplementary Information
Supplementary information
The online version contains supplementary material available at 10.1038/s41429-022-00585-9.
Acknowledgements
We acknowledge support from Mr. Yoshihisa Sei and the Materials Analysis Division, Open Facility Center, Tokyo Institute of Technology for NMR analysis, and Mr. Makoto Roppongi and center for Instrumental Analysis, Utsunomiya University for CD analysis. We also thank Dr. Arata Yajima (Tokyo University of Agriculture) for his encouragement and experimental support. This work was supported by the Ministry of Education, Culture, Sports, Science and Technology-Supported Program for the Private University Research Branding Project (2016–2020), grants-in-aid from the Japan Society for the Promotion of Science (KAKENHI 18K05343, 20H03499, 21K05299, and 22K05467), the Program for Basic and Clinical Research on Hepatitis (JP22fk0310504, JP22fk0310511, JP21fk0108589, JP22jm0210068, JP20wm0325007, and JP20fk0210036) from the Japan Agency for Medical Research and Development (AMED), and the Center for Human and Animal Symbiosis Science, Azabu University. The computation was performed by the Research Center for Computational Science, Okazaki, Japan (Project: 22-IMS-C103).
Compliance with ethical standards
Conflict of interest
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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4. Caly L Druce JD Catton MG Jans DA Wagstaff KM The FDA-approved drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro Antivir Res 2020 178 104787 10.1016/j.antiviral.2020.104787 32251768
5. Adamson CS Antiviral drug discovery: preparing for the next pandemic Chem Soc Rev 2021 5 3647 55. 10.1039/D0CS01118E
6. Andersen PI Discovery and development of safe-in-man broad-spectrum antiviral agents Int J Infect Dis 2020 93 268 76. 10.1016/j.ijid.2020.02.018 32081774
7. Matsunaga H Isolation and structure of Vanitaracin A, a novel Anti-Hepatitis B virus compound from Talaromyces Sp Bioorg Med Chem Lett 2015 25 4325 8 10.1016/j.bmcl.2015.07.067 26271586
8. Nakajima S Specific inhibition of Hepatitis C virus entry into host hepatocytes by fungi-derived Sulochrin and its derivatives Biochem Biophys Res Commun 2013 440 515 20 10.1016/j.bbrc.2013.09.100 24099774
9. Nishikori S Anti-Hepatitis C virus natural product from a fungus, Penicillium Herquei J Nat Prod 2016 79 442 6 10.1021/acs.jnatprod.5b00555 26848504
10. Nakajima S Fungus-derived Neoechinulin B as a novel antagonist of Liver X receptor, identified by chemical genetics using a Hepatitis C virus cell culture system J Virol 2016 90 9058 74 10.1128/JVI.00856-16 27489280
11. Murakami H Specific antiviral effect of Violaceoid E on Bovine Leukemia Virus Virology 2021 562 1 8 10.1016/j.virol.2021.06.010 34242747
12. Polat M Takeshima SN Aida Y Epidemiology and genetic diversity of Bovine Leukemia Virus Virol J 2017 14 209 4 10.1186/s12985-017-0876-4 29096657
13. Nekouei O VanLeeuwen J Stryhn H Kelton D Keefe G Lifetime effects of infection with bovine leukemia virus on longevity and milk production of dairy cows Prev Vet Med 2016 133 1 9 10.1016/j.prevetmed.2016.09.011 27720022
14. Brenner J Van-Haam M Savir D Trainin Z The implication of BLV infection in the productivity, reproductive capacity and survival rate of a dairy cow Vet Immunol Immunopathol 1989 22 299 305 10.1016/0165-2427(89)90017-2 2560862
15. Schwartz I Levy D Pathobiology of bovine leukemia virus Vet Res 1994 25 521 36 7889034
16. Kamisuki S Determining the absolute configuration of Vanitaracin A, an anti-Hepatitis B virus agent J Antibiot 2022 75 92 7 10.1038/s41429-021-00496-1
17. Kaneko M A Novel Tricyclic Polyketide, Vanitaracin A, specifically inhibits the entry of Hepatitis B and D viruses by targeting sodium taurocholate cotransporting polypeptide J Virol 2015 89 11945 53 10.1128/JVI.01855-15 26378168
18. Chen M NaBr-induced production of brominated azaphilones and related tricyclic polyketides by the marine-derived Fungus Penicillium Janthinellum HK1-6 J Nat Prod 2019 82 368 74. 10.1021/acs.jnatprod.8b00930 30693772
19. Senadeera SP Wiyakrutta S Mahidol C Ruchirawat S Kittakoop P A novel Tricyclic Polyketide and its biosynthetic precursor azaphilone derivatives from the endophytic fungus Dothideomycete Sp Org Biomol Chem 2012 10 7220 6 10.1039/c2ob25959a 22847560
20. Asai T Tenuipyrone, a novel skeletal polyketide from the entomopathogenic fungus, Isaria tenuipes, cultivated in the presence of epigenetic modifiers Org Lett 2012 14 513 5 10.1021/ol203097b 22201477
21. Schmidt Y Breit B Direct assignment of the relative configuration in 1,3,n-Methyl-branched carbon chains by 1H NMR Spectroscopy Org Lett 2010 12 2218 21 10.1021/ol1005399 20337421
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23. Grimblat N Zanardi MM Sarotti AM Beyond DP4: an improved probability for the stereochemical assignment of isomeric compounds using quantum chemical calculations of NMR Shifts J Org Chem 2015 80 12526 34 10.1021/acs.joc.5b02396 26580165
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Eur J Nucl Med Mol Imaging
Eur J Nucl Med Mol Imaging
European Journal of Nuclear Medicine and Molecular Imaging
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Letter to the Editor
Letter to Editor for “European Association of Nuclear Medicine (EANM) response to the proposed ASTRO’s framework for radiopharmaceutical therapy curriculum development for trainees.”
Bashir Humayun [email protected]
1
Younis Muhammad Numair 2
Naseer Hamid 3
1 grid.270474.2 0000 0000 8610 0379 Nuclear Medicine Department, East Kent Hospitals University NHS Foundation Trust, Canterbury, UK
2 Nuclear Medicine & PET Department, INMOL Hospital, Lahore, Pakistan
3 Nuclear Medicine & PET Department, The Brunei Cancer Centre, Jerudong, Brunei Darussalam
13 12 2022
12
16 11 2022
3 12 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022
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pmcDear Sir,
We have read the EANM response to the ASTRO framework for radiopharmaceutical therapy with great interest and endorse that there is a very solid perspective to nuclear medicine’s claim to the ownership of radiopharmaceutical therapy [1, 2]. Generations of physicians have spent their professional and personal life learning and delivering radiopharmaceutical therapies to patients since the first use of P-32 for the treatment of leukemia and polycythemia in California by John H. Lawrence who identified the therapeutic potential of artificial radioisotopes in 1938, even before Saul Hertz in laid foundation of theranostics with radioiodine in 1941 [3, 4].
It is unfortunate that as radiopharmaceutical applications are on the verge of unprecedented expansion, there is a clear and present danger of its balkanization. In not so distant past, similar treatment was meted to PET/CT, another grand success story of scintigraphy since the first [18F]-FDG PET scan by Abass Alavi in 1976 [5]. There is a greater than ever need of mutual respect between the three well-established medical disciplines involved in the usage of radiation, i.e. radiology, nuclear medicine, and radiation oncology. To a curious observer, it would seem that there has been a welcoming attitude from nuclear medicine towards other disciplines to get onto the nuclear medicine turf, with limited reciprocity. The upcoming dual certification pathways in nuclear medicine provide no leverage or a grandfather clause for those who are not just well trained but also have demonstrable experience and competencies in hybrid imaging acquired over 8 to 10 years. Everybody cannot engage in re-inventing the wheel due to a change in the goal post. On the contrary, radiology trainees are being lured into taking up nuclear medicine as a subspecialty interest. The marketability of skills was pre-emptively used on the wrong premise that the need for nuclear medicine physicians will decrease. It has increased, and there is a global shortage of trained nuclear medicine physicians to deliver the services to the patients in need today, and worst is projected. Interestingly, scientists: medical physicists, radiopharmacists, radiochemists, technologists, and cyclotron engineers, all are benefitting from the growth of nuclear medicine, while trained nuclear medicine physicians are being denied to celebrate the “tryst with destiny.”
In Europe, the standard for delivering radiopharmaceutical therapy can be the European Board of Nuclear Medicine (EBNM), besides the national requirements. EBNM has a well-demonstrated resilience and high standards of professionalism. It has an international standing with the capacity to deliver onsite and hybrid examination since the COVID-19 pandemic [6, 7]. Specialists in radiology and radiation oncology can be required to meet the requirements of EBNM for formal dual certification through the summation fellowship examination. Similarly, a nuclear medicine physician keen to practice radiation oncology or non-hybrid diagnostic radiology can undertake a similar course. All clinicians should be equally facilitated with credits for their background knowledge and experience from the preliminary core specialty. The future of nuclear medicine is bright; however, atmosphere, circumstances, and practical demonstration can help create greater cordiality among the diverse group of clinicians practicing radiological sciences, as recognized under the endorsement of IAEA at the global stage [8–10].
Data availability
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
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All authors are responsible for the contents of this letter-to-editor manuscript.
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References
1. Dierckx R, Herrmann K, Hustinx R, Lassmann M, Wadsak W, Kunikowska J. European Association of Nuclear Medicine (EANM) response to the proposed ASTRO’s framework for radiopharmaceutical therapy curriculum development for trainees. Eur J Nucl Med Mol Imaging. 2022 Oct 17. 10.1007/s00259-022-06011-4. Epub ahead of print. Erratum in: Eur J Nucl Med Mol Imaging. 2022 Nov 14.
2. Kiess AP Hobbs RF Bednarz B Knox SJ Meredith R Escorcia FE ASTRO’s framework for radiopharmaceutical therapy curriculum development for trainees Int J Radiat Oncol Biol Phys 2022 113 4 719 726 10.1016/j.ijrobp.2022.03.018 35367328
3. Lawrence JH Nuclear physics and therapy: preliminary report on a new method for the treatment of leukemia and polycythemia Radiology 1940 35 1 51 60 10.1148/35.1.5110.1007/s00259-022-05716-w
4. Hertz B. A tribute to Dr. Saul Hertz: The discovery of the medical uses of radioiodine. World J Nucl Med. 2019 Jan-Mar;18(1):8–12. 10.4103/wjnm.WJNM_107_18.
5. Hess S Høilund-Carlsen PF Alavi A Historic images in nuclear medicine: 1976: the first issue of clinical nuclear medicine and the first human [18F]-FDG study Clin Nucl Med 2014 39 8 701 703 10.1097/RLU.0000000000000487 24978339
6. Mirzaei S, Hustinx R, Prior JO, Ozcan Z, Boubaker A, Farsad M; European Union of Medical Specialists and European Board for Nuclear Medicine. Improving Nuclear Medicine Practice with UEMS/EBNM Committees. J Nucl Med. 2020;61(3):18N–20N.
7. Ozcan Z, Kulakiene I, Vaz SC, Garzon JRG, Boubaker A. Challenges and possibilities for board exams in the Covid-19 era: experience from the Fellowship Committee of European Board of Nuclear Medicine. Eur J Nucl Med Mol Imaging. 2022 Apr;49(5):1442-1446. 10.1007/s00259-022-05716-w. PMID: 35142864; PMCID: PMC8979912.Bok B. European Board of Nuclear Medicine (EBNM): what is it for? Eur J Nucl Med. 1995 Dec;22(12):1370-1. 10.1007/BF01791143.
8. Czernin J Sonni I Razmaria A Calais J The future of nuclear medicine as an independent specialty J Nucl Med 2019 60 Suppl 2 3S 12S 10.2967/jnumed.118.220558 31481589
9. Segall GM, Pryma DA, Fair JR. A bright future for nuclear medicine. J Am Coll Radiol. 2019 Apr;16(4 Pt A):531–532. 10.1016/j.jacr.2018.08.029. Epub 2018 Nov 6.
10. Cutler CS, Bailey E, Kumar V, Schwarz SW, Bom HS, Hatazawa J, Paez D, Orellana P, Louw L, Mut F, Kato H, Chiti A, Frangos S, Fahey F, Dillehay G, Oh SJ, Lee DS, Lee ST, Nunez-Miller R, Bandhopadhyaya G, Pradhan PK, Scott AM. Global issues of radiopharmaceutical access and availability: a nuclear medicine global initiative project. J Nucl Med. 2021 Mar;62(3):422–430. 10.2967/jnumed.120.247197.
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SN Bus Econ
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Original Article
Corporate governance, capital structure, and firm performance: a panel VAR approach
http://orcid.org/0000-0002-4152-5204
Ronoowah Rishi Kapoor [email protected]
1
http://orcid.org/0000-0003-1786-0675
Seetanah Boopendra [email protected]
[email protected]
2
1 grid.442625.3 0000 0000 8574 3575 Open University of Mauritius, Reduit Mauritius, Moka, Mauritius
2 grid.45199.30 0000 0001 2288 9451 Faculty of Law and Management, University of Mauritius, Réduit, Moka, Mauritius
13 12 2022
2023
3 1 1429 1 2022
22 11 2022
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This study aims to examine the interrelationships and interdependencies between corporate governance (CG), capital structure (CS), and firm performance (FP) of companies listed on the Stock Exchange of Mauritius from 2009 to 2019 along with a comparison between financial and non-financial firms. A panel vector autoregression (PVAR) approach is used in this study to determine the relationship dynamics between CG, CS and FP. The findings reveal a positive and significant bidirectional association between CS and FP, supporting the trade-off theory. The results also show that CG and FP jointly help to increase CS while CG and CS jointly boost the profitability of firms. A strong bidirectional relationship with varied signs between CG and CS is found only for financial firms. The results of the forecast error variance decomposition analysis support the selection of FP as the most endogenous variable. Robustness tests also support the findings. This study is the first to examine the dynamic and interdependent relationships using a PVAR model between CG, CS and FP that presents new contributions to the existing CG and CS literature with insights from an emerging economy.
Keywords
Corporate governance
Capital structure
Firm performance
Panel VAR
Granger causality
Impulse response functions
Forecast error variance decomposition
issue-copyright-statement© Springer Nature Switzerland AG 2023
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pmcIntroduction
Corporate governance (CG), capital structure (CS), and firm performance (FP) are three crucial aspects that are linked to each other. Previous studies on the association between CG and CS rely heavily on agency theory to explain a company's financing decisions (Boateng et al. 2017). Both are linked because agency cost is one of the major elements of CS and CG that mitigates agency conflicts. CS is a CG instrument that can assist a company in developing value by preserving CG efficacy (La Rocca 2007). Good CG is commonly acknowledged to improve company performance (Beiner et al. 2004; Black and Kim 2012; Padachi et al. 2017; Sheaba Rani and Adhena 2017; Mansour et al. 2022). However, FP can also influence the level of CG, often measured using the CG disclosure index (CGI) as a proxy for the overall quality of CG in different countries. For instance, profitable organisations are anticipated to have greater compliance and disclosure levels than unprofitable or less profitable organisations to attract new investors and shareholders (Suwaidan et al. 2021). Moreover, on one hand, CS can influence performance (Doan 2020; Amare 2021) but financial performance, on the other hand, may also have an impact on CS (Abdullah and Tursoy 2021). Organisations with better profitability can more easily obtain debt financing, probably at more competitive interest rates than companies with less profitability. Researchers have discovered that one of the most important elements influencing the CS mix is FP (Iyoha and Umoru 2017; Cevheroglu-Acar 2018).
In recent years, there has been a surge in attention paid to the impact of CG on CS and FP and CS on FP, respectively. However, a detailed analysis of the literature reveals significant shortcomings. First, the bidirectional causation between CG, CS and FP has rarely been considered. Second, most prior studies, although taking into account the dynamic nature of financial performance modelling, have largely ignored the issues of endogeneity and reverse causality in the CG, CS and FP nexus. Third, emerging nations such as Mauritius, and more specifically African countries, have distinct economic, institutional, legal, and political settings than developed countries; therefore, the relationships between CG, CS and FP and their reverse causalities may likely differ from those noted in developed economies. Previous studies in Mauritius on CG by Soobaroyen and Mahadeo (2008), McGee (2009), Mahadeo and Soobaroyen (2012) and Mahadeo and Soobaroyen (2016) focus on the level of compliance, whereas Appasamy et al. (2013) and Padachi et al. (2017) quantitatively study the impact of CG on FP using static models and with limited sample size. Prior studies related to CS in Mauritius have focused on the determinants of CS (Fowdar et al. 2009; Odit and Gobardhun 2011; Gourdeale and Polodoo 2016; Omrawoo et al.2017), and so far, only one study has been conducted on the effect of CS on FP by Seetanah et al. (2014), with limited sample size and no CG variables employed as potential determinants. Fifth, no study has been conducted on the impact of CG on CS and vice versa in Mauritius, and most studies (Herlambang et al. 2018; Chow et al. 2018) have used several CG variables as proxies for CG. The use of CGI as a measure of overall CG quality to assess its impact on CS is rare. Finally, previous studies have largely focused on non-financial companies, while financial firms have often been ignored.
For various reasons, Mauritius is an attractive research setting for examining the interrelationships and interdependencies between CG, CS and FP. In Mauritius, the de facto features of the corporate environment are quite different from the CG structure, which is relatively less mature, from those used in developed countries, making Mauritius an interesting case for this study. Additionally, there are major differences between emerging and developed markets in terms of market and knowledge quality, volatility and size (Al-Malkawi 2008). Moreover, the Mauritian capital market has a concentrated ownership structure based on cross-shareholdings and pyramid ownership structures as well as an inactive market for corporate control, that is, takeovers. Managerial entrenchment often results from concentrated ownership structures (Elghuweel et al. 2017). Furthermore, Mauritius is a heavily indebted country with high-leverage enterprises, as debt from banks is favoured over equity and is a relatively inexperienced equity market. In an emerging economy with strong growth prospects, it is critical to investigate the impact of such a high-leverage structure on FP and vice versa. Mauritian enterprises are regarded as small corporations around the world because of their modest size. Finally, as an emerging economy, Mauritius is rapidly evolving and aspires to become a significant foreign direct investment hub by focusing on an innovatively led framework. Mauritius' continuous growth has brought with it several new difficulties and responsibilities, as well as a closer alignment with foreign investors and global stakeholders, all of which need a stronger focus on better CG and optimum CS which improve FP and help to attract investors. As a result, Mauritius emerges as a crucial motivator to conduct a first-hand study on the relationship dynamics between the CG, CS and FP of listed firms as part of realising the country's vision in competing with international competitors.
Consequently, this study aims to add to the existing body of literature by addressing some of the shortcomings of past studies and offering new empirical findings. First, this study offers evidence on the effects of CG, with a single measure of overall CG quality, on CS and vice versa in an emerging economy, Mauritius, where no such research has been conducted. Second, this study provides new evidence on the relationships between CG and FP, CS and FP, and CG and CS with reverse causalities in a small island emerging country like Mauritius, which has different characteristics compared to developed and larger developing/emerging economies. This will be the first attempt, to the authors’ knowledge, to examine the dynamic and interdependent relationships using a PVAR model between CG, CS and FP that presents new contributions to the existing CG and CS literature. Third, this study investigates the interrelationships and interdependencies between CG, CS and FP in a panel vector autoregression (PVAR) framework which accounts for potential dynamic and endogeneity issues and sheds light on reverse causality between these variables. Finally, this study examines any differences in the interrelationships and interdependencies of CG, CS and FP between financial and non-financial firms.
Therefore, this study aims to explore empirically, using a PVAR approach, the following interrelationships between CG, CS and FP, namely, to determine the direction of causation between CS and FP, CG and FP, and CG and CS in a sample consisting of SEMDEX (29) and DEMEX (13) listed firms from 2009 to 2019 in Stock Exchange of Mauritius (SEM), and the results are compared between financial (4) and non-financial firms (38). Dynamic evaluation is established on the completion of the forecast error variance decomposition (FEVD) and impulse response functions (IRFs). Different ordering of the variables and alternative methods of estimating the PVAR model, that is, XTVAR for robustness checks, are examined.
The remainder of this paper is organised as follows. The theoretical and empirical literature on the associations between CG, CS and FP is presented in “Literature review”. “Research design” describes the data, variables and methodologies of this study. “Empirical results and discussion” discusses the findings. “Robustness analysis” determines the robustness of the findings. The summary and conclusion of this study are presented in “Summary and conclusion”.
Literature review
CG entails mechanisms to ensure that lenders of capital to firms will receive a return on their investment (Shleifer and Vishny 1997). In a CG structure, a company’s timely decision-making policies and practices regulate the obligations and rights of its diverse stakeholders. Agency theory presents board members with professional expertise to meet these requirements. This board also decides on the best mix of debt and equity for a firm’s future performance. The pecking order theory (POT) and trade-of-theory (TOT) of CS provide managers with guidelines in this context. Based on these three prominent theories, this section illustrates the interrelationships between CG, CS and FP.
Theoretical literature
Agency theory
Agency theory underpins the practice of CG. The primary tenet of this theory is that there is a working relationship in the form of a cooperation contract between the party providing the authority (the principal), that is the investor, and the party obtaining the authority (agency), namely the manager. Due to the separation of corporate ownership and control, agency conflicts develop. In an agency relationship, it is natural to anticipate that the agent (manager) will make decisions that are detrimental to the interests of the principal (owner) if economic agents are utility maximisers (Jensen and Meckling 1976). The amount of resources under the manager’s control is just one factor that influences how agency costs affect the composition of the CS. According to Jensen (1986), managers may take on debt to increase the resources under their control, which can result in debt agency costs like bankruptcy costs. CG stands out as a tool that facilitates the alignment of interests between agent and principal in this context. There are grounds to believe that CG and CS are related (Borges Júnior, 2022). This is based on the idea that agency conflict is influenced by CG mechanisms, and that these mechanisms are linked to choices concerning the composition of a firm's funding sources. Moreover, the agency theory proposes that CG and financial decisions have an impact on company value and CS must be viewed as a device that can intervene and drive governance structures within the business, and hence FP (Bashir et al. 2020).
According to agency theory, organisations voluntarily reveal additional information to reduce agency conflicts and the costs that arise from the conflict between managers and shareholders (Lambert 2001; Alves et al. 2012; Ntim and Soobaroyen 2013). As a result, increased mandatory and voluntary disclosures on CG may reduce information asymmetry between agents and owners, allowing shareholders to better supervise the management's conduct (Beekes et al. 2016).
Trade-off theory
The trade-off theory (TOT) accounts for the effects of taxes and the costs of bankruptcy. The theory assumes that firms trade-off the benefits of debt financing (favourable corporate tax structure) against increased interest rates and bankruptcy costs to find an optimal CS—the mixer that maximises a firm's worth. The TOT predicts a positive relationship, because when a company is profitable, it may take on more debt, resulting in larger interest payments that are deducted from taxes (Ponce et al. 2019).
Pecking order theory
Majluf and Myers (1984), in contrast to the TOT, developed the pecking order theory (POT), which implies that there is no optimal CS. Instead, the theory proposes that firms have a preferred funding hierarchy. According to Myers (1984), organisations with high levels of profitability have low levels of debt because they have a large number of internal sources of funding. Because POT predicts that corporations use their resources rather than borrow them, it expects a negative relationship. The validity of the POT has been proved in numerous empirical research (Acaravci 2015; Paredes Gómez et al. 2016).
Empirical literature
Capital structure and firm performance
Causal effect of capital structure on firm performance
It is expected that increasing financial leverage will strengthen management, lower information costs, and reduce inefficiencies, all of which will improve FP (Jensen 1986; Jensen and Meckling 1976). Financing decisions affect the cost of capital, allowing businesses to optimise their financial performance (Majluf and Myers 1984; Abdullah and Tursoy 2019). Empirical research demonstrates that FP can be influenced by the relative usage of both capital sources i.e., the mixture of debt and equity (Saona and San Martín 2018; Abdullah and Tursoy 2019). According to theoretical models, the link between CS and FP is unclear (Miglo 2016). Only a few empirical studies have explored the performance effect of leverage and the results vary. A few studies find that leverage is positively linked to FP, such as Vijayakumaran (2018) in China and Amare (2021) in Ethiopia, while others find it to be negatively linked, such as Li et al. (2018) in European SMEs from Austria, Belgium, Finland, France, Germany, Italy, Portugal, Spain, Sweden, and the UK; and Doorasamy (2021) in East Africa (Kenya, Tanzania, and Uganda). In Mauritius, Seetanah et al. (2014) find a negative impact of CS on the FP of listed Mauritian firms for the period 2005–2011. Abata et al. (2017) report mixed results in another study conducted in South Africa.
Causal effect of firm performance on capital structure
CS may influence FP but the latter, on the other hand, may also have an impact on a company’s CS (Abdullah and Tursoy 2021). The logic of the reverse causal relationship between performance and leverage can also be explained using TOT and POT. Researchers have discovered that one of the most important variables influencing the CS mix is FP (Iyoha and Umoru 2017; Cevheroglu-Acar 2018 Koralun-Bereżnicka 2018). This argument may be explained by the TOT, which states that profitable businesses have lower bankruptcy costs and are, hence, more inclined to borrow (Fama and French 2002). Moreover, high-profit businesses are prone to take on more debt to reap tax benefits (Frank and Goyal 2009). Therefore, FP may favourably influence CS. Previous empirical research findings support the TOT’s claim (Ajibola et al. 2018; Angkasajaya and Mahadwartha 2020; Amare 2021). POT contends that profitable businesses are more likely to rely on the generated surplus to fund their assets rather than external sources (Myers 1984). Consequently, profitability is assumed to have a negative effect on leverage, keeping the investment level stable backed by empirical studies such as Jarallah et al. (2019) in Japan and Doan (2020) in Vietnam.
Reverse causality between capital structure and firm performance
Previous research has investigated the relationship between leverage and FP but fails to account for the reverse causality of CS on FP, and a simultaneous-equations bias may emerge (Iyoha, and Umoru 2017). From 2002 to 2012, Jouida (2018) studies the dynamic relationship between CS, diversification, and FP for 412 financial companies in France using a PVAR model and observes bidirectional causation between CS and FP after controlling for individual fixed factors. She and Guo (2018) examine a sample of 49 global e-commerce businesses from 2012 to 2016 and find a negative reverse causality between FP and CS that is in line with the POT, which nonetheless shifts when the quantity of debt grows. Abdullah and Tursoy (2021) examine the reverse causality between FP and CS of listed German non-financial firms from 1993 to 2016 and find that FP and CS can positively influence each other. Adhari and Viverita (2015) investigate the reverse causality between CS and FP of 215 firms in Indonesia, Malaysia and Singapore from 2008 to 2011 and observe that CS and FP can positively affect each other.
Corporate governance and firm performance
Causal effect of corporate governance on firm performance
CG mechanisms may improve FP, amongst others, through better monitoring resulting in managers investing value maximising projects, lesser wastage of resources in unproductive activities and enhanced protection of investors implying a lower risk of losing their assets with acceptance of lower investment return triggering a lower cost of capital for firms. According to agency theory, there is a positive correlation between CG ratings and FP (Jensen and Meckling 1976). The implementation of appropriate CG mechanisms, as well as voluntary disclosure, will result in a net reduction in agency costs and an increase in FP (Fama and Jensen 1983; Siddiqui et al. 2013). CG disclosure is a critical tool for ensuring that firms’ CG practices are held within the bounds of law in terms of openness and accountability (Isukul and Chizea 2017).
A good CG is commonly acknowledged to improve FP (Padachi et al. 2017; Bhatt and Bhatt 2017; Sheaba Rani and Adhena 2017; Mansour et al. 2022). Other researchers, such as Rajput and Joshi (2014) in India and Adegboye et al. (2019) in Nigeria, find a negative connection between CG and FP, or no relationship by Hassouna et al. (2017) in Egypt, and Braendle (2019) in Austria, or find mixed results by Tariq et al. (2018) in Pakistan, Shao (2018) in China, Griffin et al. (2018) in various countries, and Dao and Nguyen (2020) in Vietnam. In Mauritius, Appasamy et al.( 2013) show that there is a relationship between CG and FP in the insurance sector from 2009 to 2011, whereas Padachi et al. (2017) find a significant positive relationship between the CG and FP of 36 listed firms from 2010 to 2014.
Causal effect of firm performance on corporate governance
Profitable firms have more financial resources to sustain the increased administrative costs in meeting compliance and enhancing their CG level as compared to less profitable firms. Moreover, FP is regarded as an essential determinant of the level of CG through enhanced compliance with the code of CG and disclosure to stakeholders. Most disclosure research indicates a positive link between corporate profitability and CG disclosures (Elfeky 2017; Cunha and Rodrigues 2018). Agency theory contends that high-profit corporate executives reveal specific information to gain individual advantages, justify their salary packages, improve their reputation in the business market, and reinforce their position (Alnabsha et al. 2018). Moreover, profitable organisations are anticipated to have greater compliance/disclosure levels than unprofitable or less profitable organisations to attract new investors and shareholders (Suwaidan et al. 2021). However, according to Ben-Amar and Boujenoui (2007), even those with weak financial performance have strong incentives to do so to attract investments and improve their financial ratios. Furthermore, increased information disclosure may be linked to lower profit levels, because corporations’ legal liability, if any, is lowered if they share unfavourable information or ‘bad news’ about themselves (Skinner 1994). This implies that a negative association may also exist between profitability and corporate disclosure (Zeghal and Moussa 2015; Suwaidan et al. 2021). Although previous research has examined the association between CG and FP, the bidirectional causation between these two variables is seldom considered which may result in simultaneous-equation bias.
Reverse causality between corporate governance and firm performance
Love (2011) observes that some prior studies argue that causality goes from governance to performance but others argue the opposite that causality runs in a reverse direction from performance to governance. There are various reasons to believe that causality can truly happen from valuation to governance. On one hand, organisations with superior operating results or greater market values may decide to adopt better governance methods, which will result in reverse causality. On the other hand, companies with poor performance prefer to adopt additional anti-takeover clauses, which are linked to poorer governance. As an alternative, businesses may embrace stronger governance processes as a predictor of future success or as a means of enforcing insiders' adherence to ethical behaviour. The signaling role of governance will be significant for share prices in this situation rather than governance itself. Reverse causation may also occur through institutional or international investors who are more inclined to companies with higher market values, which may also result in better governance practices.
Lamiri et al. (2008) examine the reverse causality between different board characteristics and FP of a panel of 36 listed Tunisian firms between 2004 and 2006 and their findings conclude that board influences FP and firms change their board structure in response to FP. Perez de Toledo (2011) assesses the relationship between the quality of CG proxied by a CGI and the market value of 106 listed Spanish firms from 2005 to 2007 and shows that CG positively impacts firm value but there is no proof of reverse causality, i.e. firm value influencing CG. Ingriyani and Chalid (2021) examine 51 listed Indonesian manufacturing firms between 2014 and 2018 and conclude that executive compensation, CG and FP are related to each other. They find that CG has a positive effect on FP and that greater FP tends to decrease the number of board of directors and the supervisory function of the commissioners but increase the proportion of independent directors.
Corporate governance and capital structure
Causal effect of corporate governance on capital structure
Managers' choices of CS are among the most important business policy decisions they make (Boateng et al. 2017). This is because leverage decisions are subject to agency problems and have an impact on a firm's riskiness and performance (Jensen and Meckling 1976). Jensen and Meckling (1976) propose that the separation of principal and agent roles in businesses causes conflicts of interest (agency costs) between shareholders and management, leading to the idea of CG. This is where the two notions of CG and CS come together. According to agency theory, managers in low-CG practice organisations are more likely to experience agency problems, therefore, they will be tempted to use sub-optimal leverage to take advantage of free cash flow. Higher levels of leverage have been considered as a good substitute for weaker governance practices (Mwambuli 2019). In this situation, leverage and governance quality are inversely associated, with companies with low-CG practice needing to use more leverage to minimise agency costs and align firm managers' interests with those of shareholders.
Several studies have shown some evidence for the above assertion, indicating that CG frameworks have an important impact on listed companies’ leverage decisions (Morellec et al. 2012). For example, using a survey-based CG index Haque et al. (2011) investigate the link between CG and the leverage pattern of listed non-financial firms in Bangladesh. They discover that firm-level governance quality has a significant impact on a company's leverage, with weakly governed businesses having a greater degree of debt financing. Mwambuli (2019) investigates the role of CG, measured by a CGI, on CS of 32 non-financial listed firms in the East African region from 2006 to 2015 and finds a significant negative effect of CG on CS decisions. Most studies (Herlambang et al. 2018; Chow et al. 2018) use several CG variables as a proxy for CG, and the use of CGI as a measure of overall CG quality to assess their impact on CS is rare.
Causal effect of capital structure on corporate governance
CS can influence CG levels through enhanced compliance with the CG Code and more corporate disclosures. According to Jensen and Meckling (1976) and Masum et al. (2020), firms with high debt are prone to report additional information to satisfy the requests of external capital providers and alleviate borrowers’ concerns about the possibility of transferring resources from debt holders to managers and shareholders. Again, agency theory shows a robust correlation between a company’s CS and disclosure (Jensen and Meckling 1976), because the existence of debt holders in a company’s leverage (particularly in highly geared businesses) intensifies agency problems (and hence increases monitoring costs), which aims to decrease these costs by revealing additional information in their annual reports. These companies should increase their disclosure levels to restore investor and creditor confidence and as a result, minimise the impact of bankruptcy risk.
A substantial positive link between CS and CG disclosure has been observed by Al-Moataz and Hussainey (2013) in Saudi Arabia and Elfeky (2017) in Egypt, and an insignificant positive impact by Zeghal and Moussa (2015) in several countries, Elgattani and Hussainey (2020) in eight countries (Bahrain, Syria, Qatar, Sudan, Jordan, Palestine, Oman, and Mauritius), and Suwaidan et al. (2021) in Jordan. However, a significant negative relationship is found in some studies by Mallin and Ow-yong (2009) in the United Kingdom and Cunha and Rodrigues (2018) in Portugal, but such a relationship is found to be insignificant by Alves et al.(2012) in Portugal and Spain, and Allegrini and Greco (2013) in Italy.
Reverse causality between corporate governance and capital structure
CS affects CG and vice versa. This is true regardless of whether management chooses to use debt as a source of funding to minimise issues with information asymmetry and transaction, increasing the efficiency of its firm governance decisions, or whether the growth in the debt level is required by the stockholders as a tool to discipline behaviour and ensure effective CG.
On one hand, a change in how debt and equity are managed affects CG practices by changing the structure of incentives and management control. If through the mixture of debt and equity, diverse types of investors all converge within the company, where they have different kinds of impact on governance decisions, then managers will typically have preferences when deciding how one of these categories will prevail when defining the company’s CS. More crucially, it is possible to significantly improve CG efficiency through the thoughtful design of debt contracts and equity.
On the other hand, CG also affects CS decisions. Myers (1984) and Majluf and Myers (1984) demonstrate how management makes decisions about a firm's financing following an order of preference; in this case, if the manager selects the financing resources, it can be assumed that the latter is avoiding a decrease in its ability to make decisions by agreeing to the discipline that debt represents. Finance from internal sources enables managers to keep outside parties out of their decision-making processes. Management can prevent outside influences from influencing their decision-making by financing internal resources. De Jong (2002) describes how managers in the Netherlands attempt to avoid utilising debt so that their ability to make decisions is unchecked, while Zwiebel (1996) observes that managers are forced to issue debt through other governance mechanisms since they are unable to freely embrace the “discipline” of debt (cited in La Rocca 2007). Jensen (1986) stated that decisions to increase corporate debt are voluntarily undertaken by management when it aims to ‘‘reassure’’ stakeholders that its governance decisions are ‘‘proper’’. Empirical studies on the bidirectional relationship between CG and CS are scarce.
Corporate governance, capital structure and firm performance
Previous research has investigated the relationships between CG, CS and FP but such research (Roy and Pal 2017; Nawaz K. and Nawaz A. 2019; Shahzad et al. 2022) has analysed each association separately, in one direction, and using various mechanisms of CG.
To the best of our knowledge, no study has investigated the interrelationship and interdependence between these three variables simultaneously, and more so, using a single composite measure of CG level.
The impacts of CG mechanisms and leverage on FP from previous studies have mixed results, and it is interesting to investigate the simultaneous interrelationships and interdependencies between these three variables in a unique economic, political and social contexts of a small and emerging economy like Mauritius, considered as a reference for the main economic aspects (including good governance) in the African region.
Research design
This section discusses the current study’s research design and philosophy, disclosure sources, CGI measurement, data collection, sample selection, PVAR models and the statistical tests that are employed.
Research questions and conceptual framework
The study’s objectives are to analyse:The interrelationships and interdependencies between CG, CS and FP of listed Mauritian firms, and
Any differences in the magnitude and impact of their interrelationships and interdependencies between Mauritian financial and non-financial listed firms.
Timeframe and statistical analysis model
A sample of firms listed on the SEM from 2009 to 2019 is examined. The PVAR approach is used to capture the multiple variables involved in the sample, according to the applicable literature discussed in “Literature review”. The STATA 16 software is used to analyse the data to obtain descriptive statistics and the PVAR model (Fig. 1).Fig. 1 Dynamic interrelationships and interdependencies between corporate governance, capital structure, and firm performance
Research and sampling design
This study applies the balanced panel data method to examine a sample of companies listed on the SEM from 2009 to 2019. The research data are collected manually, comprising four financial (excluding banks because of the difference in their CG disclosure requirements) and 38 non-financial companies listed on both SEMDEX and DEMEX of SEM. Annual reports before 2009 are unavailable for all 42 firms to have a balanced panel. The years 2020 and 2021 are excluded because of the worldwide economic crisis resulting from the COVID-19 pandemic which will not reflect the true financial performance of the selected listed companies.
Description of the corporate governance disclosure index
The CGI is measured as the ratio of compliance with each of the CG practices of all 42 companies in the sample selected, which consist of six components/sub-indices of CG. The annual reports from 2009 to 2019 are used to determine whether each of the 102 governance provisions recommended in the checklist is true for that company, as per the Mauritian Code of CG. A ‘yes’ response in form of compliance to a respective governance practice is given a value of one and a ‘no’ response in form of non-compliance is given a value of zero. The CGI is calculated by adding these values to each company annually. Given that when the index has a large number of items and both weighted and unweighted indices’ scores produce similar results (Chow and Wong-Boren, 1987; Sharma, 2014), an unweighted index is used to evaluate disclosure levels as per previous studies (Cunha and Rodrigues 2018; Masum et al. 2020). Furthermore, the unweighted approach gives each disclosure item in the annual report equal weighting and is best suited to resolve the problem of subjectivity bias (Healy and Palepu 2001). Cronbach’s alpha test of reliability of the above six sub-indices forming the CGI has a score of 0.866, which shows that the sub-indices are reliable indicators for measuring the extent of CG.
Panel data vector autoregression (PVAR) models
A summary of the variables’ descriptions and measurements based on previous literature and utilised in this study is shown in Table 1.Table 1 Description of variables
Variables Description Details Sources
ROE Firm performance Net profit after tax to total shareholders’ equity Bhatt and Bhatt (2017)
Dao and Nguyen (2020)
CGI Overall corporate governance disclosure index The ratio of overall corporate governance disclosure items (Cunha and Rodrigues (2018)
Masum et al. (2020)
CS Firm leverage The ratio of total debt to book value of equity Renders et al. (2010)
As per the definition in prior studies, three variables CGI, CS and ROE are used in this study. Bhagat et al. (2008) argue that developing a CGI is beneficial, because it incorporates the different components of a company's governance structure into a single number that can be utilised to assess governance efficiency. The interrelationships/interdependencies between CG, CS, and FP are investigated using the PVAR methodology. The PVAR method is particularly well suited to this research because it strives to model the evolution of a system of interest variables—CG, CS and FP—in a set of firms that differ significantly in various dimensions such as financial, non-financial, size, age, industry type, and listing status. The PVAR approach is a mixed econometric methodology that blends the standard VAR method, in which all variables in the model are considered endogenous, with the panel data technique, which permits the explicit insertion of a fixed effect in the structure (Shank and Vianna 2016). PVAR accounts for both static and dynamic interdependencies (Canova and Ciccarelli, 2013). This setup also enables us to investigate the Impulse Response Functions (IRFs) of various shocks and how they influence other imbalances. In this study, the model in the PVAR approach is limited to only endogeneous variables and control variables are excluded in line with prior studies (Shank and Vianna 2016; Comunale 2017; Jouida 2018; Traoré 2018; Apostolakis and Papadopoulos 2019; Trofimov 2021).
In a generalised method of moments (GMM) framework, the PVAR model selection, estimation, and inference are used, as proposed by Abrigo and Love (2016). Considering Abrigo and Love (2016), the following k-variable homogeneous panel VAR of order p, with panel-specific fixed effects characterised by the following system of linear equations:Yit=Yit-1A1+Yit-2A2+⋯⋯·+Yit-p+1Ap-1+Yit-pAp+XitB+ui+eit
1 i∈{1,2,...,42},t∈{2009,2010,...,2019},
where Y is a (1 × k) vector of dependent variables, X is a (1 × l) vector of exogenous covariates, and ui and e are (1 × k) vectors of dependent variable-specific panel fixed-effects and idiosyncratic errors, respectively. The (k × k) matrices A1, A2, …, Ap − 1, Ap, and the (l × k) matrix B are the parameters to be estimated. It is presumed that the innovations have the following attributes: E (eit) = 0, E (e’iteit) = Σ, and E (e’iteis) = 0, and for all t > s.
According to Abrigo and Love (2016), the PVAR describes in Eq. (1) has problems with dynamic interdependencies and cross-sectional heterogeneities. Consequently, the fixed-effects variable μi is the only variable that captures the heterogeneity between various units. Because the individual effect term Ai is linked to the error term in dynamic panels, the ordinary least-squares (OLS) method cannot be used, because estimation by OLS leads to biased coefficients (Jouida 2018). To address this issue, PVAR models are determined using an equation estimated with the GMM, in an 11 year study of 42 listed Mauritian companies. This method has numerous benefits. Arellano-Bond is used to generate unbiased fixed-effects average coefficients for the short panels (N > T). As a result, the findings control for all time-invariant characteristics that are often addressed in empirical research. On the left side of each equation is the first difference of an endogenous variable and on the right side is the p lagged first difference of all endogenous variables.
Panel unit root test
The Augmented Dickey and Fuller (ADF) (1981), Levin, Lin, and Chu (LLC) (2002) and Im, Pesaran, and Shin (IPS) (2003) tests for data stationarity reveal that all the series of variables used in this model are stationary at level, because the p-values are below the 5% level. Given the absence of a unit root, it is possible to investigate the causation between the three variables.
Selection order criteria
For the study of the PVAR models, the steps of Abrigo and Love (2016), who present a package of controls on STATA, are followed. The optimal lag order in the panel VAR specification and moment condition is used to perform the PVAR analysis. Since the first-order panel VAR (one lag) has the smallest MBIC (Bayesian information criteria, Schwarz, 1978), MAIC (Akaike information criteria, Akaike, 1969), and MQIC (Hannan-Quinn information criteria, Hannan and Quinn, 1979), the data in Table 2 support this option.Table 2 Selection order Criteria Sample: 2013 – 2018 No. of obs = 252 No. of panels = 42
lag CD J J p-value MBIC MAIC MQIC
1 0.999 23.778 0.643 − 125.516 − 30.222 − 68.566
2 0.999 15.799 0.607 − 83.731 − 20.201 − 45.764
3 0.999 10.868 0.285 − 38.897 − 7.132 − 19.914
4 0.999 – – – – –
J denotes Hansen’s (1982) J statistic of overidentifying restrictions; maximum likelihood-based model-selection criteria (M), namely, the Akaike information criteria (AIC)(Akaike 1969), the Bayesian information criteria (BIC)(Schwarz 1978; Rissanen 1978; Akaike 1977), and the Hannan–Quinn information criteria (HQIC)(Hannan and Quinn 1979)
Empirical results and discussion
Descriptive statistics
Table 3 shows the normal statistical characteristics of the main and other variables, including the mean, minimum, maximum, and standard deviation, of the sample of 42 listed companies.Table 3 Descriptive statistics
Variables Observations Mean Standard deviation Minimum Maximum
ROE 462 0.222 1.342 − 2.070 22.651
CGI 462 0.819 0.119 0.216 0.971
CS 462 1.016 1.141 0.002 8.368
Age 462 17.271 7.728 1 35
Size 462 8907.019 12,202.82 39.5 68,984.17
Listing 462 0.68 0.467 0 1
CGI denotes the ratio of the overall corporate governance disclosure items, CS denotes firm leverage, and ROE denotes firm profitability, AGE denotes firm age, SIZE denotes firm size by total assets, and LISTING denotes a firm’s listing status with SEMDEX firms = 0 and DEMEX firms = 1
As shown in Table 3, the average return on equity ratio (ROE), a proxy for FP, is 22.2%. The CGI, as a proxy for CG, for all 42 listed firms ranged from 21.6 to 97.1%, with a mean of 81.9% and a standard deviation of 11.9%. The mean value of the CGI of the 38 non-financial firms is 81%, while that of the four financial firms is 90.6%. The results indicate that listed Mauritian firms are highly compliant with the Mauritian CG Code, with financial firms being more compliant than non-financial firms. The average CS levels of Mauritian companies are almost 101.6% of their equity (financial firms: 131.2% and non-financial firms: 98.5%) demonstrating that they are highly leveraged firms. ROE is on average 22.2% for the whole sample and 7.1% and 165.4% for non-financial and financial firms, respectively.
Correlation analysis
The correlation analysis between the three variables in Table 4 and the variance inflation factors (VIF) for both CS and CGI is 1.00 which implies that there is no evidence of multicollinearity.Table 4 Pearson’s and Spearman’s correlation matrices of the dependent and independent variables for the whole sample
(obs = 462) ROE CGI CS
ROE 1.000
CGI 0.081* 1.000
CS 0.152*** 0.061 1.000
CGI denotes the ratio of the overall corporate governance disclosure items, CS denotes firm leverage, and ROE denotes firm profitability
*, **, *** indicate significance at the 10, 5, and 1% levels, respectively
PVAR results and discussion
PVAR results
Table 5 shows the coefficients from the PVAR model by using ‘GMM-style’ instruments for CG, CS and FP. In this model, all variables are at a level and considered endogenous. Table 5 indicates that, in the CG equation, CG responds positively and significantly to its own lag for all firms, including both non-financial and financial firms. The CG responds positively and significantly to the lag of CS only for financial firms. CS has a positive impact on CG because high levels of leverage of financial firms raise agency costs, which encourages managers to reveal more information in an attempt to lower these costs. Moreover, financial companies with high debt ratios are exposed to significant monitoring costs or specific restrictive covenants, which force them to reveal more information and also reassure their lenders to extend or lengthen the debt contract time. It can also be noted that CG responds negatively and substantially to the lag in FP, except for non-financial firms, where it is positive but insignificant. The negative impact of FP on CG is consistent with the findings of Zeghal and Moussa (2015) and Suwaidan et al. (2021), because even Mauritian firms with weak financial performance have strong motivations for CG disclosures to attract investment and enhance their financial ratios. The positive effect of FP on CG disclosure for non-financial firms, supporting the agency theory, is because they may be aiming to attract new investors and shareholders.Table 5 Panel VAR estimates
All firms Non-financial firms Financial firms
Coefficients P value Coefficients P value Coefficients P value
Dependent variable: CGI
CGI L1 0.968*** 0.000 0.968*** 0.000 0.996*** 0.000
CSL1 0.003 0.301 0.006 0.350 0.003*** 0.000
ROE L1 − 0.001* 0.096 0.010 0.417 − 0.0003*** 0.000
Dependent variable: CS
CGI L1 1.096*** 0.000 1.184*** 0.000 − 1.691*** 0.000
CSL1 0.443*** 0.000 0.681*** 0.000 0.651*** 0.000
ROE L1 0.093*** 0.000 1.258*** 0.002 0.034*** 0.000
Dependent variable: ROE
CGI L1 − 0.222 0.126 − 0.410*** 0.000 0.906 0.400
CS L1 0.152*** 0.001 0.041* 0.072 1.050*** 0.000
ROE L1 0.543*** 0.000 0.137** 0.048 0.449*** 0.000
Number of observations 378 342 36
Number of groups/firms 42 38 4
CGI denotes the ratio of overall corporate governance disclosure items, CS denotes firm leverage, ROE denotes firm profitability, CGIL1 denotes one lag in the ratio of overall corporate governance disclosure items, CSL1 denotes one lag in firm leverage, and ROEL1 denotes one lag in firm profitability
*, **, *** indicate significance at the 10, 5, and 1% levels, respectively
In the CS equation, all coefficients are significant, as indicated by their values at the 1% level. CS responds positively and significantly for the whole sample and non-financial firms to the lag of CG but negatively and significantly for financial firms. The positive effect of CG on CS implies better governed non-financial firms are in a better position to obtain more debt. As regards financial firms, CG impacts negatively on CS because firms with low-CG practice need to use more leverage to minimise agency costs and align firm managers' interests with those of shareholders. The CS responds positively and substantially to its own lag in all three cases. The lag in FP has a substantial positive effect on CS for the whole sample and two sub-samples. This implies that profitable Mauritian firms are more inclined to borrow more because of low bankruptcy costs and reap more tax benefits and support TOT.
Regarding the FP equation, FP responds significantly and positively to its own lag and the lag of CS for the whole sample and two sub-samples. CS has a positive impact on FP, because an increase in firm leverage is expected to decrease information costs, lessen inefficiency, strengthen management and thus enhance FP. Nevertheless, the response of FP to CG differs; it is negatively connected to the lag of CG for the whole sample and non-financial firms which contradicts the findings of Padachi et al.(2017). This significant negative relationship for non-financial firms can be the result of the prevalence of highly concentrated ownership among the listed Mauritian companies which often leads to managerial entrenchment (Elghuweel et al. 2017) that can have adverse impacts on management behaviour and incentives. Another possible reason for the negative impact of CG on FP can be that directors of the board and its board committees may not be having a total commitment to the cause of the company because of other commitments which limit their contribution. For financial firms, FP responds positively but insignificantly to CG lag.
There is no indication of any reverse causation between CG and FP for all firms, including non-financial and financial firms. Causality runs negatively and significantly in just one direction for the whole sample and financial firms—from FP to CG and not vice versa. For non-financial companies, however, causality only flows negatively and significantly in one direction, from CG to FP which is in line with the studies by Rajput and Joshi (2014) and Adegboye et al. (2019) and not vice versa. Additionally, CS has a positive and significant impact on FP and vice versa, demonstrating a strong bidirectional relationship between CS and FP for all firms, including non-financial and financial firms, and supporting the agency cost hypothesis and CS trade-off theory, which contradicts the findings of Jouida (2018) with varying relationships but consistent with the findings of Abdullah and Tursoy (2021) and Adhari and Viverita (2015). Moreover, the analysis reveals a unidirectional relationship between CG and CS for the whole sample and non-financial firms, because CG has a positive significant influence on CS, implying that better governed firms have more debt, but not vice versa. For financial firms, however, substantial bidirectional correlations between CG and CS have been established with varied signs. For instance, CG has a major negative effect on CS, meaning that better governed financial firms have less leverage (Haque et al. 2011; Mwambuli 2019), and CS has a considerable positive impact on CG in line with the findings of Al-Moataz and Hussainey (2013) and Elfeky (2017) and which supports the agency theory.
Overall, the findings reveal that better governed firms can increase their leverage to boost FP which in turn helps to obtain further debt. Therefore, in an emerging economy with steady economic growth and growth opportunities, profitable and better governed firms are prone to finance their investments with additional debt that significantly improves their profitability. However, as a firm increases its debt holdings, the probability of financial distress increases and creditors are less likely to re-finance or renegotiate. In this context, given the importance of debts and good CG, policymakers can consider measures relating to monetary (interest rates) and fiscal (tax) policies to make loans from financial institutions more accessible and attractive/competitive and to further improve CG standards that jointly help to improve FP. However, policymakers can also consider policy measures for steady positive economic growth because any decline may increase bankruptcy risks with serious repercussions due to the presence of highly leveraged companies.
Granger causality
In Table 6, the null hypothesis that all lags of all variables can be excluded from each equation in the PVAR system is evaluated in the final row, which displays the joint probability of all lagged variables in the equation.Table 6 Panel VAR-Granger causality Wald test
Equation/excluded df All firms Non-financial firms Financial firms
Chi2 Prob > chi2 Chi2 Prob > chi2 Chi2 Prob > chi2
CGI
CS 1 1.068 0.301 0.873 0.350 247.949*** 0.000
ROE 1 2.771* 0.096 0.658 0.417 370.691*** 0.000
ALL 2 3.841 0.147 0.951 0.622 724.889*** 0.000
CS
CGI 1 14.037*** 0.000 13.751*** 0.000 28.003*** 0.000
ROE 1 25.615*** 0.000 10.043*** 0.002 144.336*** 0.000
ALL 2 29.571*** 0.000 17.365*** 0.000 260.090*** 0.000
ROE
CGI 1 2.337 0.126 27.660*** 0.000 0.708 0.400
CS 1 11.977*** 0.001 3.247* 0.072 322.990*** 0.000
ALL 2 14.734*** 0.001 30.676*** 0.000 3196.255*** 0.000
CGI denotes the ratio of overall corporate governance disclosure items, CS denotes firm leverage, and ROE denotes firm profitability
*, **, *** indicate significance at the 10, 5, and 1% levels, respectively
Table 6 shows that the joint significance Chi-square statistics in the last row show that all three variables i.e., CS, CG and FP variables are granger-caused by all the lagged variables for financial firms only. CS and FP variables are jointly and significantly granger-caused by all the lagged variables for all firms including non-financial and financial firms. However, the CG variable is not jointly and significantly granger-caused by all the lagged variables for the whole sample and non-financial firms. In general, the findings reveal that CG and FP jointly help to increase leverage, and CG and CS jointly boost the profitability of firms. Policy measures can, therefore, be focused on jointly improving CG standards and leverage to boost FP (Fig. 2).Fig. 2 Stability test for all firms, non-financial firms, and financial firms. All Eigen values are strictly less than one and lie inside the unit circle
Stability test
PVAR satisfies stability conditions for the whole sample and two sub-samples (Table 7).Table 7 Eigen value stability condition
All firms Non-Financial Firms Financial Firms
Real Imaginary Modulus Real Imaginary Modulus Real Imaginary Modulus
0.975 0 0.975 0.980 0 0.980 0.982 0 0.982
0.621 0 0.621 0.754 0 0.754 0.773 0 0.773
0.359 0 0.359 0.054 0 0.054 0.341 0 0.341
Panel variance decompositions
After a particular amount of time, forecast error variance decompositions (FEVDs) demonstrate the percentage of the total variation in one variable explained by the shock of another variable. As a result, they show the size of the total effect of one variable on another. A cumulative effect over ten years is provided. Table 8 reports the FEVDs of the baseline PVAR model and for the financial and non-financial sectors from 0 to 10 years. The implied FEVDs are derived using the causal ordering proposed by Abrigo and Love (2016). Based on the FEVD estimates, Table 8 indicates that for the baseline model and non-financial firms, the three variables are explained mainly by variations in their own variables. However, for financial firms, FP explains only 33.6% of its own lag, but explains 61.2% of the variation in CS. For all firms, 13.6% of the variation in CS is explained by CG and 13.2% of the variation in FP can be explained by CS. FP explained 5.5% of the total variance in the CS. The variation in CG is not explained by CS. Similarly, the variation in CG cannot be explained by FP and vice versa. For non-financial firms, CG and FP explain approximately 16 and 8% of the total variance in CS, respectively. CS explains only a small portion (1.8%) of the variance in CG. The 18.8% and 10.5% variations in FP can be explained by CG and CS, respectively. For financial firms, 8.6% of the variation in CG can be explained by CS, while 2% and 5% of the variation in CS can be explained by FP and CG, respectively. The 61.2% and 5.2% variations in FP can be explained by CS and CG, respectively. The FEVD results support the selection of FP as the most endogenous variable.Table 8 Forecast error variance decomposition
Model Response variable and forecast horizon (from 0 to 10 years) Impulse variables
CGI CS ROE
All firms CGI
0 0 0 0
10 0.997 0.003 0.000
CS
0 0 0 0
10 0.136 0.809 0.055
ROE
0 0 0 0
10 0.000 0.132 0.868
Non-financial firms CGI
0 0 0 0
10 0.978 0.018 0.004
CS
0 0 0 0
10 0.160 0.757 0.083
ROE
0 0 0 0
10 0.188 0.105 0.707
Financial firms CGI
0 0 0 0
10 0.910 0.086 0.004
CS
0 0 0 0
10 0.050 0.929 0.021
ROE
0 0 0 0
10 0.052 0.612 0.336
CGI denotes the ratio of the overall corporate governance disclosure items, CS denotes firm leverage, and ROE denotes firm profitability
Panel impulse response functions
Based on the calculated model, 200 Monte Carlo draws are used to calculate IRF confidence intervals. The IRFs are estimated using the same ordering as that used in PVAR. Figure 3 depicts the reactions to a one-standard-deviation shock. The impulse response function describes how one variable reacts to changes in another variable in the system while keeping all other shocks equal to zero.Fig. 3 Orthogonalised Impulse Response Function (IRF) for all firms. OVCGDI (CGI) denotes the ratio of the overall corporate governance disclosure items, TDBTNEV (CS) denotes firm leverage, and ROE denotes firm profitability
In terms of levels, the IRF plot in Fig. 3 shows that the shocks to CG have a constant insignificant positive effect on the FP of all Mauritian-listed firms over the 10 years. Shocks to the CG created a smaller but constant positive significant response to CS over a longer period. However, the shocks to the CS create a positive significant response in FP and fall to zero after approximately 8 years. Shocks to the CS create a smaller but constant response to the CG over a longer period. Moreover, shocks to FP result in an insignificant but negative response to CG over a longer period and a significant positive response to CS in the first 2 years which eventually dies to zero after 10 years period. The positive response from CS to a shock in FP is in line with TOT. For all firms, the Granger causality Wald test results together with the time path of the impulse response provide robust statistical evidence for the existence of a strong positive bidirectional association between CS and FP.
For non-financial firms in Fig. 4, a shock in CG results in a positive response to CS which is relatively lower in the first two periods, increases until period 6, and then starts declining at a negligible rate but remains positive. A shock in the CG has a negative effect on the FP over the 10 years. A shock in FP has a positive but negligible impact on CG over the years and a positive effect on CS, with the impact being significant in year 1 and gradually declining but remaining positive over the years. A shock in CS has a positive but negligible impact on CG but improves insignificantly over the 10 years. The response of FP to a shock in CS is negative in period zero, positive in period 1 to period 7, and then restarts a negative impact. For non-financial firms, the Granger causality Wald test outcomes, together with the time path of the impulse response, provide solid statistical evidence for the existence of strong positive reverse causality between CS and FP.Fig. 4 Orthogonalised Impulse Response Function (IRF) for non-financial firms. OVCGDI (CGI) denotes the ratio of the overall corporate governance disclosure items, TDBTNEV (CS) denotes firm leverage, and ROE denotes firm profitability
For the financial firms in Fig. 5, FP responds positively and significantly up to 7 years, returning to negative from period 8 to a shock in CG. A shock in CG has a significant positive effect on CS until year 5 and then turns negative from period 6. A shock in CS has had a significant positive impact on FP over the 10 years with the initial 4 years being much higher. The CG also responds positively and significantly to a shock in the CS over a long period. Conversely, a shock in FP negatively affects CG for a longer period, similar to all firms, while it has a positive impact on CS for a period above 10 years, with the initial 2 years being much higher. For financial firms, the Granger causality Wald test results together with the time path of the impulse response present robust statistical evidence for the existence of a strong bidirectional correlation between CS and FP, and CS and CG, respectively.Fig. 5 Orthogonalised Impulse Response Function (IRF) for financial firms
Robustness analysis
Another estimator XTVAR
The least-squares dummy variable estimator XTVAR, developed by Cagala and Glogowsky (2014), is used to compare the results of PVAR to assess its robustness. The results of the IRFs using this approach indicate that for all firms, the sign of XTVAR results is the same with different magnitudes of the coefficients, but the lags of FP on CG, CG on CS, and CS on FP show no significance compared to PVAR results. Moreover, there are a few differences between the IRFs and the variance decomposition analysis results of XTVAR and PVAR for CG and CS on FP.
The XTVAR and PVAR results are, therefore, almost similar for the whole sample and non-financial firms, although some minor differences are noted for financial firms and confirm the robustness of the results.
Alternative orderings of variables
Instead of CGI → CS → ROE in the baseline model, alternative orderings are tried, that is, ROE → CS → CGI, and the variance decomposition analysis for CG and CS on FP is similar for the whole sample and non-financial firms, respectively. Conversely, differences are noted in the variation in FP and CS explained by shocks in FP and CS, respectively.
Moreover, for all firms, the signs of the effects in general shapes of IRF are similar, except for the response of CG to the shock of FP and vice versa, which are slightly different. For non-financial firms, the signs and general shapes are similar. Concerning financial firms, the sign of the effect and general shapes of IRFs are similar except for the response of CS and FP to a shock in CG having slightly different shapes and the response of CG to a shock in FP.
Overall, the sensitivity analysis indicates that the findings are strongly robust to an alternative estimator, XTVAR, and the alternative ordering of the variables.
Summary and conclusion
This study aims to analyse the interrelationships and interdependencies between CG, CS and FP. In this study, the PVAR with a GMM framework is used and the analysis is based on IRF and FEVD. First, there is no evidence of reverse causality between CG and FP for all firms, including non-financial and financial firms, because, for the whole sample and financial firms, the causality runs negatively and significantly in one way only—from FP to CG and not vice versa. However, for non-financial firms, causality runs negatively and significantly in one way only, from CG to FP, and not vice versa. Second, CS positively and significantly affects FP and vice versa, showing a robust bidirectional relationship between CS and FP for the whole sample and two sub-samples, respectively, and strongly supporting TOT. Third, the findings show that for the whole sample and non-financial firms, there is a unidirectional relationship between CG and CS, since there is a substantial positive effect of CG on CS but not vice versa. However, strong bidirectional correlations between CG and CS are found for financial firms with varying signs. For instance, CG has a strong negative impact on CS, supporting agency theory, implying that better governed financial firms have less leverage, and CS has a significant positive effect on CG which also supports agency theory. Fourth, the FEVD results support FP as the most endogenous variable. For the baseline model and non-financial firms, the three variables are explained mainly by variations in their own variables, whereas for financial firms, 61.2% of the variation in FP is explained by CS. Variation in CG is in all three cases, negligibly explained by other variables, FP and CS.
For the whole sample and non-financial firms, the Granger causality Wald test results, together with the time path of the impulse response, provide robust statistical evidence for a strong positive bidirectional correlation between CS and FP. For financial firms, a strong bidirectional relationship exists between CS and FP, CS and CG, respectively. Overall, the results remain robust after using XTVAR as an alternative approach to PVAR and the alternative ordering of the variables for the whole sample and non-financial firms. Some discrepancies are noted in the case of financial firms; however, in general, the results remain robust.
This study contributes to the existing CG and CS literature and FP effects by employing a PVAR method that overcomes the endogeneity issue due to the possible existence of reverse causality or interdependencies between the three variables which is being done to the best of the authors’ knowledge for the first time for this topic. Moreover, statistical analysis is potentially useful to policymakers in their endeavour to articulate CG recommendations and policies. The implications of the present study can also be of significant value to investors (both local and foreign) and managers, enlightening them that, in this small island emerging economy, although firms are highly geared, more debt has a significant positive impact on FP. Investors while having their investment and credit decisions may also rely on the results that better governed Mauritian financial firms have better financial performance although its effect is short-lived and reduces its significance with the elapse of time but remains positive. In general, better governed firms are more able to have more debt and with growth opportunities in an emerging economy, such additional debt can be invested in viable/profitable projects to increase profitability (results show a significant positive impact of CS on FP). Policymakers can consider the monetary policies to make loans more easily accessible at competitive interest rates to firms, because as a firm increases its debt holdings, the probability of financial distress increases and creditors are less likely to re-finance or renegotiate and also take measures to improve CG standards that jointly help to further improve their profitability. Improving CG standards through better information disclosure not only reduces the cost of capital of loanable funds but also tends to attract more institutional investors and financial analysts to firms. However, policymakers can explore their fiscal measures to ensure consistent positive economic growth, since any slowdown can increase the risk of bankruptcy, which can have major ramifications due to the presence of heavily indebted enterprises.
However, the current study is constrained by certain inherent constraints and limitations: first, the restrictions that are imposed by utilising annual CG reports and accounts; second, this study is confined to listed companies. The small size of the Mauritian economy and its stock exchange limits the possibility of increasing the sample size more specifically for financial firms. Moreover, the quantitative analysis does not provide much insight into the unobserved and unmeasured factors that may influence the interactions, which can be overcome through qualitative methods.
The limitations listed above imply that future studies can build on and use current research as a foundation. Future studies may focus on using qualitative methodologies to better understand the interrelationships between CG, CS and FP, particularly for variables where no connection is detected. Furthermore, the current study may be expanded to compare with other emerging economies and estimate alternative profitability indicators (market performance and Return on Assets). Longitudinal studies can also be undertaken by comparing pre-COVID and post-COVID-19. The dynamic interrelationships between concentrated ownership structure or other CG components, CS and FP can also be examined in future research.
Acknowledgements
The authors acknowledge the Editor-In-Chief and two anonymous referees for their constructive feedback to improve the quality of the paper.
Author contributions
RKR bears full responsibility for the submission and confirms that the authors listed on the title page have contributed significantly to the work. Specifically, RKR has written all parts of the manuscript (introduction, literature), collected, analysed, and interpreted the findings of the PVAR approach on the interrelationships and interdependencies among corporate governance, capital structure, and firm performance of listed Mauritian companies. BS has reviewed the manuscript to put it into perspective. The authors read and approved the final manuscript.
Funding
The authors received no financial support for the research.
Data availability
All data and materials used in this study from the annual reports of the listed firms are available upon subscription on https://www.african-markets.com/en/annual-reports.
Declarations
Conflict of interest
The authors declare that they have no competing interests that are relevant to the content of this article.
Ethical approval
Not applicable.
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| 0 | PMC9745712 | NO-CC CODE | 2022-12-15 00:02:40 | no | SN Bus Econ. 2023 Dec 13; 3(1):14 | utf-8 | SN Bus Econ | 2,022 | 10.1007/s43546-022-00382-4 | oa_other |
==== Front
Support Care Cancer
Support Care Cancer
Supportive Care in Cancer
0941-4355
1433-7339
Springer Berlin Heidelberg Berlin/Heidelberg
7472
10.1007/s00520-022-07472-x
Research
The least costly pharmacy for cancer supportive care medications over time: the logistic toxicity of playing catch up
Etteldorf Andrew 1
Sedhom Ramy 2
Rotolo Shannon M. 3
Vogel Rachel I. 1
Booth Christopher M. 4
Blaes Anne H. 1
Virnig Beth A. 1
Dusetzina Stacie B. 5
Gupta Arjun [email protected]
1
1 grid.17635.36 0000000419368657 Division of Hematology, Oncology & Transplantation, University of Minnesota, 516 Delaware Street SE, MMC 480, PWB 14-100, Minneapolis, MN 55455 USA
2 grid.25879.31 0000 0004 1936 8972 University of Pennsylvania, Philadelphia, PA USA
3 grid.170205.1 0000 0004 1936 7822 University of Chicago Medicine, Chicago, IL USA
4 grid.410356.5 0000 0004 1936 8331 Queen’s University, Kingston, Ontario Canada
5 grid.152326.1 0000 0001 2264 7217 Vanderbilt University School of Medicine, Nashville, TN USA
13 12 2022
2023
31 1 318 7 2022
1 11 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Purpose
No single pharmacy in an urban zip code is consistently the least expensive across medications. If medication prices change differently across pharmacies, patients and clinicians will face challenges accessing affordable medications when refilling medications. This is especially pertinent to people with cancer with multiple fills of supportive care medications over time. We evaluated if the lowest-priced pharmacy for a formulation remains the lowest-priced over time.
Methods
We compiled generic medications used to manage nausea/vomiting (14 formulations) and anorexia/cachexia (12 formulations). We extracted discounted prices in October 2021 and again in March 2022 for a typical fill at 8 pharmacies in Minneapolis, Minnesota, USA (zip code 55,414) using GoodRx.com. We examined how prices changed across formulations and pharmacies over time.
Results
Data were available for all 208 possible pharmacy-formulation combinations (8 pharmacies × 26 formulations). For 172 (83%) of the 208 pharmacy-formulation combinations, the March 2022 price was within 20% of the October 2021 price. Across pharmacy-formulation combinations, the price change over time ranged from − 76 to + 292%. For 12 (46%) of the 26 formulations, at least one pharmacy with the lowest price in October 2021 no longer was the least costly in March 2022. For one formulation (dronabinol tablets), the least expensive pharmacy became the most expensive, with an absolute and relative price increase of a fill of $22 and 85%.
Conclusion
For almost half of formulations studied, at least one pharmacy with the lowest price was no longer the least costly a few months later. The lowest price for a formulation (across pharmacies) could also change considerably. Thus, even if a patient accesses the least expensive pharmacy for a medication, they may need to re-check prices across all pharmacies with each subsequent fill to access the lowest prices. In addition to safety concerns, directing medications to and accessing medications at multiple pharmacies can add time and logistic toxicity to patients with cancer, their care partners, prescribers, and pharmacy teams.
Keywords
Cancer
Financial toxicity
Time toxicity
Logistic toxicity
Lowest cost pharmacy
Drug prices
issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2023
==== Body
pmcIntroduction
Facing high medication costs, people with cancer, their care partners, and the clinical team sometimes explore less costly sources of medications [1–4]. This is particularly true for supportive care medications; drugs used to prevent and treat symptoms of cancer or side effects of its treatment [5]. Supportive care medications are often available at multiple local pharmacies (within a zip code), with transparent out-of-pocket costs available through drug price comparison websites [1, 5].
We have previously demonstrated that no single pharmacy in an urban zip code consistently offered the lowest discounted price for 26 generic formulations of medications used to treat nausea/vomiting and anorexia/cachexia [1]. “Shopping around’’ for the least expensive source of each medication by visiting multiple pharmacies can save direct out-of-pocket costs in the moment, but can add time and logistic toxicity for patients and care partners [1, 2, 6–8]. Even in an urban area with a high density of pharmacies, a patient seeking the least expensive source of five common supportive care medications may have to visit five different pharmacies to get the lowest price on all medications [1]. In one example, just the driving time (without accounting for traffic or time spent parking, waiting in line, medication processing, and getting back to the car) was over an hour, with > 30 miles distance covered [1]. The potential cost savings in this example were approximately 20% (saving $20 on $100), but patients may face more difficult trade-offs between financial, time, and logistic toxicity when cost differences and time burdens are more significant.
Patients with cancer may require multiple fills of supportive care medications over months or years as they manage the disease. Even if patients or their care team members identify the least expensive source of a medication, and decide to pursue it for the first fill, a complicating factor is that medication prices are dynamic, changing with time and across pharmacies. This potentially creates additional complexity for patients and clinicians even if they identify the least expensive pharmacy for a medication at the outset. A key question is whether the lowest cost pharmacy for a medication formulation remains the lowest-cost over time.
Methods
We included 14 generic formulations for medications used to treat nausea/vomiting and 12 used to treat anorexia/cachexia. We selected these symptoms since they are common, clinically relevant, and several approved and off-label medications are available and used to treat them. Detailed methods are available in prior work [1, 2]. Briefly, we used the GoodRx website — a nationally available medication price comparison tool that provides real-time information on discounted cash-pay medication prices available to consumers at participating pharmacies in (or near) their zip code — to calculate prices for a typical fill for each product across the 8 unique pharmacies in the region [9]. These pharmacies included large and small chain pharmacies and independent pharmacies [1, 2]. In prior work, we had included 9 pharmacies, but more recently, there are no active Kroger pharmacy locations near the zip code under the study. Thus, we restricted analyses to 8 pharmacies (excluding Kroger). GoodRx reports an “average retail price”, and a discounted “lowest price with coupon” at individual pharmacies—a best-case scenario of out-of-pocket costs for a patient without or opting not to use prescription drug coverage. We extracted discount prices for each formulation at each pharmacy at two time points (in October 2021 and March 2022) in Minneapolis, Minnesota, USA (zip code 55414, population approximately 400,000). Minneapolis is an urban area with 19% of families living below the poverty rate [10]. We examined how prices changed across formulations and pharmacies over time.
Because we used publicly available data, and this was not human subjects research, in accordance with 45 CFR §46.102(f), we did not submit this study to an institutional review board or require informed consent procedures. We used Microsoft Excel v16.0 (Redmond, WA, USA) and GraphPad Prism v7.0 (San Diego, CA, USA) for analyses.
Results
Complete pricing data at both time points were available for all 208 pharmacy-formulation combinations (26 formulations × 8 pharmacies).
For 142 (68%) of the 208 pharmacy-formulation combinations, the price in March 2022 was within 10% of the price in October 2021 (Fig. 1). For 30 (14%) of the pharmacy-formulation combinations, the price in March 2022 was within 11–20% of the price in October 2021. Thus, 172 (83%) of pharmacy-formulation combinations had a price change of < 20%.Fig. 1 Percent change in GoodRx generic discount prices used to manage anorexia/cachexia and nausea/vomiting from October 2021 to March 2022 (Each dot represents a percent difference for a given formulation at a pharmacy, # denotes fill count)
The range of price changes for a pharmacy-formulation combination from October 2021 to March 2022 was − 76 to + 292%. For example, the price for a 7-count fill of 1 mg granisetron tablets increased by 238% (from $79 to $268) at one pharmacy, and the price for a 15-count fill of 4 mg ondansetron tablets increased by 292% (from $14 to $53) at another pharmacy. For 4 pharmacy-formulation combinations, the price decreased by more than 50%. For example, the price of a 15-count of 5 mg olanzapine oral disintegrating tablets decreased by 76% (from $63 to $15) at one pharmacy (Fig. 1).
For a given formulation, the least expensive pharmacy in October 2021 was no longer the least expensive pharmacy in March 2022 for 7 of the 26 studied formulations (27%) (Fig. 2). Additionally, for 5 of the remaining 19 formulations, multiple pharmacies shared the lowest cost in October 2021, but only one of these pharmacies retained the lowest price in March 2022. As an example, the lowest cost in October 2021 for a 30-count of 5 mg dronabinol capsules was $58, and this price was available at Costco, Hy-Vee, and Thrifty White. In March 2022, Hy-Vee still had the lowest price (now $57), but prices had increased to $89 and $63 at Costco and Thrifty White, respectively. Consequently, for 12 of the 26 studied formulations (46%) at least one pharmacy with the lowest cost in October 2021 no longer were the least expensive in March 2022. For one formulation (30-count fill of 2.5 mg dronabinol tablets), the least expensive pharmacy in October 2021 was the most expensive in March 2022, with an absolute and relative price increase of $22 and 85%, respectively.Fig. 2 Standardized discounted prices for drugs used to manage anorexia/cachexia and nausea/vomiting in March 2022 (Standardized March 2022 prices are equal to the March 2022 price divided by the October 2021 price across formulations and pharmacies. Color indicates whether the lowest March 2022 price is at the same pharmacy as the lowest October 2021 price. “Multiple” means that multiple pharmacies had the lowest price in October 2021 but they did not all retain the lowest price in March 2022).< 1.0 means March 2022 price is lower, and > 1.0 means March 2022 prices are higher than prices in October 2021
For a given formulation, the least expensive price (regardless of the pharmacy) in March 2022 was > 20% different (increased or decreased) than the October 2021 price for 5 (19%) formulations (Fig. 2). The difference in the least expensive price of the 26 formulations (irrespective of pharmacy) ranged from − 50 to + 35%. For example, the lowest costs for a 30-count of 2.5 mg dronabinol tablets and a 15-count of 15 mg mirtazapine oral disintegrating tablets were 25% and 35% higher in March 2022, compared to October 2021. For a 15-count of 4 mg ondansetron tablets, the least expensive price in March 2022 is 50% less than in October 2021. Changes in the least expensive price over time differed for formulations for the same medication. For example, both metoclopramide and olanzapine are available as tablet and oral disintegrating tablets; prices of oral disintegrating tablets increased by 0–4%, while prices of tablets increased by 28–36% over time.
We also assessed the financial impacts of remaining at the lowest cost pharmacy when it was no longer the lowest cost pharmacy (n = 12) (Table 1). For the majority of these pharmacy-formulations, the “added cost” of not switching to the new lowest cost pharmacy (difference between the October 2021 least expensive pharmacy’s price in March 2022 minus the lowest available price in March 2022) is relatively small: < $5, for 10 of the 12. In some instances, the “added cost” of not switching is higher. For example, Costco offered the lowest cost for a 30-count of 5 mg dronabinol capsules in October 2021, but a patient who still filled this prescription at Costco in March 2022 would pay $32 more than the lowest price in March 2022 ($89 versus $57).Table 1 Cost of remaining at the October 2021 least expensive pharmacy for formulations when the least expensive pharmacy changes in March 2022
Symptom Chemical Dosage Formulation Fill Quantity Name of least expensive pharmacy in October 2021 Price at least expensive pharmacy in October 2021
(US Dollars) Price at the same pharmacy in March 2022
(US Dollars) Price at a different least expensive pharmacy in March 2022
(US Dollars) Cost of remaining at the original pharmacy
(US Dollars)
Anorexia/cachexia Cyproheptadine 4 mg Tablet #60 Hy-Vee 12.2 13.1 11.7 1.4
Dexamethasone 2 mg Tablet #30 Walgreens 12.0 12.8 12.0 0.8
Community 12.0 12.0 12.0 0.0
Dronabinol 2.5 mg Tablet #30 Community 25.5 47.1 31.8 15.3
Megestrol acetate 40 mg/ml Oral Solution 150 ml Costco 17.4 19.8 17.5 2.3
Megestrol acetate 40 mg Tablet #90 Thrifty White 22.8 20.6 19.6 1.0
Mirtazapine 15 mg Oral Disintegrating Tablet #15 Costco 10.2 15.4 13.8 1.6
Mirtazapine 15 mg Tablet #15 Thrifty White 6.5 6.5 5.6 0.9
Olanzapine 5 mg Oral Disintegrating Tablet #15 Hy-Vee 14.6 10.1 10.1 0.0
Thrifty White 14.6 11.1 10.1 1.0
Nausea Dexamethasone 4 mg Tablet #21 Costco 6.9 7.5 7.5 0.0
Hy-Vee 6.9 7.5 7.5 0.0
Thrifty White 6.9 12.5 7.5 5.0
Dronabinol 5 mg Capsule #30 Costco 58.3 89.0 56.7 32.3
Hy-Vee 58.3 56.7 56.7 0.0
Thrifty White 58.3 62.6 56.7 5.9
Olanzapine 5 mg Oral Disintegrating Tablet #7 Hy-Vee 8.4 8.7 8.7 0.0
Thrifty White 8.4 9.7 8.7 1.0
Ondansetron 4 mg Tablet #15 Thrifty White 6.9 8.1 3.5 4.6
Discussion
In this study of supportive care medication prices at different pharmacies within an urban zip code, we found that (1) for almost half the formulations, at least one pharmacy with the lowest price in October 2021 no longer was the least expensive in March 2022, and (2) the lowest possible price for a given formulation across pharmacies changed considerably over a few months.
In a prior work, we highlighted that no single pharmacy in an urban zip code consistently offers the lowest price for the full range of medications commonly used to treat two classes of cancer-related symptoms [1]. Seeking the least expensive source of medications across multiple pharmacies can be time-consuming, expensive, and frustrating. This work highlights that even if clinicians and patients identify and pursue the least expensive pharmacy for a medication at a particular point in time, re-filling the same medication at the same pharmacy may not remain the “best-deal”. Patients “planning” out-of-pocket costs for later fills of the same medication — especially people with fixed income — should be cautioned that it is unlikely that they will pay a similar amount as during the first fill, whether they fill at the same or at a different least expensive pharmacy.
This work has important implications for all stakeholders. To guarantee that the patient accesses the lowest price possible in subsequent fills, a person or process would have to re-check prices across pharmacies prior to each fill, transmit prescriptions to that pharmacy, and ensure that a patient could pick up the medication in a safe and timely manner. This entire process can add significant additional time and logistic toxicity for patients and care partners, and also prescribers and pharmacists [2, 6, 8, 11]. This is especially pertinent with record rates of clinician burnout [12–14], with a major contributor being administrative burdens of navigating supportive care medications [15]. Additional issues with using multiple pharmacies are decreased adherence [16], and safety concerns — prescription duplications and drug-drug interactions, especially if each individual pharmacy’s staff assumes that another pharmacy serves as the primary pharmacy for the patient, and is primarily responsible for checks. A 2019 survey of over 10,000 U.S. older adults revealed that nearly 1 in 5 reported trouble getting to places like the doctor’s office [17]. Traveling to multiple pharmacies may magnify these burdens, with the additional aspect of people (especially immunocompromised people with cancer and their care partners) trying to minimize exposures in the COVID era. Further, filling opioids — essential cancer supportive care medications — at multiple pharmacies can be flagged as a sign of misuse, rather than an attempt at affordability [9, 18]. For patients and care partners, coordinating pickup of medications across pharmacies can be extremely burdensome, particularly if these pharmacy locations are not located near one another. This could lead to additional patient-requested medication transfers from one pharmacy to the next, need for coordination with the prescriber’s office, or potential wait times if patient prescriptions are not transferred quickly. With pharmacies facing increasing workload and staffing shortages throughout the COVID-19 pandemic, patients may be exposed to delays up to or exceeding the 1–4 days pre-pandemic anticipated turn-around time [19, 20]. At a time when mitigation of financial toxicity is receiving much attention, this work highlights the complexity of designing and implementing meaningful pharmaceutical interventions, even when efforts to decrease out-of-pocket costs are well intentioned. Oncology clinicians have limited time, training, and resources to address out-of-pocket medication costs for patients, especially at the point of prescribing, since these costs can be opaque and unpredictable [21]. There is a critical need for systems-level changes to allow oncology clinicians to help patients access affordable medications. For example, electronic medical record tools can provide clinicians with the price of medications and their suitable alternatives at different pharmacies at the time of ordering (e.g., real-time benefit tools) [21, 22]. We have previously demonstrated how prices of supportive care medications can vary dramatically by the dose/formulation; for example, the cost of a 37.5 mcg/h transdermal fentanyl patch is much higher than the combined cost of 25 and 12 mcg/h patches, and is even higher than a 50 mcg/h patch [23]. Such information can help guide prescribing when clinically suitable. Of course, in an ideal world, drug prices would be more stable, logical, and affordable for patients. Implementing real-time benefit tools across pharmacies would require the cooperation of multiple stakeholders: electronic medical record vendors, payers, pharmacies etc. [21].
This work has limitations [1]. We only explored prices for formulations for two cancer-associated symptoms. We evaluated only discounted prices (not retail prices or average wholesale prices) in a single urban zip code. When availing discounted prices using coupons, patients cannot use prescription drug coverage (if any), but given high rates of underinsurance and uninsurance these data are widely applicable. Additionally, given that all of the studied formulations were generic, the cash pay (the discounted price) may be lesser than the cost-sharing requirement with insurance. Thus, these data may also apply to people with insurance who face deductibles or higher copayments or coinsurance for filling prescriptions under their health plans. For people with insurance opting to use their insurance, the complexity of pharmacy shopping may be increased, since exact cost-sharing responsibility is more opaque. However, insured people are often also locked in to only using a specific network of pharmacies, since plans typically have preferred pharmacy contracts. We did not inflation-adjust prices since the data points were just 5 months apart — data suggest cash prices of generic drugs may be rising despite decreased costs earlier in the supply chain and competition [24]. Generic drug products had a median list price increase of 1% in January 2022, with 82% of generic products experiencing any price increase [25]. Drug price changes might also relate to drug shortages, which can influence pricing/demand; however, none of the specific formulations included in this study (or similar symptom control drugs) had reported shortages during the study period. For reference, the FDA database reported a shortage of haloperidol tablets and scopolamine patches in 2018–2019 [26].
In conclusion, we demonstrate that even if a patient identifies the least expensive pharmacy for a medication, the pharmacy may not remain the least expensive option over time. Patients, care partners, prescribers, and pharmacists face significant time and logistic toxicity in playing “catch-up” with an imperfect system. Novel processes are needed to ensure that patients have access to the most affordable medications without exposing them and their care partners to time and logistic toxicity.
Author contribution
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Andrew Etteldorf and Arjun Gupta. The first draft of the manuscript was written by Andrew Etteldorf and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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11. Banerjee R George M Gupta A Maximizing home time for persons with cancer JCO Oncol Pract 2021 17 9 513 516 10.1200/OP.20.01071 33661703
12. Golbach AP et al (2022) Evaluation of burnout in a national sample of hematology-oncology pharmacists. JCO Oncol Pract 18(8):e1278–e1288. 10.1200/OP.21.00471
13. Singh S Prevalence and workplace drivers of burnout in cancer care physicians in Ontario Canada JCO Oncol Pract 2022 18 1 e60 e71 10.1200/OP.21.00170 34506217
14. Tetzlaff ED Changes in burnout among oncology physician assistants between 2015 and 2019 JCO Oncol Pract 2022 18 1 e47 e59 10.1200/OP.21.00051 34292762
15. Haque W Payer-imposed quantity limits for antiemetics: everybody hurts JCO Oncol Pract 2022 18 5 313 317 10.1200/OP.21.00500 34807740
16. Marcum ZA Effect of multiple pharmacy use on medication adherence and drug-drug interactions in older adults with Medicare Part D J Am Geriatr Soc 2014 62 2 244 252 10.1111/jgs.12645 24521363
17. Ganguli I et al (2022) Which Medicare beneficiaries have trouble getting places like the doctor's office, and how do they do it? J Gen Intern Med. 10.1007/s11606-022-07615-0
18. NCQA. Use of opioids from multiple providers (UOP). Available at:https://www.ncqa.org/hedis/measures/use-of-opioids-from-multiple-providers/#:~:text=Evidence%20suggests%20that%20people%20who,for%20opioid%20overuse%20and%20misuse . Accessed May 22, 2022
19. How to transfer a prescription to another pharmacy. ScriptSaveWellRx. Publised July 31, 2019. Available at:https://www.wellrx.com/news/how-to-transfer-a-prescription-to-another-pharmacy/ . Accessed June 10, 2022.
20. Bookwalter CM. Challenges in community pharmacy during COVID-19: the perfect storm for personnel burnout. US Pharxmacist. Published May 14, 2021. Available at:https://www.uspharmacist.com/article/challenges-in-community-pharmacy-during-covid19-the-perfect-storm-for-personnel-burnout . Accessed June 10, 2022
21. Giap F Chino F Gupta A Systems-level changes to address financial toxicity in cancer care JCO Oncol Pract 2022 18 4 310 311 10.1200/OP.22.00085 35271297
22. Everson J Frisse ME Dusetzina SB Real-time benefit tools for drug prices JAMA 2019 322 24 2383 2384 10.1001/jama.2019.16434 31651954
23. Hussaini SMQ Intermediate strengths and inflated prices: the story of transdermal fentanyl patches J Palliat Med 2022 25 9 1335 1337 10.1089/jpm.2022.0241 35763285
24. Teasdale B Trends and determinants of retail prescription drug costs Health Serv Res 2022 57 3 548 556 10.1111/1475-6773.13961 35211965
25. Schondelmeyer SW. Prescription drug price changes in January 2022. Published February 9, 2022. Available at:https://www.warren.senate.gov/imo/media/doc/Prescription%20Drug%20Price%20Increases%20in%20January%202022%202022-02-24.pdf , Accessed June 10, 2022
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| 36512134 | PMC9745713 | NO-CC CODE | 2022-12-15 00:02:40 | no | Support Care Cancer. 2023 Dec 13; 31(1):3 | utf-8 | Support Care Cancer | 2,022 | 10.1007/s00520-022-07472-x | oa_other |
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Sci Educ (Dordr)
Sci Educ (Dordr)
Science & Education
0926-7220
1573-1901
Springer Netherlands Dordrecht
408
10.1007/s11191-022-00408-1
Article
Thomas Kuhn and Science Education
Learning from the Past and the Importance of History and Philosophy of Science
http://orcid.org/0000-0003-4795-922X
Matthews Michael R. [email protected]
grid.1005.4 0000 0004 4902 0432 School of Education, University of New South Wales, Sydney, NSW 2052 Australia
13 12 2022
170
14 11 2022
© The Author(s), under exclusive licence to Springer Nature B.V. 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Beginning 60 years ago, Thomas Kuhn has had a significant impact across the academy and on culture more widely. And he had a great impact on science education research, theorising, and pedagogy. For the majority of educators, the second edition (1970) of his Structure of Scientific Revolutions (Kuhn, 1970a) articulated the very nature of the science, the discipline they were teaching. More particularly, Kuhn’s book directly influenced four burgeoning research fields in science education: Children’s Conceptual Change, Constructivism, Science-Technology-Society studies, and Cultural Studies of Science Education. This paper looks back to the Kuhnian years in science education and to the long shadow they cast. The discipline of science education needs to learn from its past so that comparable mistakes might be averted in the future. Kuhn’s influence was good and bad. Good, that he brought HPS to so many; bad, that, on key points, his account of science was flawed. This paper will document the book’s two fundamental errors: namely, its Kantian-influenced ontological idealism and its claims of incommensurability between competing paradigms. Both had significant flow-on effects. Although the book had many positive features, this paper will document how most of these ideas and insights were well established in HPS literature at the time of its 1962 publication. Kuhn was not trained in philosophy, he was not part of the HPS tradition, and to the detriment of all, he did not engage with it. This matters, because before publication he could have abandoned, modified, or refined much of his ‘revolutionary’ text. Something that he subsequently did, but this amounted to closing the gate after the horse had bolted. In particular, the education horse had well and truly bolted. While educators were rushing to adopt Kuhn, many philosophers, historians, and sociologists were rejecting him. Kuhn did modify and ‘walk back’ many of the head-turning, but erroneous, claims of Structure. But his retreat went largely unnoticed in education, and so the original, deeply flawed Structure affected the four above-mentioned central research fields. The most important lesson to be learnt from science education’s uncritical embrace of Kuhn and Kuhnianism is that the problems arose not from personal inadequacies; individuals are not to blame. There was a systematic, disciplinary deficiency. This needs to be addressed by raising the level of philosophical competence in the discipline, beginning with the inclusion of HPS in teacher education and graduate programmes.
Keywords
Thomas Kuhn
Relativism
Idealism
Constructivism
Philosophy
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pmcIntroduction
Thomas Kuhn’s impact on science education has been immense. This is reflected in the opening sentence of a 2022 article by David Treagust, one of Australia’s foremost science educators:1Perhaps one of the major influences on our understanding of how scientific research and scientific knowledge evolves and develops was the publication of Thomas Kuhn’s (1962) The Structure of Scientific Revolutions. This small book really changed the way we look at the enterprise that is science. (Treagust, 2022, p.16)
Treagust spoke for the science education research community. In Peter Fensham’s landmark study of the discipline of science education, leading science educators repeatedly identify Kuhn’s Structure as the main influence on their understanding of science (Fensham, 2004). Richard Duschl, in 1990, described Structure as ‘the most acclaimed book in history of science’ (Duschl, 1990, p.36).2
The immediate educational impact of Structure was on educators’ understanding of the nature of science (NOS) which is, increasingly, a stand-alone inclusion in worldwide national and provincial science curricula.3 An explicit or implicit view of NOS informs curricular decisions, pedagogical practices, and wider national policies about the extent, duration, and funding of science in schools and beyond. It is widely agreed that students learning science should learn what science is, how it works, and what it accomplished. In brief, they should learn the nature of science. This is a truism, but its implication, namely, that science students and teachers need to learn the history and philosophy of science (HPS), has been less recognised and followed through. The seldom faced question is: How is it possible to learn about NOS without knowledge of HPS?
Many educators who, after the publication of the second edition of Structure in 1970, did look for history and philosophy of science, saw just Kuhnianism, more particularly Kuhn-inspired constructivism. It is important to distinguish Kuhn’s understanding of NOS from the many versions of Kuhn-inspired NOS. At many points, Kuhn was at pains to separate his views from those being advanced in his name. ‘Kuhnianism’ is an appropriate inclusive label for the latter. It includes Kuhn’s genuine views but also those mistakenly advanced in his name. In education, Kuhnian NOS not only informed, but it also underpinned Science-Technology-Society (STS) curricula and Cultural Studies in Science Education research and framed the narrative about inclusion of indigenous science within school science programmes.
Kuhn’s Structure not only dealt with revolutions in the history of science but also painted a revolutionary account of the nature and practice of science. But did Kuhn give a correct account? Many in HPS thought he did not. For the million-plus who bought the book,4 reading Structure was a Rorschach test. Kuhn recognised this. In 1969, at a large Frederick Suppe-organised symposium on ‘The Structure of Scientific Theories’ Kuhn, reflecting on the reception of the first edition, wrote:I have sometimes found it hard to believe that all parties to the discussion had been engaged with the same volume. Part of the reason for its success is, I regretfully conclude, that it can be too nearly all things to all people. (Kuhn, 1977c, p.459)
He regretted the book’s ‘excessive plasticity’, particularly blaming his casual introduction of the term ‘paradigm’ (ibid). He should, more to the point, have regretted writing unclear and sloppy sentences about vital subjects. Philosophers, above all, need be cognisant of the importance of clarity in writing.
The argument of this paper is that the most important lesson to be learnt from the problems of science education’s wholesale embrace of Kuhnianism is the pressing need to raise the level of philosophical competence in the discipline, beginning with the inclusion of both history and philosophy of science, and philosophy of education, in science-teacher education programmes, and in education doctoral programmes.
Kuhn’s Status
It is oft claimed that Thomas Kuhn was the twentieth century’s most influential historian of science. This can hardly be disputed. He was a Harvard-trained physicist5 who published a great deal over a 55-year span.6 However, his global reputation was based upon one book—The Structure of Scientific Revolutions—which was first published in 1962 as a monograph in a little-read Vienna Circle-inspired International Encyclopedia of Unified Science,7 and then, eight years later, republished as a stand-alone second edition by University of Chicago Press (Kuhn, 1970a). The second edition precipitated the Kuhnian tsunami. Structure was quickly translated into two-dozen languages and sold over a million copies. In Australia’s Arts and Humanities Citation Index, it was the most cited book on any subject through the 1970s and 1980s. In the USA, the Social Science Citation Index listed 4970 Kuhn citations in just the decade 1971–1981 (Brush, 2000, p.54). Doubtless, it held much the same position in comparable indexes in other countries, both English-speaking and otherwise. Google Scholar, in October 2022, listed 71 versions of the book, having 143,303 citations.
For a combination of philosophical, sociological, and cultural reasons, the book had stratospheric sales and influence; sales way beyond that of almost any other HPS book published in the twentieth century; and probably beyond all HPS books. David Hull observed: ‘All the wrong people seemed attracted to his book for all the wrong reasons’ (Hull, 1988, p.112). There have been efforts to give a sociological or naturalist account of the explosion of Kuhnianism: Why was the book such a huge publishing success, and why did the constellation of ideas it contained spread so widely and quickly while its components had sat in isolation for decades?8
Some regard Kuhn as ‘the most influential philosopher writing in English since 1950, even the most influential academic’ (Sharrock & Read, 2002).9 For others, he is ‘one of the historically most significant philosophers of the twentieth century’ (Bird, 2000, p.vii). Kuhn’s vocabulary (‘paradigm’, ‘paradigm shift’, incommensurability’, ‘gestalt’) and thought-to-be Kuhnian ideas (scepticism, relativism, subjectivism, science as power play) have become a part of everyday culture. As recently as 8 October 2022, a correspondent writing on a local political issue, in The Age, a major Australian newspaper, confidently related that:Thomas Kuhn’s The Structure of Scientific Revolutions … exposed the influence of inertia, interests and the irrational on scientific explanation and understanding. (p.34)
And this is 60 years after the book’s publication. Countless readers of the newspaper would be nodding their heads. Most of them not asking: What is the extent and degree of such influences? Were the influences determinate, or otherwise, of scientific explanations and understandings? Were they were brought to light and corrected? Science educators also nodded their heads, and very few followed through with the obvious questions. Gerald Doppelt gave an accurate, and neutral, account of Kuhn’s impact:Putting the merits of Kuhn’s philosophical claims to one side, it is still undeniable that his work has reshaped the terms of debate, and much research, in philosophy. In short, his work had given a new centrality and relevance to the history of science, and the examination of specific scientific practices, for philosophers. (Doppelt, 2001, p.160)
This paper does not put Kuhn’s philosophical merits to one side: It appraises them, recognising the positives, but detailing its key demerits and their deleterious educational, and cultural, influence.
There are many informative accounts of Kuhn’s personal, educational, and academic life.10 And, of course, there are many more accounts of his achievements, real and contested. Separating Kuhn’s real from his imagined achievements has, for 60 years, engaged legions of scholars.11 In 2012, the 50-year anniversary of publication of Structure was marked by numerous celebratory conferences in many countries.12 A large international centenary conference celebration of Kuhn’s life and work, held in July 2022, is witness to his enduring interest among historians, philosophers, and other scholars.13
Kuhn’s philosophy, his account of the nature of science, and the conditions for, and mechanisms of, theory change in science have been exhaustively appraised by historians and philosophers.14 Richard Duschl and Richard Grandy are of the opinion:The most recent movements in philosophy of science can be seen as filling in some of the gaps left by Kuhn’s demolition of the basic tenets of logical positivism. (Duschl & Grandy, 2008, p.8)
This is an orthodox, majority account of Kuhn’s influence. And it is generous. An alternative reading would be to describe recent movements as ‘correcting mistakes in’ or ‘clarifying ambiguity about’, rather than ‘filling in gaps’, and further, pointing to how much he, and more generally Kuhnians, shared, rather than demolished, some of the basic tenets of logical positivism.15
Different Structures: Ernest Nagel’s Structure (1961) and Thomas Kuhn’s Structure (1962)
In successive years, two HPS books part-titled Structure were published. Ernest Nagel’s (1901–1985) 600 + page The Structure of Science: Problems in the Logic of Scientific Explanation was published in 1961 (Nagel, 1961). Kuhn’s 170 + page The Structure of Scientific Revolutions was published in 1962. Beginning with his choice of title, Kuhn took aim at Nagel’s book and largely displaced it from academic discussion. Kuhn’s Structure opened a new chapter in the history of HPS. It sold a million-plus copies in at least 18 languages; Nagel’s sold the smallest fraction of that in a handful of languages. Kuhn sold to the masses and Nagel to captive philosophy students, including the current author. The Nagel/Kuhn contrast is an informative background for the arguments of this paper.
Nagel’s was a widely adopted philosophy text giving a detailed exposition of the logical empiricist ‘picture’ of science. This encapsulated the dominant philosophical, cultural, and educational understanding of science of the era.16 The book was the received view’s manual. Its Preface encapsulates post-war, progressive society’s hopes for science. Nagel speaks of science as an ‘institutionalized art of inquiry’ that has yielded precious fruit. Foremost among these are:The achievement of generalized theoretical knowledge concerning fundamental determining conditions for the occurrence of various types of events and processes; the emancipation of men’s minds from ancient superstitions in which barbarous practices and oppressive fears are often rooted. (Nagel, 1961, p. vii)
He proceeds down a long list of social and cultural achievements, concluding:Despite the brevity of this partial list, it suffices to make evident how much the scientific enterprise has contributed to the articulation as well as the realization of aspirations generally associated with the idea of a liberal civilization. (ibid)
This was a restatement of core Enlightenment convictions. The book was to be the first of three volumes laying out Nagel’s philosophical reflections on science.17 He rightly observed that: ‘there are few notable figures in the history of Western philosophy who have not given serious thought to problems raised by the sciences of their day’ (Nagel, 1961, p. viii).18 He recognises there are many problems occasioned by science that warrant philosophical attention, but:… the present book is controlled by the objective of analyzing the logic of scientific inquiry and the logical structure of its intellectual products. (Nagel, 1961, p.viii)
Nagel’s Structure had a very low profile, if any, in science education. However, the discipline enthusiastically embraced Thomas Kuhn, especially after publication of the 1970s edition of Structure. But, as shown in the following sections, Kuhnianism was more embraced than appraised by educators. This indicates a fundamental deficiency in the discipline: The failure to incorporate history and philosophy of science into teacher education or graduate programmes.
Unheralded Birth of Kuhn’s Structure
The first edition of Structure appeared in 1962 in the Vienna Circle-inspired, International Encyclopedia of Unified Science (Volume 2 Number 2). It had been founded by Otto Neurath and subsequently edited in the USA by Rudolf Carnap and Charles Morris. The Encyclopedia was the post-war flagship of logical empiricism; it had an almost entirely philosophical readership. The first edition was hardly noticed outside of philosophy departments, and not at all outside the academy.
An exception to the general neglect was a famed panel discussion titled ‘Criticism and the Growth of Knowledge’ at the July 1965, London International Colloquium for the Philosophy of Science. The contributors were Thomas Kuhn, John Watkins, Stephen Toulmin, L. Pearce Williams, Karl Popper, Margaret Masterman, Imre Lakatos, and Paul Feyerabend. This was a sort of ‘HPS fights back’ event. The papers were published as a book in 1970, and enjoyed huge sales, becoming a basic text in upper-level philosophy of science courses (Lakatos & Musgrave, 1970). It was published the same year as the second edition of Structure.
The first edition was not noticed by science educators. John Robinson’s The Nature of Science and Science Teaching (Robinson, 1968) was the first book whose title brought together philosophy of science and science teaching. Kuhn is nowhere mentioned in its 150 pages (Matthews, 1997). In 1968, there was an important panel discussion on ‘Philosophy of Science and Science Teaching’ at the annual US National Association for Research in Science Teaching conference. Contributors included John Robinson, Michael Connelly, and Marshall Herron. The papers were published the following year in Volume Six of The Journal of Research in Science Teaching. Kuhn is not mentioned.
In 1969, Hans O. Andersen published Readings in Science Education for the Secondary School (Andersen, 1969). It was a collection of 60 research papers informed by commitment to the principle:Science instruction should be based on a series of principles selected for their value in projecting science as a process of inquiry designed to discover new facts, improve quantitative descriptions of known facts, and organize these facts into conceptual schemes which more adequately describe the phenomena of the universe and beyond. (Andersen, 1969, p.2)
And:The only way to succeed in increasing science enrolments without a subsequent loss of positive attitude is to make the course offerings so interesting and so valuable to the student that he will demand more. (Andersen, 1969, p.2)
Kuhn does not appear in the anthology’s 430 pages, and 60 readings. In 1974, Michael Connelly commented of the post-Sputnik curricular boom that:While this activity began with philosophical concerns for knowledge and for enquiry, it was largely dominated by the works of a few psychologists, notably, Bruner, Ausubel, Gagne, Piaget. (Abimbola, 1983, p.182)
A few rare commentators in the 1960s, who were familiar with both the philosophical and the educational literature, noted this neglect of ‘new’ philosophy by science educators. Yehuda Elkana (1934–2012) observed that science education during the 1950s, and leading up to the Sputnik era, was formed in the image of ‘inductivist-realist’ philosophy of science (Elkana, 1970, p.3). He said of post-Sputnik PSSC and BSCS curricula and teaching material, that they ‘reflect the positivistic-Instrumentalist philosophy of science [logical empiricism], which was at the height of its influence in the early days of space travel’ (Elkana, 1970, p.8).
Elkana lamented that two important books—Kuhn’s Structure and Joseph Schwab’s The Teaching of Science (Schwab, 1960)—were published at the same time yet shared no common literature. They were: ‘two very important books, both highly influential in their own fields, both relying on two traditions and two bibliographies which completely ignore each other’ (Elkana, 1970, p.15). Elkana sketched out the ‘practical implications for the teaching of science’ that Kuhn’s new philosophy of science generated.
Michael Martin (1932–2015), a Boston University philosopher, a few years later surveyed the same literature as Elkana. He paid particular attention to the rush of ‘inquiry’ and ‘discovery’ curricula and recommendations put into Western educational orbit by Sputnik. Martin drew attention to the important 1966 Educational Policies Commission report, Education and the Spirit of Science (EPC, 1966), and charted the myriad ways in which it, and other curricula as well, reproduced simplistic, mistaken, inductivist understanding of scientific inquiry (Martin, 1972, 141–147). The homely inductivism of Education and the Spirit of Science had the imprimatur of the highest office in US education.
Much had happened in HPS in the decade leading up to the EPC report. It was published eight years after Norwood Russell Hanson’s Patterns of Discovery (Hanson, 1958) which received wide philosophical attention for its ‘theory dependence of observation’ thesis; seven years after Popper’s anti-inductivist work The Logic of Scientific Discovery (Popper, 1934/1959) was translated into English and also given wide philosophical attention; and four years after the publication of Feyerabend’s essay ‘Explanation, Reduction, and Empiricism’ that shook the foundations of inductivist accounts of science (Feyerabend, 1962). Science educators, especially those at the highest levels advising Federal Government curricular and education-funding bodies, should have had an inkling of the shifting ground in HPS and should have recognised its relevance to its report on the ‘Spirit of Science’.
In 1974, Martin opined:a great deal has been written on the philosophy of science; perhaps even more has been written in science education. However, surprisingly little has been written on the relation between the two areas. (Martin, 1974, 293)
The era’s unfortunate divide between HPS and science education was well documented in a study by Richard Duschl titled ‘Science Education and Philosophy of Science: Twenty-five Years of Mutually Exclusive Development’ (Duschl, 1985).19
Embrace of the Second Edition
The second edition (1970), unchanged except for addition of a Postscript,20 took Kuhn to the world. Kuhn was enthusiastically taken into education and into nigh on all other academic disciplines. In 1985, Derek Hodson reported that of 22 research articles published, and theses submitted, in the field of ‘Philosophy of Science, Science and Science Education’, in the period 1974–1984, fourteen addressed Kuhnian themes (Hodson, 1985).
In 2000, Cathleen Loving and William Cobern conducted a citation analysis of two major science education journals—Science Education and Journal of Research in Science Teaching—for the 13-year period 1985–1998 and, not surprisingly, found that there were numerous citations of Kuhn covering such Kuhnian themes as: paradigms (30 articles), conceptual change theory (12 articles), constructivist epistemology, incommensurability, authenticity of textbooks, the social components of science, and also the philosophical comparison of Kuhn and other methodologists of science (Loving & Cobern, 2000).
Clearly, there were many Kuhn enthusiasts in the science education community. It was close to being a Kuhnian cheer-squad (Matthews 2004a).
The embrace of Kuhn is demonstrated in one of the first science education articles to engage with Kuhn’s theory, namely, Ted Cawthron and Jack Rowell’s ‘Epistemology and Science Education’ (Cawthron & Rowell, 1978). They drew parallels between Piaget’s theory of knowledge and his psychological account of the constructive knowing subject, and what they found in Kuhn. For them, Kuhn established that:We see things not just as they are but also partly as we are, and this is not due simply to differences in interpretation of otherwise stable facts or data. The “objective” real world becomes merged with its “subjective” interpretation and the Cartesian Dichotomy is replaced by a dialectic epistemology with distinctly relativistic implications. (Cawthron & Rowell, 1978, p.45)
What they are identifying as Kuhn’s ‘dialectic epistemology with distinctly relativistic implications’ is Kuhn’s embryonic and unsophisticated, Kantianism, something he picked up in a Harvard General Education course.
Structure: An Outline
As it was Kuhn’s Structure, and almost Structure alone, that impacted science education, that book will be the focus of this paper’s argument. More particularly, the book’s anti-realist and incommensurability claims will be examined as these had the most enduring impact in science education. They are still, for example, centre stage in important debates in Canada, Australia, New Zealand, and elsewhere, about whether indigenous science should be included in a science programme or a social science programme.21
Key elements of Structure can be seen in Kuhn’s, 1951 Lowell Lectures delivered in the Boston Public Library—The Quest for Physical Theory. These ‘adult education’ or ‘university outreach’ lectures remained unpublished until 2021 when they were edited by George Reisch and published by the MIT Library (Kuhn, 1951/2021). In criticism of Karl Pearson’s popular empiricist account of science which embodied the ‘orthodox’ logical empiricist view of the time (Pearson, 1892/1937), Kuhn averred:I should like to suggest that the impartial, dispassionate observation of nature is impossible, that there are no “pure facts” from which alone valid theories can be derived, and that the effort toward “self elimination” which Pearson proposes as the scientist’s goal, would, in practice, result in the abolition of productive research. (Kuhn, 1951/2021, p.3)
The core argument of Structure is well known and could be summarised as follows.22 All communities seek knowledge and understanding of nature. This can amount to pre-science, pseudoscience, protoscience, or science. Normal science is heralded by the appearance of a common paradigm, or exemplar, that dictates methods of inquiry and constrains the kind of entities, or ontology, that can be appealed to in scientific explanations. The paradigm provides theoretical and practical puzzles that scientists work away at solving. When some pressing practical or theoretical puzzles resist solution with tools and concepts provided by the paradigm, then science enters a crisis period, and either drastic renovation is done (maybe new rooms added or boarders taken in) or scientists embrace a new paradigm (move house). This is revolutionary science. Crucially, while decisions within a paradigm are rule regulated, as evidenced in processes of journal review, decisions about how extensive a renovation should be—whether a particular addition is permissible, or whether to pick up and move house—are not rule regulated.
For Kuhn, values and interests, including personal ones, determine those decisions; they are an unavoidable part of science; and values are embedded within paradigms. Productive paradigms, and theories within them, unavoidably embody standards (values) of accuracy, consistency, breadth, simplicity, and fruitfulness. These are qualities that scientists, with good reason, prefer for their theories (McMullin 2008). And these values are common across paradigms, even incommensurable ones. As Kuhn later elaborates:such values as accuracy, scope, and fruitfulness are permanent attributes of science …. (Kuhn, 1977b, p.335)
But he advises that:the relative weights attached to them have varied markedly with time and also with the field of application. (Kuhn, 1977b, p.335)
So subjectivity is built into science.
Purple Passages
In the first edition, and remaining unchanged in the second, there were many ‘purple passages’ as Kuhn later labelled them (Kuhn, 1970a). These were head-turning claims that threatened the orthodox logical empiricist, and widespread cultural, understanding of science, understandings that were codified by Nagel:‘…once current views of nature were, as a whole, neither less scientific nor more the product of human idiosyncrasy, than those current today’ (p.2).
viewing all fields together science ‘is a rather ramshackle structure with little coherence between its various parts’ (p.49).
‘Like the choice between competing political institutions, that between competing paradigms proves to be a choice between incompatible modes of community life’ (p.94).
‘What occurred [when paradigms changed] was neither a decline nor a raising of standards, but simply a change demanded by the adoption of a new paradigm’ and ‘it could be reversed’ (p.108).
‘I have so far argued that paradigms are constitutive of science. Now I wish to display a sense in which they are constitutive of nature as well’ (p.110).
‘after discovering oxygen Lavoisier worked in a different world’ (p.118).
transition to a new paradigm occurs ‘not by deliberation and interpretation, but by a relatively sudden and unstructured event like a gestalt switch’ (p.122).
‘the competition between paradigms is not the sort of battle that can be resolved by proofs’ (p.148), and … ‘in these matters neither proof nor error is at issue’.
‘the proponents of different paradigms practice their trades in different worlds … the two groups of scientists see different things when they look from the same point in the same direction’ (p.150).
‘The transfer of allegiance from paradigm to paradigm is a conversion experience that cannot be forced’ (p.151).
‘a man who embraces a new paradigm at an early stage must often do so in defiance of the evidence provided by problem solving. … A decision of that kind can only be made on faith’ (p.158).
‘the phrases “scientific progress” and even “scientific objectivity” may come to seem in part redundant’ (p.162).
‘with respect to normal science … progress lies simply in the eye of the beholder’ (p.163).
‘we may have to relinquish the notion, explicit or implicit, that changes of paradigm carry scientists and those who learn from them closer and closer to the truth’ (p.170).
And so on and on.
Kuhn would later regret writing some of these passages, but he held on to others. In 1969, he wrote: ‘I now recognize aspects of its initial formulation that create gratuitous difficulties and misunderstandings’ (Kuhn, 1970a, p.174). Steven Shapin generously called such passages ‘Kuhn’s sound-bites’ (Shapin, 2015, p.11). He could equally have called them ‘ill thought out’, ‘careless’, or ‘irresponsible’ claims. In 1969, in the Postscript to Structure, Kuhn wrote ‘I now recognize aspects of its initial formulation that create gratuitous difficulties and misunderstandings’ (Kuhn, 1970a, p.174). A year later, in distancing himself from charges of ‘irrationality’, ‘mob rule’, and ‘relativism’, with which he had rightly been charged, Kuhn admitted that his ‘own past rhetoric is doubtless partially responsible’ (Kuhn, 1970b, p.260).
Kuhn does not regret his lack of training in philosophy; on the contrary, he thought the lack advantageous as it did not give him a certain, but not spelt out, philosophers’ ‘cast of mind’. But if the above passages had been written into a graduate, or even undergraduate, philosophy thesis in most decent programmes, they would have been struck out: ‘this work cannot be presented, take it away and clarify’. Such guidance in 1960 would have made a seismic difference to subsequent philosophical and cultural thought.
Anticipations of Structure
The central philosophical ideas in Structure were not novel, something Kuhn often acknowledged.23 Many elements of his philosophy of science were extant; indeed, many elements were in residence just along the Harvard corridors. But these were barely, if at all, acknowledged, much less engaged with when the first edition of Structure was published in 1962. The intellectual ground for the Kuhnian ‘revolution’ had been well prepared. Simple empiricist, individualist, logical positivist understandings of science—the knower confronting the world—had been challenged on many fronts; the time was ripe for a philosophical upheaval, if not revolution.24
Marx’s 1852 Eighteenth Brumaire of Louis Bonaparte could have been, and by a few was, appealed to by opponents of the orthodox empiricist account of science. Marx memorably wrote:Men make their own history, but they do not make it just as they please … they make it under circumstances directly found, given and transmitted from the past. The tradition of all the dead generations weighs like a nightmare on the brain of the living. (Tucker, 1978, p.595)
This is an early statement of the sociology of knowledge, and was acknowledged as such by Karl Mannheim, the founder of that discipline (Mannheim, 1936/1960). It denies all ‘Robinson Crusoe’, individualist, observer-confronts-the-world epistemologies. It lays out how the ‘we think’ determines, or at least constrains, the ‘I think’. Marx’s observation was consistent with Kuhn’s epistemological programme and might be reformulated as ‘the paradigms of all the dead generations weighs like ….’.
In the 1930s, Ludwik Fleck wrote on the social construction of facts and on the necessity of an historical component for understanding (Fleck, 1935/1979, Cohen & Schnelle, 1986). At the same time, Gaston Bachelard wrote on epistemological ruptures in the history of science and on the impact of epistemological obstacles on cognition (Bachelard, 1934/1984).
In the 1930s and 1940s, Alexandre Koyré extensively documented the centrality of metaphysics in the science of Galileo and Newton (Koyré, 1957, 1968). In the 1940s, R.G. Collingwood elaborated how particular periods in the history of science had different metaphysical presuppositions which were fundamental assumptions about the constituents of the world and their properties that were not given directly in experience (Collingwood, 1940, 1945).
James Conant (1893–1978), while President of Harvard and the director of Kuhn’s own General Education course, had written popular books pointing to ‘conceptual schemes’ as the skeleton of science, and their transformation as the consequence of ‘scientific tactics and strategy’ (Conant, 1947, pp.104–111). Kuhn, with enthusiasm and gratitude, embraced Conant’s ‘conceptual schemes’ as a means to elucidate the nature of science and its history (Wray, 2016).25
Philipp Frank (1884–1966), a Harvard physics professor and a major exponent of logical empiricism, had been since the 1930s publishing accounts of science that shared a great deal with Kuhnian views. In the opening chapter of his The Law of Causality and its Limits (1932), he observes:The more a physicist or biologist refuses to concern himself with ‘philosophy’, respectfully or contemptuously, the more we can be sure that he adopts the views of the oldest traditional scholastic philosophy in good faith, because he has not given careful thought to the fundamental concepts of his science. In the elementary textbooks of purely experimental physics, the most astonishing metaphysical claims can be found. (Frank, 1932/1998, p.25)
This is a constant theme in his work. In the Preface to his Philosophy of Science, he says ‘the deeper we dig into actual science the more its links with philosophy become obvious’ (Frank, 1957, p.iv). Further, he is well aware of the need for concrete historically based analysis, warning that:Presentations of this field have very often started from a concept of science that is half vulgar and half mystical. Other presentations have linked science with a philosophy that has actually been a mere system of logical symbols without contact with historical systems of philosophy. (Frank, 1957, p.iv)
The ‘historical turn’ in philosophy of science did not have to await the Kuhnian revolution. Consequently, Frank’s Philosophy of Science contains analyses of the scientific and philosophical contributions of Aristotle, Bacon, Copernicus, Descartes, Einstein, Foucault, and pretty much down the rest of the alphabet to Whewell and Young. In all of his writing, Frank stresses the importance of extant conceptual frameworks for science and relentlessly examines grounds for choosing frameworks and for changing frameworks. Herbert Feigl provides an accurate summary of Frank’s philosophical orientation, saying that it:combines informal logical analysis of the sciences with a vivid awareness of the psychological and socio-cultural factors operating in the selection of problems, and in the acceptance or rejection of hypotheses, and which contribute to the shaping of styles of scientific theorizing. In a sense this is a genuine sequel to the work of Ernst Mach. (Feigl, 1956, pp.4-5)
All of this was grist for the Kuhnian mill, but Frank’s name appears in Structure only as the biographer of Einstein. Kuhn’s failure to engage with the work of such an eminent Harvard colleague is the more surprising as Frank had explicitly written on education. In 1947, he published an article in the American Journal of Physics titled: ‘The Place of Philosophy of Science in the Curriculum of the Physics Student’ (Frank, 1947/2004).
Gerald Holton, a Harvard colleague and fellow contributor to the General Education programme, had in the 1950s written on the role of organising principles, or ‘themata’, in science (Holton, 1952/1984, 1973/1988).26 Holton acknowledges Frank as the person who opened his eyes to the intimate connection of physics with philosophy:… the interaction between science and epistemology was at the center of attention in discussions over many years with Philipp Frank, that most humanistic and conciliatory of logical empiricists, and biographer of Albert Einstein. (Holton, 1973, p.25)
Holton’s Thematic Origins of Scientific Thought (Holton, 1952/1984) was published in 1952, eight years before the first edition of Structure, but is not mentioned in either the first or second edition. Had Kuhn made clear the commonalities and differences between his paradigms (or disciplinary matrices, as he would relabel them in the 1970 ‘Postscript’)27
In response to criticisms of his notion of paradigm, Kuhn changed terminology to ‘disciplinary matrix’. A matrix had four components: symbolic mathematised generalisations and formulae; metaphysical interpretations of basic models and analogies; epistemic and non-epistemic values shared by all practitioners; and exemplars showing productive puzzle generation and solutions (Kuhn, 1970a, pp.182–187). These have obvious connections to Holton’s themata. Science education would have gained if educators had paid as much attention to Thematic Origins as they did to Structure.28
Willard van Orman Quine (1908–2000), Harvard’s most eminent philosopher, in 1951 published his famed ‘Two Dogmas of Empiricism’ (Quine, 1951). His argument was widely acknowledged to have dissolved the analytic/synthetic distinction so fundamental to the empiricist tradition with which Kuhn was battling. For Quine, theoretical statements never confront experience or experiment in isolation, but always as part of a constellation including methodological and metaphysical commitments, and where adjustments can be made elsewhere to reconcile theory and observation.Beliefs were not isolated; they were always part of a web.29
Hilary Putnam (1926–2016), yet another distinguished Harvard colleague, recognised Kuhn as ‘one of the most ingenious contemporary philosophers and historians of science’ (Putnam, 1990, p.123). In 1962, Putnam, in a much-cited paper, engaged with, and criticised, Quine’s supposed dissolution of the analytic/synthetic distinction. In doing so, he wrote:It has been necessary to consider problems connected with physical science (particularly the definition of ‘kinetic energy’, and the conceptual problems connected with geometry) in order to bring out the features of the analytic-synthetic distinction that seem to me to be the most important. (Putnam, 1962, p.358)
In defending analyticity as a genuine, realistic, and informative category in the science of energy, Putnam gives, in the publication year of Structure, an almost mirror account of a Kuhnian paradigm without using the word:If a physicist makes a calculation and gets an empirically wrong answer, he does not suspect that the mathematical principles used in the calculation may have been wrong (assuming that those principles are themselves theorems of mathematics) nor does he suspect that the law ‘F = ma’ may be wrong. Similarly, he did not frequently suspect before Einstein that the law ‘E = 1/2mv2’ might be wrong or that the Newtonian gravitational laws might be wrong (Newton himself did, however, suspect the latter). These statements, then, have a kind of preferred status. They can be over-thrown only if someone incorporates principles incompatible with those statements in a successful conceptual system. (Putnam, 1962, pp.371-372)
Putnam and Kuhn, though in the same Harvard ‘corridor’, did not, in print, publicly engage. This is more than peculiar as one of Kuhn’s most substantial historical studies was his ‘Law of Energy Conservation’ (Kuhn, 1959b). Kuhn saw himself as a philosopher and, outside Harvard, was widely seen to be one. But in writing Structure, he engaged very little with the arguments and analyses of the top-flight philosophers who were literally all around him. Putnam is not even in the index of The Essential Tension which was Kuhn’s selection of his own HPS studies (Kuhn, 1977b), and he does not appear in the collection of Kuhn’s 1970–1993 philosophical essays (Conant & Haugeland, 2000).
The foregoing amounted to Kuhn’s missed local opportunities for philosophical engagement.30 But sympathetic philosophers had been writing in many other places on topics germane to Structure. Stephen Toulmin (1922–2009) wrote on how discoveries in the physical sciences consisted, in part, of finding fresh ways of looking at phenomena, and advocated the importance of history when doing philosophy of science (Toulmin, 1953). A little later, Norwood Russell Hanson (1927–1964) famously wrote on the theory dependence of observation and on the contested nature of the facts in scientific disputes (Hanson, 1958). In Hanson’s work, two of the foundations of logical empiricism were cut adrift. Ludwig Wittgenstein had made philosophers attentive to the distinctions between seeing and seeing as; between looking and noticing; and between object perception and propositional perception. The last requires language and judgement and hence varying degrees of theory (Wittgenstein, 1958).
Michael Polanyi (1891–1976), in his book Personal Knowledge (Polanyi, 1958) and elsewhere, wrote on the place of tacit, assumed, ‘subterranean’ knowledge in science; the corrective function of the scientific community; and the importance of initiation into accepted methodologies and practices for the conduct of science. In 1961, in a conference commentary on a pre-Structure paper of Kuhn’s, Polanyi wrote:A commitment to a paradigm has thus a function hardly distinguishable from that which I have ascribed (Polyani, 1958, chaps.5,6,7) to a heuristic vision, to a scientific belief, or a scientific conviction. (Polyani, 1963, p.375)
Rom Harré (1927–2019) in the early 1960s wrote on the centrality and necessity of general conceptual schemes in science, their impacts, how they were modified, and on the ubiquity of metaphor and metaphysic in science (Harré, 1960, 1964). He recognised, as most did, that:Empirical investigations do not exhaust the kinds of question raised by a conceptual crisis. There are also questions of a more metaphysical kind. Empirical investigations are not immediately relevant to these, nor do empirical facts provide conclusive answers. (Harré, 1964, p.65)
Max Black (1909–1988) had written extensively on the role of metaphor and analogy in scientific thinking and had rejected the notion of language as a mirror of nature (Black, 1962). Mary Hesse (1924–2016), a historically informed philosopher, argued in different publications that in neither science nor history of science are there ‘bare uninterpreted facts; all facts, whether experimental or historical, are interpreted in the light of some theory’ (Hesse, 1961 p.v).
Kuhn’s failure to engage with Rudolf Carnap’s (1891–1970) philosophy is especially noteworthy.31 In the mid-late 1950s, while Kuhn was teaching in the General Education Programme and when Structure was being penned, Carnap was at the height of his powers and academic standing (Schilpp, 1963). He was a doyen of logical empiricism, the ‘system’ that Kuhn’s work was consciously directed against. He was co-editor of the Encyclopedia of Unified Science that commissioned Kuhn’s Structure essay. In that editor’s capacity, Carnap wrote to Kuhn in 1960 and again in 1962 commending the manuscript, and saying in 1962 when accepting the manuscript for publication, that:In my own work on inductive logic in recent years I have come to a similar idea: that my work and that of a few friends in the step for step solution of problems should not be regarded as leading to “the ideal system”, but rather as a step for step improvement of an instrument. (Reisch, 1991, p.267)
And Carnap addressed in 1963 (originally in German in 1935) ‘revolutionary’ change in science when theories finally cannot be reconciled with observation. He writes that the scientist has two options:a change in the language, and a mere change in or addition of, a truth-value ascribed to an indeterminate statement.... A change of the first kind constitutes a radical alteration, sometimes a revolution, and it occurs only at certain historically decisive points in the development of science. (Reisch, 1991, p.270)
Michael Friedman, in his article ‘Kant, Kuhn and the Rationality of Science’, wrote on the unexpected comparability of Carnap’s and Kuhn’s account of science:Thus Kuhn’s central distinction between change of paradigm or revolutionary science, on the one side, and normal science, on the other, closely parallels the Carnapian distinction between change of language or linguistic framework and rule-governed operations carried out within such a framework. (Friedman, 2002, p.181)
John Earman, writing as ‘a distant student of Carnap and a close student of Kuhn’ (Earman, 1993, p.32), says:Although I am no apologist for logical positivism, it does seem to me that many of the themes of the so-called postpositivist philosophy of science are extensions of ideas found in the writings of Carnap and other leading logical positivists and logical empiricists. (Earman, 1993, p.9)
For Carnap, the choice of a particular linguistic framework is not driven by rules; but moves within the framework are so driven or governed. This is close to Kuhn’s choosing between paradigms, and working within paradigms. But for science, nature comes into the picture. Here was common ground that could have been explored with Kuhn’s own academic sponsor, but this did not happen.32
In Kuhn’s biographical interview, he confesses that he:read a little bit of Carnap, but not the Carnap that people later point to as the stuff that has real parallels to me. … I have confessed to a good deal of embarrassment about the fact that I didn’t know it. (Baltas et al., 1997/2000, p.305-306)
Disarmingly, he proceeds to say:On the other hand, it is also the case that if I’d known about it, if I’d been into that literature at that level, I probably would never have written Structure. (Baltas et al., 1997/2000, p.306)
This is likely a true conjecture, and what a momentous one it is: The post-1960 scholarly and cultural worlds would be very different if Kuhn had spent his time reading, understanding, and engaging with Carnap, and other extant literature, rather than writing Structure. His decision to write rather than read had a butterfly effect. An avalanche of publications and book sales followed upon the decision. Other physicists did do the ‘hard yards’ in philosophy and so they better served the long-term philosophical and educational purposes that Kuhn himself sought to serve, though they did not have his sales or citation figures.33
In brief, by 1960, much had been written on the intellectual complexity of science, on the challenging junction of science and metaphysics,34 and on the ‘embeddedness’ of science in society and culture. Much of this had been written on under the heading of ‘Internal versus External History of Science’ (Basalla, 1968). A good deal of these noteworthy elements of Structure had been written about by Kuhn’s own Harvard colleagues—Frank, Conant, Quine, Scheffler, Putnam, and Holton. In the first edition (1962), Kuhn recognised few of these antecedents and engaged with only a subset of those. There was some engagement in the Postscript of the second edition (1970), but not much. Engagement with philosophers picked up in his subsequent philosophical writing,35 but only the smallest proportion of the million-plus readers of Structure read his later essays.
Alexander Bird, in his biography of Kuhn, gives an accurate, but understated, account of the degree to which Kuhn’s positions had already been voiced:There are the seeds of Kuhn’s own revolution in such historians and sociologists as Ludwick Fleck, Karl Mannheim and Robert Merton, as well as philosophers such as Toulmin and Hanson. (Bird, 2000, p.2)
To Kuhn’s credit, his Structure brought all these contra-empiricist elements together within a seemingly coherent narrative that could be easily read, though not always understood, by many.
A good deal of what educators found attractive and engaging in Structure was out there and public in earlier books by other philosophers and historians. Unfortunately, there was no tradition, or expectation, that science educators, teachers, or students would read and engage with such literature. Philosophy, or HPS more specifically, was not part of teacher education or seen to be an essential part of a science teacher’s professional responsibility. And HPS was not an expected part of an education-researcher’s repertoire.
Interpreting Kuhn
Before appraising the claims and arguments of an author, the first task is the exegetical one of laying out just what are the author’s claims and then determining if they are consistent over time or change with maturation and criticism. For Kuhn, exegesis is uncommonly difficult. He was not a disciplined writer, or at least not as disciplined as his subject matter—the history, processes, methods, and achievements of science—deserved. In a delightfully revealing and lengthy 1995 interview conducted in Athens less than a year before his death, Kuhn relates how he attended an undergraduate seminar at Princeton where, in response to audience enthusiasm for ‘Kuhnian’ ideas, he objected:I kept saying ‘But I didn’t say that! But I didn’t say that! But I didn’t say that! (Baltas et al., 1997/2000, p.308)
In his 1991 Rothschild Harvard lecture—‘The Trouble with the Historical Philosophy of Science’—he said of the hugely popular Edinburgh-based sociology of scientific knowledge programme36 that it:Frequently troubles me, not least because it was initially emphasized and developed by people who often called themselves Kuhnians. I think their viewpoint damagingly mistaken, have been pained to be associated with it, and have for years attributed that association to misunderstanding. (Kuhn, 1991/2000, p.106)
This refrain of ‘I did not say that’, or ‘you have misunderstood me’ is common. Kuhn does not pause to reflect on why senior scholars such as David Bloor, Harry Collins, Trevor Pinch, John Henry, and Barry Barnes, to say nothing of multiple hundreds of thousands, if not millions, of lesser scholars and students, could misunderstand what he wrote. He attributes this to their lazy reading, not to his careless writing. Slow, tedious, sometimes page-by-page exegesis is a bugbear, but a necessary one in analysis of Kuhn and Kuhnian argument. Philosophers resented having to do this; they expected clearer, less ambiguous writing.
The deficiency of Kuhn’s ‘soft-focus’, or undisciplined, writing was shown in an early review of Structure. Dudley Shapere, who acknowledged the ‘vast amount of positive value in Kuhn’s book’, focused, as so many did, on Kuhn’s introduction of ‘paradigm’. At the very outset paradigm was defined as:a set of “universally recognized scientific achievements that for a time provide model problems and solutions to a community of practitioners”. (Kuhn, 1962/1970 p. viii)
Shapere went on to argue that Kuhn’s truly revolutionary account of theory changes in the history of science:… is made to appear convincing only by inflating the definition of ‘paradigm’ until that term becomes so vague and ambiguous that it cannot easily be withheld, so general that it cannot easily be applied, so mysterious that it cannot help explain, and so misleading that it is a positive hindrance to the understanding of some central aspects of science; and then, finally, these excesses must be counterbalanced by qualifications that simply contradict them. (Shapere, 1964, p.393)
None of these considerations prevented ‘paradigm’ appearing, like Spring blossoms (to use a generous simile), across the scholarly, social, and cultural worlds after Structure’s publication in 1962. For Kuhn, Hume’s ‘slow, lingering method’ of philosophical analysis was alien. It is something that requires schooling, and Kuhn repeatedly acknowledges that he did not have it.
Margaret Masterman, at the important 1965 London conference session on Structure, identified 21, ‘or was it 23’, different meanings of ‘paradigm’ in the book’s first edition (Masterman, 1970). Kuhn was in the conference audience and, thirty years later, commented:And I sat there, I said, my God, if I had talked for an hour and a half, I might have gotten these all in, or I might not have. But she's got it right! And the thing I particularly remember, and I can't make it work quite but it's very deeply to the point: a paradigm is what you use when the theory isn't there. And she and I interacted then, during the rest of my stay, quite a lot. (Baltas et al., 1997/2000, p.299-300)
Scholars do change, or refine, their positions in response to criticism and upon further reflection. This is commendable and Kuhn did so (Hoyningen-Huen, 2015). In 1993, he wrote:Whatever I may have believed when I wrote the Copernican Revolution [1957], I would not now assume … ‘that the simpler, the more beautiful [astronomical] models are more likely to be true’. (Kuhn, 1993, p.331)
He changed his mind on this point simply because he gave up altogether on truth as a realisable goal of science.
Abandoning truth was a seismic change. Less seismic was his discarding of ‘paradigm’ which soon enough became a mixture of ‘lexical structure’ plus ‘exemplar’ (Kuhn, 1993, p.326). This construction did not catch on; it did not have the ring of ‘paradigm’ which lived on enjoying a life of its own long after its creator abandoned it. Exegesis details where and when change occurs. Further attention, beyond exegesis, might reveal why the change occurs, and whether it was justified.
Philosophers on Kuhn
Philosophers did not entirely ignore the first edition of Structure. Most notably, and publicly, Paul Feyerabend, Imre Lakatos, Margaret Masterman, Stephen Toulmin, and Karl Popper engaged with it at the 1965 London Philosophy of Science Congress (Lakatos & Musgrave, 1970). Many other philosophers, including those mentioned below, rose to the Kuhnian challenge.
John Searle, a philosopher, points to the need for externalist, sociological, or naturalist, rather than internalist, epistemic explanations for the embrace of Kuhnianism:… the remarkable interest in the work of Thomas Kuhn on the part of literary critics did not derive from a sudden passion in English departments to understand the transition from Newtonian Mechanics to Relativity Theory. Rather, Kuhn was seen as discrediting the idea that there is any such [objective] reality. If all of ‘reality’ is just a text anyway, then the role of the textual specialist, the literary critic, is totally transformed. (Searle, 1994, p.38)
Kuhn’s ‘novel’ ideas were taken out of the philosophy corridor and broadcast in the marketplace. The Kuhnian wave broke over philosophy departments, and in quick succession of other humanities, social science, and education departments. There have been many substantial monographs and collections on Kuhn’s real and imagined philosophy.37
Kuhn cites just a handful of philosophers in the first edition: Wittgenstein, Braithwaite, Polanyi, Whewell, Popper, Goodman, Quine, Nagel, and Hanson. And these, with the notable exception of Hanson, are mentioned only in passing. Kuhn regarded Structure primarily as a contribution to philosophy. Yet only 10% of its sources are philosophical.38 There is no prolonged analysis or evaluation of any philosophical argument, excepting a three-page analysis of arguments about perception, and what contributions the observer makes to the object as perceived.
In Structure, what philosophical arguments there were amounted to empiricism in new clothes: Theory dependence of observation still took observation as fundamental for a theory of knowledge. But debate about the theory dependence, or otherwise, of observation was just an in-house empiricist family-squabble; it occurred within an empiricist ‘paradigm’, as some would say, or within an empiricist ‘problematic’ as others might say. Wallis Suchting (1931–1997) commented:The central deficiency of empiricism is one that it shares with a wide variety of other positions, namely, all those that see objects themselves, however they are conceived, as having epistemic significance in themselves, as inherently determining the ‘form’, as it were, of their own representation. (Suchting, 1995, p.13)
Mario Bunge (1919–2020), a physicist and philosopher who published significant work in both fields (Matthews, 2019c), recounts in his autobiography that in 1966 he attended an influential colloquium on causality convened in Geneva by Jean Piaget. Kuhn, an admirer of Piaget, was a participant. Bunge observed:Kuhn’s presentation impressed no one at the meeting, and it confirmed my impression that his history of science was second-hand, his philosophy confused and backward, and his sociology of science non-existent. (Bunge, 2016, p.181)
This is a harsh judgement, but it was made in 1966 after the first edition of Structure (1962), but before publication of the second edition’s Postscript (1970) and Kuhn’s ‘Response to My Critics’ in the Criticism and the Growth of Knowledge collection (Lakatos & Musgrave, 1970). At the time, Kuhn’s most widely known historical work was his book The Copernican Revolution (Kuhn, 1957). He acknowledged that this was entirely derivative and put together from secondary sources for the benefit of his Harvard General Education classes.39
David Stove (1927–1994), an Australian philosopher, wrote of Kuhn:his entire philosophy of science is actually an engine for the mass-destruction of all logical expressions … [he] is willing to dissolve even the strongest logical expressions into sociology about what scientist’s regard as decisive arguments. (Stove, 1982, p.33)
Stove maintained that Kuhn’s confusion of sociology with epistemology is the reason why:Kuhn can, and must, sentence all present and future philosophers of science to the torments of the damned: that is, to reading the sociology of science. (Stove, 1982, p.19)
This seems an ‘over the top’ charge, but, in its mitigation, David Bloor, who recognised Kuhn as his philosophical inspiration, published a piece titled: ‘The Sociology of Reasons: Or Why “Epistemic Factors” are really “Social Factors”’ (Bloor, 1984, 295–324). So logical expressions—‘inconsistent with’, ‘entails’, ‘subset’, ‘contradiction’, etc.—only function as such in as much as people believe them. The validity of an argument depends on people thinking it is valid. The effect of this is to replace logic by psychology; the latter substitutes for the former. A consequence is that the important psychological study of poor and aberrant reasoning cannot be conducted, as correct reasoning cannot be identified independently of convictions. Separating ‘good’ psychology from ‘mob’ psychology is otiose.
Israel Scheffler (1923–2014), who had joint appointments in the Harvard Philosophy and Education departments, responded to the first edition of Structure, arguing that Kuhn’s charge of irrationality in paradigm choice:fails utterly, for it rests on a confusion. It fails to make the critical distinction between those standards or criteria which are internal to a paradigm, and those by which the paradigm is itself judged. (Scheffler, 1966, p.84).
Jan Golinski, a historian, wrote:I see Kuhn as having little positive influence on philosophers and almost none (directly) on historians. His most significant influence within science studies was mediated by sociologists, whose reading of his work he specifically repudiated. (Golinski, 2012, p.15)
Alexander Bird concluded a sympathetic appraisal of Kuhn with the qualification:Kuhn’s treatment of philosophical ideas is neither systematic nor rigorous. He rarely engaged in the stock-in-trade of modern philosophers, the careful and precise analysis of the details of other philosophers’ views, and when he did so the results were not encouraging. (Bird, 2000, p. ix)
Consequently, Bird stated:Structure is not primarily a philosophy text. Rather it is a work in what I call ‘theoretical history’. (Bird, 2000, p.vii)
Abner Shimony (1928–2015), a Boston University physicist and philosopher with substantial publications in both fields (Myrvold & Christian, 2009), said of the key Kuhnian move of deriving methodological lessons from scientific practice that:His work deserves censure on this point whatever the answer might turn out to be, just because it treats central problems of methodology elliptically, ambiguously, and without the attention to details that is essential for controlled analysis. (Shimony, 1976, p.582)
The ‘controlled analysis’, to which Shimony refers, is a controlled and competent ‘philosophical’ analysis.40
Wolfgang Stegmüller (1923–1991), an Austrian philosopher, opined that the crux of Kuhn’s theory of science was ‘a bit of musing by a philosophical incompetent’ (Stegmüller, 1976, p.216). This was a harsh judgement, but Kuhn was candid in admitting that he had no training in philosophy and was an ‘amateur’ in the discipline (Kuhn, 1991/2000, p.106). And, to a point, he thought that having no formal training was advantageous. This because as he was not schooled in ‘old thinking’, he did not develop a certain ‘cast of mind’ that characterised academic philosophy. This is a pity, as this cast of mind traditionally espoused clear and coherent writing; the cast was uncomfortable with ‘purple passages’ and endeavoured not to compose them.
Michael Devitt agrees with some of Kuhn’s epistemology concerning theory-ladenness and revolutionary theory change, but does not think such agreement requires abandoning truth, or even abandoning the correspondence theory of truth. He regards Kuhn’s ‘semantic and vaguely ontological doctrines as largely, if not entirely, mistaken’ (Devitt, 1991, p.155). And says later: ‘Constructivism is prima facie absurd, a truly bizarre doctrine’ (Devitt, 2001, p.147). The ‘absurd’ doctrine has traction because:Constructivists typically vacillate between talk of theories or experience and talk of the world. This vacillation is important to the appeal of their message. For, although it is false that we construct the world by imposing concepts on the world, it is plausible to suppose that we construct theories of the world by imposing concepts on experience of the world. The vacillation helps to make the falsehood seem true. (Devitt, 2001, p.148)
It is noteworthy that Kuhn’s long, and charming, 1997 autobiographical interview with Aristides Baltas, Kostas Gavroglu, and Vasso Kindi is, significantly, titled: ‘A Physicist who became a Historian for Philosophical Purposes’.41 Kuhn relates:I had made that attempt to investigate going into philosophy immediately after the war when I first came back and got into [Harvard] graduate school and I decided I wasn’t going to go back to fulfill undergraduate philosophy. And in certain respects, I’m extremely glad I didn’t, because I would have been taught things that would have given me a cast of mind which would have, in many ways, helped me as a philosopher, but they’d have made me into a different sort of philosopher. So, I had decided, when I applied to the Society [Harvard Society of Fellows], to do history of science. My notion was, and my application indicated, that there was important philosophy to come out of it; but I needed first to learn more History. (Baltas et al., 1997, p.166)
In the light of the philosophical critiques of the first and second editions of Structure, Kuhn did, in a number of important publications, attempt to ‘walk back’ and refine his claims;42 hence, the accepted differentiation between Kuhn I and Kuhn II, or between Radical Kuhn and Mild Kuhn. For the most part, educators and social scientists did not attend to this walking back; they were not aware it had happened. After the blinding relativist and idealist flash of Structure, few recovered their philosophic vision. Although Kuhn’s walk back was applauded by many philosophers, realists thought that he did not walk back far enough. Kuhn’s reality was still too dependent upon the views of the scientist and scientific community; his ontology remains wedded to subjectivity.
Kuhn did not become a professional philosopher. When he was denied tenure in the Harvard General Education Department, there was no question that the Philosophy Department, in which Rawls, Quine, Putnam, and others were in residence, would give equal standing to someone untrained in philosophy. After Harvard, he went to University of California, Berkeley, and had appointments and teaching duties in both the History and the Philosophy departments. At tenure time, the Acting Chancellor called him into his office, and relayed:The recommendation for your promotion has now gone all the way through, it’s favourable, and I have it on my desk. There is just one thing. The senior philosophers voted unanimously for your promotion – in History. (Baltas et al., 1997, p.182)
For Kuhn:I was extraordinarily angry … and very deeply hurt, I mean that’s a hurt that has never altogether gone away. (Baltas et al., 1997, p.182)
Kuhn was deeply hurt, and intellectually troubled, telling interviewers in October 1995, less than a year before his death, that he was an ‘anxious neurotic’. In the same interview, he recognised, perhaps with regret, that ‘I’ve never directed a philosophy graduate student’ (Baltas et al., 2000, p.319). He admitted in 1995 that his treatment of the orthodox philosophical tradition was ‘irresponsible’ (Conant & Haugeland, 2000, p.305). This was not a good admission for someone seeking a position in a philosophy department. And elsewhere he confessed: ‘I should never have written the purple passages.’ He was surprised at their impact:To my dismay, … my ‘purple passages’ led many readers of Structure to suppose that I was attempting to undermine the cognitive authority of science rather than to suggest a different view of its nature. (Kuhn, 1993, p.314)
And it was not just the ‘purple passages’ that were irresponsible; at many points, he advanced ill-considered philosophical and historical arguments. For example, he dismissed Joseph Priestley as an ‘elderly holdout who had ceased to be a scientist’ (Kuhn, 1970a, p.159). This was an assertion that, unjustifiably, blackened Priestley’s name for the million-plus readers of Structure who themselves who had never, and probably would never, read Priestley.43 Many other philosophers and historians pointed to problems and errors in Kuhn’s account of both normal science and the processes of revolutionary change in science.44
Kuhn’s Reach and Overreach
Kuhn’s impact was felt in nearly all disciplines—economics, sociology, psychology, cultural studies, education, and feminism, for starters—and beyond academia into society and culture.45 But his disciplinary impact was in inverse relation to his training and qualifications; he pressed the right buttons and raised important questions, but he disastrously overreached. From the beginning, his impact on HPS puzzled him and should have puzzled many others.
Kuhn is rightly seen as putting ‘paradigm’ and ‘paradigm change’ into the philosophical and social science vocabulary. The word, and expression, is a commonplace in newspaper opinion pieces, political debates, sports reporting, and much else. Its occurrence in the Google Book Ngram Viewer jumped 26-fold between 1960 and 2020.46 Other now-commonplace words and concepts owe their currency to Kuhn: ‘incommensurability’ is oft heard in political and religious debate, ‘theory dependence’ is ubiquitous in social science, ‘gestalt switch’ is now as common in history of science as it has long been in psychology, ‘conversion experience’ moved out of Evangelical sermons into history of science debates, ‘alternative reality’ is not just part of modern US politics but underpins a great deal of educational debate about the teaching of indigenous science, and many other expressions moved out of their Kuhnian home into wider discourse.
There are significant disciplinary and cultural lessons to be learnt from the phenomenon of Kuhnianism. Kuhn had no training in history, philosophy, or sociology; he modestly described himself as an amateur in all three fields. As related in his 1991 Rothschild lecture:Though most of my career has been devoted to the history of science, I began as a theoretical physicist with a strong avocational interest in philosophy and almost none in history. Philosophical goals prompted my move to history; it’s to philosophy that I’ve gone back in the last ten or fifteen years. (Kuhn, 1991/2000, p.106)
History of Science
Charles Gillispie (1918–2015), a major figure in the history of science community, reviewed Structure in 1962 and wrote: ‘Thomas Kuhn is not writing history of science proper. His essay is an argument about the nature of science’ (Gillispie, 1962, p.1251). But disarmingly, in as much as articulating the nature of science is a philosophical endeavour, Kuhn keeps saying he had no training in philosophy. Outside physics, Kuhn’s education fell between disciplinary stools.
Thomas Nickles, a philosopher sympathetic to Kuhn’s programme of historically informed philosophy, wrote:Kuhn was always something of an amateur, largely self-taught in philosophy and even in history of science. (Nickles, 2003, p.9)
Kuhn may not have taken a PhD in history of science, but he did take his own teaching of history seriously. Stephen Brush, who took a Harvard General Education course of Kuhn’s, recalls:In Kuhn’s seminar we learned that the history of science must be studied by careful reading of original sources. That means reading them in the original language, not relying on translations; it also means becoming aware of the precise meaning of technical terms by reading other works by the same author and works by other authors on the same subject at that time. One must be careful not to read modern meanings into older writings. (Brush, 2000, p.40)
This is the pedagogy of normal science in a history classroom. There was a lot to learn and be mastered before inquiry and negotiation began. And, as with science, doing the latter without the former was whistling in the dark.
Kuhn’s, 1978 Black-Body Theory and Quantum Discontinuity (Kuhn, 1978) is regarded by all commentators as his most substantial, archive-informed, and focussed historical work. The book, among other things, traces in detail Planck’s initial resistance to the new discontinuity theory of atomic radiation and the quantum effects, advanced by Einstein and others. It documents the tenacity with which Planck held on to the classical, continuous view of radiating energy. Trevor Pinch (1952–2021) a prominent ‘new wave’ sociologist of science, praised Kuhn’s ‘penetrating analysis’ of the relationship between Boltzmann’s statistical mechanics and quantum theory but, tellingly, points out that the book makes no mention of Structure. Further, none of the historiographic ‘apparatuses’ of Structure are utilised. Pinch remarked: ‘Kuhn has disregarded almost all the issues that grip current sociology and philosophy of science’ (Pinch, 1979, p.440) and has provided a ‘largely internal history of how discontinuity emerged at the turn of the century’ (Pinch, 1979, p.437). Pinch suggests that ‘it is quite possible’ that Kuhn’s indifference to his own ambiguous formulations meant that he was ‘unaware’ of the radical implications of Structure, and so could not carry them through in his serious historical study.
This is a problem for educators and others: The conceptual apparatus of the supposed blinding new Kuhnian light on our understanding of science is not even used by its author in his ‘display’ work. Further, Abner Shimony, the philosopher-physicist, in reviewing Kuhn’s book, wrote:On the whole, the intellectual processes of the few physicists immersed in blackbody research seems to me to have been wonderfully rational. (Shimony, 1979, p.436)
Sociology of Science
Nickles, above, does not mention sociology which was at the core of Structure’s argument about the conduct of science and of scientific revolutions. From the beginning, Kuhn was sensitive to sociological factors in science. In 1952, he wrote to Philipp Frank:It would seem to me that for any sociologist of science, it would be more fruitful to example the ubiquitous role of the sociology of the professional group than to concentrate solely on those factors (like government, church, etc.) which at this time and place have relatively little impact upon decisions made by professional scientists about problems arising within their own sciences. (Reisch, 2017, p.242)
This sensitivity meant he was attentive to the formative, educational influences, including textbooks, on the professional group and how that group’s dynamics bore upon research decisions. But this was sensitivity, not research. Arrestingly, Kuhn admitted that, when writing Structure, he ‘knew very little about sociology’ and further ‘he proceeded to make up the sociology of [scientific] communities as he went along’.47 In 1983, when receiving the John D. Bernal Award, he wrote:Structure is sociological in that it emphasizes the existence of scientific communities, insists that they be viewed as the producers of a special product, scientific knowledge, and suggests that the nature of that product can be understood in terms of what is special in the training and values of those groups. (Kuhn, 1983, p.28)
But Kuhn continued:Having insisted upon those points, however, I proceeded to make up the sociology of such communities as I went along, or rather to draw it from my experience with the interpretation of scientific texts supplemented by my experience as a student of physics. (ibid)
And admits:That is an abominable way to do sociology, and it did not occur to me that its outcome would, qua sociology, have a claim on the attention of members of that profession. (ibid)
Kuhn made little, if any, effort to master extant literature in sociology of science. The argument of Structure seems not to have benefited from engagement with either J.D. Bernal’s work (Bernal, 1939) or that of Robert Merton, the founder of sociology of science (Merton, 1938/1973, 1942/1973). These fundamental works had been published 20 years before Structure. Merton’s, 1942 claim about the universality of scientific knowledge is assuredly something that Kuhn might have, for the benefit of everyone, profitably engaged with:The cultural context in any given nation or society may predispose scientists to focus on certain problems … But this is basically different from the second issue: the criteria of validity of claims to scientific knowledge are not matters of national taste and culture. Sooner or later, competing claims to validity are settled by universalistic criteria. (Merton, 1942/1973, p.271)
Kuhn neither conducted nor oversaw empirical research studies on laboratory practice or any other scientific practice. His repeated admissions of ‘little training’ are striking and exemplify the argument of this paper: Kuhn consistently made claims about matters of which he, confessedly, knew little. Kuhn simply did no empirical sociology of science; he did not examine laboratories, research funding, political constraints or support, or control of journals. Barry Barnes, a founder of the powerful Edinburgh school of sociology of science, pointed to Kuhn’s superficial grasp of the practice of science:In general, Kuhn’s work reveals little sensitivity to the highly differentiated structure of science and the importance of competition and mobility between different ‘schools’ or specialities. It leaves us unprepared for the finding that a combination of the skills of several specialties led to the elucidation of the structure of DNA and hence the creation of a new basic model for biological investigators. (Barnes, 1974, p.95)
A psychologist and a biologist, in a co-authored paper, drew attention to Kuhn’s distance from ‘coal face’ science and his subsequent misconceptions and underestimations of normal science:Although Kuhn was trained as a physicist, he writes in the most general and vague terms about the scientific process and conveys little familiarity with the nuts and bolts of conducting research. Consequently, much of Kuhn’s analysis amounts to abstract speculation that bears little relation to how scientists normally think and what scientists normally do. (Sanbonmatsu & Sanbonmatsu, 2017, pp.134-135)
Some have thought that Kuhn’s account of normal science missed so much of its creativity, value commitments, and personal judgement that he was writing about something better described as ‘sub-normal’ science (Mody, 2015, p.99).
Science Classrooms
If Kuhn spent little time researching laboratory practice, he spent even less time researching science classrooms where, supposedly, the paradigms of science were being incubated and reproduced. Kuhn had been a student in physics classrooms and had taught in General Education classrooms, and so had inklings and intuitions about the impact of such instruction, but no education ‘research data’. Few sociology journals would publish any claim about purported scientific practice if there was no supporting empirical evidence. Yet founders of the Edinburgh Strong Programme in sociology of science consistently, as shown below, cite ‘evidence-free’ Kuhn as their inspiration, indeed their authority on the subject. Just the unpaginated citation ‘Kuhn’ was deemed sufficient to establish many contentious points.
The Limits of Overreach
That Kuhn had no immediate empirical evidence for his claims about the conduct of normal science, or for the processes whereby revolutions in science were initiated and accepted, does not mean that his claims are without warrant. Speculation in advance of evidence is standard scientific practice, but whether the speculation is correct, or justified, is something for the disciplines of philosophy, history, sociology, and perhaps social psychology to ascertain. Some did so and supported Kuhn; others did the same and rejected the Kuhnian picture. Thus the ‘Science Wars’ were constituted.48 It is a peculiar situation that so many professionals in these disciplines, including education, so lightly took Kuhn’s word for the book’s many philosophical, historical, and sociological claims. They adopted and promulgated the Kuhnian picture even when their interpretations were being rejected by Kuhn himself.
John Ziman (1925–2005), a physicist and educator, was sympathetic to Kuhn’s cross-disciplinary excursions. He saw this as a strength of Kuhn:The deep message of THE STRUCTURE OF SCIENTIFIC REVOLUTIONS was that these jurisdictional disputes were futile. A scientific theory can only be grasped metascientifically as an entity with intertwined philosophical, historical, and sociological characteristics. … That is why we are all Kuhnians nowadays. (Ziman, 1983, p.24)
Doing research across the disciplinary board is as commendable as it is rare, but it does not mean that standards need not be reached; it just means that more of them need to be reached.
Wes Sharrock and Rupert Read, in their careful and sympathetic study of Kuhn, are decisive: ‘To say it again, Kuhn is a philosopher above all’ (Sharrock & Read, 2002, p.110). And it is as such that he needs ultimately to be understood and appraised. For them:Kuhn, we have argued, neither provides a general and true theory of science, nor a set of normative prescriptions for how to pursue science correctly. (Sharrock & Read, 2002, p.210)
These two caveats take a large ‘bite’ out of Kuhnianism as a guiding educational, or any other, light. And should cause pause when reading David Treagust’s claim about Structure that opened this essay: ‘This small book really changed the way we look at the enterprise that is science’ (Treagust, 2022, p.16). What are the consequences of something so described by Sharrock and Read having such impact? What does it say about the science education community and its influence on public understanding of science?
Steven Weinberg (1933–2021), a physicist, historian, and Nobel laureate, observed that:But even when we put aside the excesses of Kuhn's admirers, the radical part of Kuhn’s theory of scientific revolutions is radical enough. And I think it is quite wrong. (Weinberg, 1998)
Elaborating, he writes:It is important to keep straight what does and what does not change in scientific revolutions, a distinction that is not made in Structure.There is a “hard” part of modern physical theories … that usually consists of the equations themselves, together with some understandings about what the symbols mean operationally and about the sorts of phenomena to which they apply. Then there is a “soft” part; it is the vision of reality that we use to explain to ourselves why the equations work. The soft part does change; we no longer believe in Maxwell’s ether, and we know that there is more to nature than Newton's particles and forces. (Weinberg, 1998)
There are important lessons to be learned about the academy, and culture more generally, from how Kuhn, untrained in any meta-scientific discipline, could have such an international impact and influence. Outside of science, this phenomenon is, depressingly, common. It is the mainstay of political and religious movements and associated rallies.49 Building HPS into teacher training programmes could mitigate it.
Kuhn’s Philosophy I: Undergraduate Encounter with Kant
As a Harvard undergraduate, Kuhn completed an elective ‘History of Philosophy’ course. He admits that not much of the course made an impression, but ‘Kant was a revelation’ (Baltas et al., 1997/2000, p.264).50I gave a presentation on Kant and the notion of preconditions for knowledge. Things that had to be the case because you wouldn’t be able to know things otherwise.
Fifty years later, reflecting on that undergraduate episode and summarising his philosophy, he said:Oh, it’s an important story because I go round explaining my position saying I am a Kantian with moveable categories. (Baltas et al., 1997/2000, p.264)
In his 1993 ‘Afterwords’ reflections on his career, Kuhn writes:Though it is a more articulated source of constitutive categories, my structured lexicon [Kuhn’s new term for paradigm] resembles Kant’s a priori when the latter is taken in its second, relativized sense. Both are constitutive of possible experience of the world, but neither dictates what that experience must be. (Kuhn, 1993, p.331)
Due to the war, his Harvard programme was cut by a year, and so also cut was the possibility of him doing more philosophy courses. More is the pity as his Kantianism might have been refined or abandoned.51
Observation and Perception
Three years after graduating from Harvard with a physics PhD, Kuhn, in 1951, confidently strode into the philosophers’ domain when he wrote:For scientific observation is always a process of abstraction. One abstracts the length, the color, the texture from a natural object which always provides an infinity of alternate abstractions. Some choice is demanded, and the choice must ultimately rest upon personal prejudice. (Kuhn, 1951/2021, p.17)
Understanding the epistemic function of observation and perception has been central to philosophy since at least Plato who affirmed that ‘we see through the eyeball, not with the eyeball’. Bacon and the British empiricists cemented the centrality of perception for science; Kant built a whole system by underwriting, and fleshing out, the observational foundations of Newtonian theory. The crucial role of observation for science was embraced by Mach and then by logical empiricism. On perception, Kuhn states the truism:What a man sees depends both upon what he looks at and also upon what his previous visual-conceptual experience has taught him to see. (Kuhn, 1970a, p.113)
And he refers to research on the psychology of perception. Philosophers have also, since Plato, been writing on sensation, perception, and observation, but he largely ignored this tradition.52
Ontological Idealism and Epistemological Relativism
To the end, Kuhn held on to three foundational claims of Kantianism: (i) Reality as it is (the noumena) is beyond our knowledge.
(ii) The known world, the world of which we can have knowledge (the phenomena), is constructed by us, and depends upon our cognitive machinery.
For Kant, the mind’s cognitive machinery—forms of sensibility and a priori categories, including, space, time, and causality—that it imposes on the noumena, is universal; they are part of having a human mind. Crucially, social constructivists, and cultural theorists in education, remove universality from the second bedrock and substitute cultural plurality. So, they post:
(iii) The concepts used to construct the known world vary among linguist, scientific and social groups. Consequently, they live in different worlds.
This third claim is not the banal truth that different people have different experiences in the same situation. This is so banal as to hardly warrant being called a claim. Consider, for example, a Chinese and an Australian standing in front of a sign:
The Chinese person has propositional perception STOP and behaves accordingly; the Australian simply has, at best, propositional perception SIGN and does not know what to do. The third claim above is the ontological claim that the real world, not the experiential worlds are different for different groups; they live in different real, not experiential, worlds. This is relativistic metaphysical constructivism, the philosophical position that became a best seller in the academy, and beyond.
A popular, and extended, statement of this third, socialised-ontology, position was Peter Berger and Thomas Luckmann’s The Social Construction of Reality. There they are adamant that ‘reality’ and ‘knowledge’ must be in scare quotes because these supposed realities always ‘pertain to specific social contexts’ (Berger & Luckmann, 1966, p.15). Their failure to distinguish reference from description, and their ontological conjuring, is endemic. At science education conferences, presenters use fingers to indicate that their use of ‘knowledge’, ‘truth’, ‘reality’, ‘proven’, and the like is not literal; finger movement shows that the presenter is not simple-minded and is not among the philosophically unwashed.
Observation, more correctly propositional perception, is theory dependent, but it is also nature dependent. Making basic observations has a strong survival value for animals. Science requires, in the way that non-sentient beings do not, that such observations be articulated as propositions—‘I see that p’ where p is some propositional statement.53 For example, ‘I see that there is a magnetic field’, ‘I see that President Biden is on TV’, and ‘I see that the proportion of tall plants is 1:3’. The practice of science requires the communication, and evaluation, of such observations. Propositional perception requires language, hence some level of theory, but there also needs be some state of affairs to be described. Not all communication need be propositional—gestures, pointing, expressions, body language, a whistle, or music can suffice in many circumstances—but not for scientific communication.
Kuhn’s Philosophy II: Separation of Truth from Science
In the 1970 Postscript, Kuhn famously, and for some infamously, said that truth was irrelevant to judgements of scientific progress:Does it really help to imagine that there is some one full, objective, true account of nature and that the proper measure of scientific achievement is the extent to which it brings us closer to that ultimate goal?’ (Kuhn, 1970a, p.171)
Separating truth from science was a major break from orthodox understanding. Kuhn repeats his pre-Structure conviction:We can have no recourse to notions like the ‘truth’ or ‘validity’ of paradigms in our attempt to understand the special efficacy of the research which their reception permits. (Kuhn, 1963, p.358)
This is subsequently elaborated as:There is, I think, no theory-independent way to reconstruct phrases like ‘really there’; the notion of a match between the ontology of a theory and its ‘real’ counterpart in nature now seems to me illusive in principle. (Kuhn, 1970a, p.206)
The separation is maintained twenty years later, in his ‘Afterwords’ contribution to a 1990 MIT conference dedicated to appraising the gamut of his philosophical and historical claims. There he makes a much-referenced claim with ontological and epistemological dimensions:On the one hand, I aim to justify claims that science is cognitive, that its product is knowledge of nature, and that the criteria I use in evaluating beliefs are in that sense epistemic. But on the other, I aim to deny all meaning to claims that successive scientific beliefs become more and more probable or better and better approximations to the truth and simultaneously to suggest that the subject of truth claims cannot be a relation between beliefs and a putatively mind-independent or ‘external’ world. (Kuhn, 1993, p.330)
Concerning ontology, his use of scare quotes around ‘external’, and reference to ‘putative’ reality, suggests, if not downright means, that, for Kuhn, there is no such thing as an external, observer-independent world. Otherwise, why use such quotes?
He elaborates puzzle solving, not truth-finding, as the goal of science. Twenty years after publication, and despite all the criticism, he writes that his claim in Structure was the ‘right one’ (Kuhn, 1993, p.338). But Kuhn says his reader has to:… set aside the notion of a fully external world toward which science moves closer and closer, a world independent, that is, of the practices of the scientific specialties that explore it. (Kuhn, 1993, p.338)
Again, what function and purpose does ‘fully’ play in this claim? Might an external world be partly dependent upon the observer? Seemingly, for Kuhn, this is so. This, at best semi-idealism, was clearly stated in the first edition, and it was not retracted in the second, nor thereafter:I have so far argued only that paradigms are constitutive of science. Now I wish to display a sense in which they are constitutive of nature as well. (Kuhn, 1970a, p.110)
This is the beginning of an ontological idealist slope that ends, as John Passmore observes, in ‘the French intellectual’s dream … of a world that exists only in so far as it enters into a book’ (Passmore, 1985, p.32). There are many social constructivists, in and out of education, lining the slope, and cheering all who slide down it.
Concerning epistemology, if truth is taken off the science table, then what is progress toward? Economic betterment? Political power? Research funds? All Kuhn offered was better ‘puzzle solving’. In the Postscript, he writes:Taken as a group or in groups, practitioners of the developed sciences are, I have argued, fundamentally puzzle-solvers. (Kuhn, 1970a, p.205)
And once they are initiated into their puzzle-solving craft:Whether or not individual practitioners are aware of it, they are trained to and rewarded for solving intricate puzzles be they instrumental, theoretical, logical, or mathematical at the interface between their phenomenal world and their community’s beliefs about it. (Kuhn, 1993, p.338)
As with so much of Kuhn, readers need to pass quickly over clauses such as ‘the interface between their phenomenal world and their community’s beliefs about it’. Staying too long and asking: ‘What does this mean?’ makes for very slow reading without guarantee of any resolution.
Shape of the Earth
Demonstrably, competing theories can be appraised with respect to how adequately or approximately they depict the world. Consider the 2000 + years investigation of the Earth’s shape. Pythagoras’ 500bc claim that the Earth is spherical is closer to the shape of the Earth, and was progressively seen to be so, than competing claims that the Earth was flat. Until the fifteenth century, official Chinese astronomers (and there were no astronomers apart from official ones) were ‘flat earthers’. This is seen in the important early fourteenth-century astronomy book, Ge xiang xin shu, written between 1324 and 1335 by the Daoist priest and astronomer Zhao Youqin. In his version of neo-Confucian cosmology, the earth is likened to a flat board floating on water, with China in its centre, and surrounded by the heavens; the cosmos had a globular or egg structure.
In 1583, Matteo Ricci the Jesuit priest, astronomer, and natural philosopher began his mission to China (Brockey, 2008). He advanced the Copernican system, though it was banned in Rome, against official ‘flat earthers’. His accurate predictions of the 1601 solar eclipse in comparison to the failure of the court astronomers made such an impact on the Ming Emperor Wanli that the Copernican spherical earth theory became official policy.54 Scientific understanding could be, and was, shaped by how the world was.
In the eighteenth century, the spherical theory was adjusted. The realisation that the seconds pendulum was slowing at the equator prompted refined views about the Earth’s supposed spherical shape. Some, the ‘squeezers’, constricted the equator; others, the ‘flatteners’, expanded it. The latter, who included Newton, eventually won a debate that folded metaphysics, theology, mathematics, national interest, and technology into science.55 Thereafter, belief in the spheroidal, oblate Earth became the cultural and scientific norm. Different of Darwin’s theories of evolution might not fully ‘capture’ the natural realities of evolution, but they do better than Special Creation and so on across the landscape of science. Why agree with Kuhn’s denial of any meaning to ‘claims that successive scientific beliefs become more and more probable or better and better approximations to the truth’? Progressively, the true shape of the Earth was ascertained. Contra Kuhn, John Worrall sensibly writes:
It seems difficult to deny, I suggest, that the development of science has been, at least to a very good approximation, cumulative at the observational or experimental level. (Worrall, 2002, p.32)
Pseudoscience
It is of significant philosophical and social importance to distinguish science from pseudoscience. With difficulty, this can be done.56 But if science in its totality is just puzzle solving, as Kuhn would have it, without a voice from the world, then the separation of scientific puzzle solving from pseudo puzzle solving becomes impossible. Any book of pseudoscience is full of solved puzzles; most pseudoscience websites will, for a fee, solve your puzzle. Most pseudosciences have a large or small dash of technology which might well solve puzzles. But technology is not science. In addition, there are personal and social consequences of not distinguishing science from pseudoscience. Why set up ‘Truth and Reconciliation’ commissions if there is no truth to be found?57
Kuhn’s Philosophy III: Anti-Realism
The realism/anti-realism divide is perhaps the longest-running debate in philosophical reflection on science beginning at least when Aristotle asserted his realism against forms of Platonic idealism. The modern form of the debate was initiated when the Protestant scholar Andreas Osiander inserted an unsigned Preface into Copernicus’s 1543 On the Revolution of the Heavenly Spheres. The instrumentalist preface asserted that Copernicus’s Earth was not really revolving, and it was just said to be so in order to simplify astronomical calculations. Galileo famously upheld the realist reading of Copernicus. Only under inquisitorial pressure did he formally adopt an anti-realist, instrumentalist position.58 Publication of Structure brought this philosophical debate to quarters hitherto unaware of it.
Ernan McMullin (1924–2011) correctly recognised that ‘The radical challenge of Structure is directed not at rationality but at realism’ and went on to observe that ‘Kuhn’s influence on the burgeoning anti-realism of the last two decades can scarcely be overestimated’ (McMullin, 1993, p.71). Kuhn concurred with McMullin’s, and earlier critics’, charges of anti-realism:Despite my critics, I do not think that the position developed here leads to relativism, but the threats to realism are real and require much discussion, which I expect to provide in another place. (Kuhn, 1990, p.317)
The threats do require more discussion than Kuhn gave them. Some have endeavoured to elaborate, and make consistent, Kuhnian anti-realism. One such interpreter, Michela Massimi, does add the obvious proviso that ‘Kuhn’s view is either relativist or realist; it cannot be both at the same time’ (Massimi, 2015, p.143).
There are a variety of realisms.59 One book, titled Varieties of Realism, has 22 contributions (Agazzi, 2017). In recent decades, three dominant variants have emerged: Structural Realism advanced by John Worrall (Worrall, 1989), Ontic Structural Realism advanced by both Steven French (French, 2017) and James Ladyman (1998), and Selective Realism advanced by Alberto Cordero (Cordero, 2017).
Realism maintains that there exists an observer-independent world, that scientific theories make claims about both observational (compass needle movements) and non-observational (magnetic fields) things in that world, that those claims are approximately true, and that scientific progress occurs and is marked by widening and deepening the pool of such true and approximately true claims. Realist positions share the following commitments:An ontological commitment to the reality and independence of the world: external things and events, including unobservable and inferred entities, exist independently of cognising subjects.
A semantic commitment to the linkage of scientific claims to external things and events: science makes claims about the world.
An epistemological commitment: namely, that science has made some truthful, or approximately truthful, claims about entities and processes in both the observed and unobserved world. The observed or experienced world is the everyday world revealed by ordinary vision (billiard balls, fish, clouds, etc.); the unobserved world is that indicated by instruments and about which inference are made (molecules, atoms, magnetic fields, proteins, gravity waves, etc.).
An axiological commitment that the aim and purpose of science is to produce statements and theories about the world that are true; other purposes, such as utility, economic gain, professional advancement, or national pride, are secondary, or merely by-products of truthfulness.
Counter-wise, there is a family of anti-realist positions that are united by their rejection, sometimes for different reasons, of one or more of the above claims. The anti-realist family include positivism, empiricism, instrumentalism, constructivism, constructive empiricism, idealism, and of course the whole gamut of postmodernisms.
Some scholars reject the dichotomous division of realism/anti-realism. In the Introduction to a recent collection Contemporary Scientific Realism, the editors write:The debate has come a long way since the 1970s and the solidification of its framework in the ’80s. The noted dichotomy of “realism”/“antirealism” is no longer a given, and increasingly “middle ground” positions have been explored. (Lyons & Vickers, 2021, p.1)
The ‘middle ground’ that they identify are those ‘partial’ or ‘select’ realisms for whom putative existence is only claimed for the components of a successful theory that ‘do the heavy lifting’, the hypotheses within the theory that generate testable and confirmed predictions. Realism does not need to assert that all postulates of a successful theory are real just the effective parts need to be real. And epistemically, claims about these parts need to be true or approximately true. So, when experiment confirmed Fresnel’s theory of light, initially its associated ether, along with its transversal microscopic particle oscillations, was thought to be real. This was wholesale realism. When, eventually, the ether was discarded, selective realists could stand-by the components and argue that experiment confirmed their existence and efficacy. Select realism is still realism; it is no concession to idealism; the effective parts need to be real. And epistemically, claims about these parts need to be true or approximately true.
Kuhn’s anti-realism recurs in his historical studies. He provided a detailed study of the overthrow of Stahl’s and Priestley’s phlogiston account of combustion by Lavoisier’s oxygen account, oft named ‘The Chemical Revolution’. The episode had been the second of eight case studies in Conant’s celebrated Harvard Case Histories in Experimental Science (Conant, 1948, vol.1, pp.67–115). Kuhn taught the case. He correctly recognised that what Lavoisier discovered in 1777 was not ‘so much oxygen as the oxygen theory of combustion’ (Kuhn, 1970a, p.56). For Kuhn, ‘discovery means seeing both that something is, and what it is’. Priestley regarded the new oxygen as ‘dephlogistated air’. Irrespective of the translatability of ‘dephlogistated air’ into ‘oxygen’, the two theories could be, and were, compared by natural philosophers on their scientific merit. Lavoisier’s account triumphed, though it came into the world with its own anomalies.60
In a much-cited passage, Kuhn goes on to assert: ‘after discovering oxygen Lavoisier worked in a different world’ (Kuhn, 1970a, p.118). It reads nicely, but it cannot be literal. They corresponded with each other; the furniture of their houses and laboratories remained the same; and they breathed the same oxygen. And, more to the point, their rival theories and conceptual schemes could be and were compared. Whatever the standing of incommensurability, it does not mean incomparability.
Kuhn says, in discussing the acceptance by chemists of Dalton’s new atomic theory and law of constant proportions, that subsequently: ‘even the percentage composition of well-known compounds was different’ (Kuhn, 1970a, p.135). Taken literally, this is gold medal idealism. For realists, and most thoughtful people, the actual percentage composition of chemicals did not change, and the percentage remained constant. Chemical bonds are not made, and unmade, atomic constituents do not come, and then go, as beliefs about a compound change among those researching it, or at the same time while competing researchers look at it. What changes is the understanding of chemists. Another case of Kuhn’s lazy writing that fuels idealism and relativism.
Kuhn’s Philosophy IV: Incommensurability
Kuhn consciously tried to make up lost philosophical ground. He wrote different pieces responding to his philosophical critics (Conant & Haugeland, 2000). In his 1991 Rothschild lecture, and in his 1993 ‘Afterwords’ (Kuhn, 1993), he held out the promise of finally, after working for many years, making a substantial philosophical statement. This would be a book that would elaborate and defend his thesis of incommensurability. It was the subject of a 1989 NSF grant for a book provisionally titled: The Plurality of Worlds: An Evolutionary Theory of Scientific Development. A version of the book finally appeared in 2022 (Mladenovic, 2022).61
Writing such a book was always going to be a hard task for Kuhn. It was with good reason that Nicholas Maxwell, an English philosopher of science, succinctly stated:Incommensurability was Kuhn’s worst mistake. If it is to be found anywhere in science, it would be in physics. But revolutions in theoretical physics all embody theoretical unification. … It always astonished me that anyone took incommensurability seriously for a moment, especially as Michael Faraday solved the problem around 1834, long before Kuhn and Feyerabend invented it. … It is at once clear that the picture of science Kuhn gives us in Structure is very seriously inadequate. (Maxwell, 2014, pp.133, 140)
Paul Feyerabend gave prominence to incommensurability in his landmark contra-logical empiricist, 1962 paper ‘Explanation, Reduction and Empiricism’ (Feyerabend, 1962). Kuhn made comparable use of the concept in his 1962 Structure. He stressed that different paradigms had different vocabularies for seemingly the same things, they had different puzzles to solve, what were puzzles in one paradigm did not arise in others, methodological and testing techniques and standards differed between paradigms, adherents saw different things when looking at the same object, and so on (Kuhn, 1970a, pp.148–150).
For Kuhn, incommensurability had semantic, perceptual, methodological, and ontological dimensions. Ontological, because different realities came into being with different paradigms. With a new paradigm, ‘scientists lived in different worlds’, they ‘talked through’ each other, and they had ‘incompatible modes of community life’. He maintained that, for different puzzle-solving traditions, there was ‘no one world within which to work on them’ (Kuhn, 1970a, p.147). For many, after Kuhn, incommensurability functioned as a form of diplomatic immunity: ‘You cannot criticise, evaluate or even question me, as I am in a different paradigm, I live in a different world’.62
Kuhn made several efforts to amplify, modify, walk-back his original ‘radical’ claims about incommensurability across paradigms and its consequent epistemologically relativist and ontologically idealist implications.63 When he abandons paradigms in favour of ‘lexical structures’, he writes:Applied to a pair of theories in the same historical line, the term [‘incommensurability’] meant that there was no common language into which both could be fully translated. Some statements constitutive of the older theory could not be stated in any language adequate to express its successor and vice versa. (Kuhn, 1990, p.299)
Consequently, ‘Incommensurability thus equals untranslatability’ (ibid).64
Untranslatability might be a genuine linguistic problem, one language might lack the required word or words to express something that another language does, but this is unrelated to epistemological incommensurability. Theories are rivals because they are about the same thing. And they can be compared even if not completely translatable. Incommensurability does not mean unable to be compared. Alternative views, theories, and systems can be compared with respect to intelligibility, consistency, coherence, testability, evidence, originality, heuristic power, and agreement with established science.65 Ideally, after some debate and with some difficulty, sub-scores can be allocated, a total derived, and a best-contender chosen. Kuhn and others stress that this is ideal; in reality, the declaration of a short-term winner often depends on many external inputs (money, culture, religion, careers, political pressure, etc.), but in the long term, these factors are minimised. The well-known histories of Catholic anti-Copernican astronomy, Nazi science, Stalinist science, Maoist science, and tobacco science all fit this pattern. Very powerful forces maintained errant theories but could not keep doing so; better, more truthful ones prevailed. External authority can only carry science so far and for so long.
Kuhn’s Influence on Education I: Conceptual Change Research
Notwithstanding all of the foregoing caveats, qualifications and trenchant criticisms, Kuhnian philosophy,66 more particularly Kuhn’s purported epistemological relativism and his ontological idealism, had enormous impact on educational theory, research, curriculum, and classroom teaching. Four fields where the impact was most felt will be examined here: Conceptual Change Research, Constructivism, Science-Technology-Society education, and Cultural Studies in Education.
Early in Kuhn’s research career, and certainly by 1966, he sought to collaborate with Jean Piaget, the internationally renowned developmental psychologist and author of Genetic Epistemology (Piaget, 1970). Kuhn relates how accidental and serendipitous was his discovery of Piaget:A footnote encountered by chance [reading Merton’s thesis] led me to the experiments by which Jean Piaget has illuminated both the various worlds of the growing child and the process of transition from one to the next. (Kuhn, 1970a, p.vi)
This was an encounter with consequences. By Kuhn’s admission:Part of what I know about how to ask questions of dead scientists has been learned by examining Piaget’s interrogations of living children. (Kuhn, 1977a, p.21)
Kuhn provided an entrée to HPS for educators. In the 1970s and 1980s, pupil’s conceptual change in science learning was a prime focus of educational research. The field was energised and vindicated by Kuhn’s so public making of parallels between the growth of science and children’s conceptual change.
In the 1970s and early 1980s, there was much research published on children’s and adults’ scientific misconceptions.67 Well-attended research conferences on ‘Misconceptions and Education’ were staged (Novak. 1987). R.L. Doran’s, 1972 article ‘Misconceptions of selected science conceptions held by elementary school students’ (Doran, 1972) and James Wandersee’s, 1985 article ‘Can the History of Science Help Science Educators Anticipate Students' Misconceptions?’ (Wandersee, 1985) are representative of the genre.
The noun ‘misconception’ was the then norm. But soon enough, the research field caught up with Kuhnian ‘new philosophy’. John Gilbert and Michael Watts documented how supposed advanced philosophy of science of the time—citing Kuhn, Feyerabend, and Lakatos—had moved ‘from realism to relativism’, and catching up with this move, educators no longer researched misconceptions, but rather researched alternative conceptions (Gilbert & Watts, 1983). This was not merely a change of vocabulary; it was a serious epistemological reorientation.
This move, ultimately, had great consequence in arguments over appropriate multicultural and indigenous education. For these researchers, some groups and cultures do not have misconceptions about COVID infection, the healing power of crystals, the use of divining rods, or the efficacy of prayer in treatment of malaria: they just have alternative conceptions. If it is a misconception, then there is some inherent educational ground for correcting it, difficult though it might be. If it is an alternative conception, then there is no particular educational ground for correction. An alternative is not wrong; it is just an alternative, much like a music preference.
As an anthropological and cultural fact, there are millions of alternative conceptions. Some held by whole societies, and others held just by small, down to family-sized groups. The crucial philosophical and educational question is when, and where, to label some as misconceptions and endeavour to rectify them. Not all alternative conceptions need be corrected. They can be left as misconceptions if they do no personal or cultural harm, but not so left in a science class when they are at odds with enabling children to understand how the world has been shown to work. If pupils are to understand the aetiology and transmission of COVID, the teachers cannot be relaxed and indifferent to their misconceptions.
A very influential article in the programme was George Posner and colleagues’ ‘Accommodation of a Scientific Conception: Toward a Theory of Conceptual Change’ (Posner et al., 1982).68 It is explicitly based on Kuhn’s analysis of paradigm change in science. One of the authors of that study noted this dependence and itemised how Kuhn’s analysis of scientific change was transferred to the study of individual conceptual change (Hewson, 1981, p.387). The authors proposed that, for individual conceptual change, or learning to take place, four conditions had to be met:There must be dissatisfaction with current conceptions.
The proposed replacement conception must be intelligible.
The new conception must be initially plausible.
The new conception must offer solutions to old problems and to novel ones; it must suggest the possibility of a fruitful research programme.
Hewson, in his elaboration, says:Provided that due consideration is given to discussion of the metaphysical and epistemological ideals underlying modern science, the teaching of the current conceptions need not be viewed as indoctrination, because the basis for a rational justification is available. (Hewson, 1981, p.395)
Clearly, discussion of the ‘metaphysical and epistemological ideals underlying modern science’ requires the rudiments of history and philosophy of science. But, how can such ideals be discussed without knowledge of HPS? The shame is that, internationally, science teacher education, and research, carries on with little, if any, input from HPS.69
Strike and Posner, in retrospect, describe their original conceptual change theory as ‘largely an epistemological theory, not a psychological theory... it is rooted in a conception of the kinds of things that count as good reasons’ (Strike & Posner, 1992, p.150). They say that their original theory is concerned with the ‘formation of rational belief’ (p.152); it does not ‘describe the typical workings of student minds or any laws of learning’ (p.155). They focus on learning where there is good reason for coming to hold the belief. This is an echo of Piaget’s distinction between epistemic and psychological subjects.
Despite their explicit entreaty, much conceptual change research, or research on the learning of science, which followed Posner and Strike’s paper was poorly, or not at all, informed by philosophy.70 Where epistemology is mentioned, it is commonly taken to be ‘personal epistemology’, that is, investigations of what learners thought knowledge was. So, one much-cited book was titled Personal Epistemology: The Psychology of Beliefs About Knowledge and Knowing (Hofer & Pintrich, 2002). This detour from philosophy into psychology is hardly surprising as philosophy is not part of science teacher education and is rarely part of graduate programmes in education.71 Educational research did not, and more seriously could not, engage with what might constitute rational conceptual change, or believing with good as distinct from bad reason: philosophical competence, or at least interest, was needed to identify such change.
Cleavage Between Epistemology and Psychology
With the exception of the Piagetian tradition,72 and some cognitive psychologists,73 there was a deep cleavage between epistemology and psychology in educational research. This is evidenced in the title of an article: ‘Psychology and Epistemology: Match or Mismatch When Applied to Science Education?’ (Duschl et al., 1992). For example, the study by educators of knowledge acquisition has largely been the study of changing beliefs: Supposedly, if beliefs develop, then knowledge grows. Psychologists and educational researchers are indifferent to the distinction between knowledge and belief: whether beliefs are true or false, whether they are held for good or bad reasons, whether any change of belief is rational or irrational, and so on down a standard philosophers’ list of epistemological queries. The better learning by heart of the Bible, the Koran, mathematical tables, or a science textbook constitutes, for psychologists, knowledge growth. This was manifested during the regime of behaviourist psychology, and the neutrality principle has not been discarded in the successor regime of cognitive psychology. This epistemically indifference route in psychology is the same as constructivists advocate for sociology and anthropology. For Berger and Luckmann:… the sociology of knowledge must concern itself with whatever passes for ‘knowledge’ in a society, regardless of the ultimate validity or invalidity (by whatever criteria) of such ‘knowledge’. … we contend that the sociology of knowledge is concerned with the analysis of the social construction of reality. (Berger & Luckmann, 1966, p.15)
The cleavage of epistemology from psychology was front-of-stage for the long-entrenched behaviourist tradition in educational psychology. Ernest Hilgard and Gordon Bower, in their much-reprinted textbook, write:Learning is the process by which an activity originates or is changed through reacting to an encountered situation, provided that the characteristics of the change in activity cannot be explained on the basis of native response tendencies, maturation, or temporary states of the organism (e.g. fatigue, drugs, etc.). (Hilgard & Bower, 1966, p.2)
The study of learning makes no contact with reason, justification, evidence, rationality, or any other such epistemological consideration. Such an account of learning flowed easily into accounts of teaching which was also seen as a ‘philosophy-free zone’. So, as described in a major 1973 NSSE Yearbook:Teacher education programs may be conceptualized as behavior modification systems designed to modify complex behavioral repertoires which are adaptable to a variety of learning problems. (McDonald, 1973, p.41)
It was not psychologists, but philosophers, who called out the inadequacy, and inaccuracy, of such truncated and miserable understanding of teaching and learning. Israel Scheffler, Kuhn’s Harvard colleague and critic, wrote:Teaching ….is clearly not, as the behaviourists would have it, a matter of the teacher’s shaping the student’s behaviour or of controlling his mind. It is a matter of passing on those traditions of principled thought and action which define the rational life for teacher as well as pupil. (Scheffler, 1967, p.133)
And Richard Peters, a psychologist turned philosopher and co-founder with Israel Scheffler of analytic philosophy of education,74 wrote:Teaching is a complex activity which unites together processes, such as instructing and training by the overall intention of getting pupils not only to acquire knowledge, skills and modes of conduct, but to acquire them in a manner which involves understanding and evaluation of the rationale underlying them. (Peters, 1966, p.261)
These more sophisticated and, frankly, more intelligent accounts of teaching and learning arise from philosophy of education. This once important and valued component of teacher education has, unfortunately, now all but disappeared throughout the world.75 Sadly, too many teachers, curriculum writers, and administrators just stumble around without philosophical direction. And in the worst case, they take direction from the last political, ideological, religious, or commercial foot that trod upon, or funded, them. Being ‘employment ready’ is now, mantra like, taken as the educational aim for numerous school and university systems.
Kuhn’s Influence on Education II: Constructivism
Kuhn is front and centre of constructivism which for nearly 40 years has dominated educational research and theorising. Kenneth Tobin says that, in literature published in high-impact journals from mid-1970s to 2005, more than 3000 used ‘constructivism’ in their title or in their associated key words (Tobin, 2007, p.291).76 The reach of constructivism was well captured in the sub-headings of a single article: ‘A constructivist view of learning’, ‘A constructivist view of teaching’, ‘A view of science’, ‘Aims of science education’, ‘A constructivist view of curriculum’, and ‘A constructivist view of curriculum development’ (Bell, 1991). Multiple thousands of constructivist-inspired research articles, and hundreds of books, were published.77 Leading constructivists acknowledge Kuhn as the fount of their relativist and idealist view of science.
Constructivist Philosophy
The metaphysical idealism of Structure, when adopted by educators, had enormous consequences for the goals and justification of science teaching. Kuhnian constructivism informed a great deal of educational policy, pedagogy, curriculum writing, and decision-making. Egon Guba and Yvonna Lincoln, authors of a multi-edition, major education-methodology handbook (Guber & Lincoln, 1989), having 23,000 + citations, embrace Kuhn’s ‘new philosophy’ and say of their handbook that:Chapter 3 develops the paradigm in detail, contrasts its basic belief system with that of positivism, and cites arguments and evidence supporting the rejection of positivism and the acceptance of constructivism in its place. (Routledge website)
With their constructivism comes multi-ontologies and subjectivist and relativist epistemology.
Richard Duschl and Richard Grandy, in the Introduction to an important anthology Teaching Scientific Inquiry, correctly note:What views teachers hold about constructivism will affect not only the content of what they teach and the methods they use, but also what they take as the goals of science teaching. (Duschl & Grandy, 2008, p.23)
David Hawkins (1913–2002), a physicist and educator, spoke for many, when in an article on the history of constructivism, wrote that Kuhn’s Structure ‘provided ‘“constructivist” justification’ for ‘philosophies of relativism and subjectivism’ (Hawkins, 1994, p.10). Joseph Novak, a leading science education researcher, acknowledged Kuhn as instrumental in the development of his own constructivist epistemology that underscores the research programme on children’s alternative conceptions (Novak, 1998, p.6).78 He wrote:In philosophy, a consensus emerges that positivism is neither a valid nor a productive view of epistemology … What is emerging is a constructivist view of epistemology, building on ideas of Kuhn (1962), Toulmin (1972) and others. (Novak, 1977, pp.5-6)
Ernst von Glasersfeld (1917–2010) in the opening sentences of a much-cited paper—‘Cognition, Construction of Knowledge and Teaching’79—points out that Kuhn’s Structure:brought to the awareness of a wider public the professional crisis of faith in objective scientific knowledge. (Glasersfeld, 1989, p.121)
For many science educators, von Glasersfeld was their conduit to Kuhn. His ‘radical constructivism’ blossomed across the science and mathematics education landscapes.80 Andreas Quale’s book is typical of the genre: Radical Constructivism: A Relativist Epistemic Approach to Science Education (Quale, 2008). For Glasersfeld, ‘Truth in constructivism, as I keep repeating, is replaced by viability’ (Glasersfeld, 1993, p.25).81 Little, if any, attention was paid to philosophical criticisms of the position. The criticisms mirrored the criticisms of Kuhn’s Structure made by Shapere, Masterman, Devitt, Shimony, and so many others. The Sydney philosopher, Wallis Suchting, wrote a long, 22-page, careful analysis of von Glasersfeld’s, 1989 paper. He employed the philosopher’s ‘lingering line-by-line method’ of analysis, concluding:First, much of the doctrine known as ‘constructivism’ ... is simply unintelligible. Second, to the extent that it is intelligible ... it is simply confused. Third, there is a complete absence of any argument for whatever positions can be made out. ... In general, far from being what it is claimed to be, namely, the New Age in philosophy of science, an even slightly perceptive ear can detect the familiar voice of a really quite primitive, traditional subjectivistic empiricism with some overtones of diverse provenance like Piaget and Kuhn. (Suchting, 1992, p.247)
Von Glasersfeld did reply (Glasersfeld, 1992), but Suchting’s paper was ignored, while von Glasersfeld was given ‘Plenary Speaker’ status at education conferences and repeatedly cited in research literature, having 20,000 + Google Scholar citations in October 2022.
Duschl and Grandy, in their Scientific Inquiry publication, adopt the familiar distinction between cognitive constructivism and metaphysical constructivism, recognising that ‘both … trace back to the work of Kuhn’ (Duschl & Grandy, 2008, p.24). The former, in brief, is a psychological theory about learning, concept acquisition, and change of belief. The latter, also in brief, is a philosophical theory (ontological idealism) about the furniture of the world; namely, things are created by either individuals or groups. Duschl and Grandy repeat the comfortable, non-disruptive view that debate about metaphysical constructivism is:irrelevant for science education once we understand fully the implications of cognitive constructivism. (Duschl & Grandy, 2008, p.25)
The comfort is deceptive. Many influential educators reject realism and affirm idealism. When this is spelt out, their position is not so comforting. John Staver (1944–2022), a prominent science educator, affirmed:…For constructivists, observations, objects, events, data, laws, and theory do not exist independently of observers. The lawful and certain nature of natural phenomena are properties of us, those who describe, not of nature, that is described. (Staver, 1998, p.503)
That observations and theory do not exist apart from agents is a truism, but the ontological status of events and objects is a different matter. This should be obvious. To run them together requires additional argument.
Rosalind Driver (1941–1997), an influential science educator and constructivist, claimed:science as public knowledge is not so much a “discovery” as a carefully checked “construction” … and that scientists construct theoretical entities (magnetic fields, genes, electron orbitals …) which in turn take on a “reality” (Driver, 1988, p.137).
For her, and all the other metaphysical constructivists, the Earth does not have a structure until geophysicists impose it; there is no natural selection in the animal world until Darwinian biologists impose it; atoms have no structure until physicists propose one; DNA was not a double helix until it was found to be such; Neptune did not exist, and thus could not have influenced the motion of Uranus, until John Galle, guided by the calculations of Le Verrier, observed it; and so on. One might ask: If gravity waves are our own creation, why spend so much time and money looking for them?
Driver’s basic argument form is common:
Premiss Concept X is a human construction.
Conclusion Therefore, the referent of X does not exist.
One only has to state this argument to see that it is an invalid inference, and its validity depends upon making explicit a suppressed premiss:
Suppressed premiss All concepts that are human constructions can have no existential reference.
But this suppressed premiss is simply philosophical dogma for which no evidence is provided. Not only are ‘electron orbitals’ and ‘magnetic fields’ human constructions, but so also are ‘my house’, ‘that mountain’, ‘this table’, and all the other observational terms we use. If the foregoing widespread constructivist argument were valid, then not only would electron orbitals not independently exist, neither would our house, the tables in it, nor mountains that we might live near. Indeed, given that the personal pronoun ‘I’ is a human construction, individual cognising subjects might not exist.
These considerations are not ‘philosophical quibbles’ that can be put aside while the business of teaching and learning science proceeds. They are matters with which students should, in ways appropriate to their ages, engage. This will contribute to social well-being. A great deal hinged on whether the SARS-CoV-2 virus does actually exist, independently of anyone recognising it, so also its mutant Alpha, Beta, Gamma, Delta, and Omicron variants. The conjunction of ontological idealism and epistemological relativism provides succor to denialisms of all kinds and props up the minority non-scientific responses to the COVID pandemic (McIntyre, 2019). When a student, or citizen, asks: ‘Does the virus exist, and should money be spent looking for it?’ realists can give a straight answer: ‘we think it exists and money should be spent looking’. Idealists must give a more complicated answer, one that can only diminish trust in science.
The fact that theories and their posits are humanly constructed (this is, after all, tautological), and that natural objects are considered in science only in their theoretical dress—apples as point masses in physics, as exchange values in economics, as calories in biochemistry, as rewards in psychology, or metaphors in art history—does not imply that there are no apples, that real objects are human creations, or that the real objects have no part in the appraisal of the scientific worth of the conceptual structures brought to bear upon them. Realism is consistent with there being no privileged description; the adequacy of the propositional description is bound to the adequacy of the theory providing it. Different disciplines have different languages, lexical structures, and vocabularies, for describing the same thing. Realism recognises a difference between real objects and theorised objects.
Constructivist Pedagogy
As well as educational theorising, Kuhnianism informed pedagogical practice. Derek Hodson, a prominent New Zealand, then Canadian, science educator made a direct link between Kuhn and constructivist pedagogy:It has been argued earlier that Kuhnian models of science and scientific practice have a direct equivalent in psychology in the constructivist theories of learning. There is, therefore, a strong case for constructing curriculum along Kuhnian lines. (Hodson, 1988, p.32)
The connection to curriculum is not as direct as Hodson writes; indeed the link is orthogonal. But the link to pedagogy was easy because much of the teacher-training establishment adopted the principle that ‘science should be taught as it is practised’. This was an old principle that had its origins in John Dewey’s distinction between science as subject matter and as method, and his conviction that the latter needs be taught by being practised (Dewey, 1910/1995). And taught not just for the sake of science, but for the health of culture and society. Beginning in the 1980s, advocates of this tradition spoke of ‘the pupil as scientist’.82 The Deweyan conviction underwrote internationally ubiquitous ‘Science as Inquiry’ programmes.83
It was a misfortune that advocates looked at science as it was practised, not at the training and formation that was required for scientists to engage in scientific practice. To be a musician, or a good player of sport, requires the repetitive practise of a great amount of tedious, low-level skills. The learner of any intellectual or practical craft needs to see exemplary practice, be shown the best, hopefully be motivated by it, but also understand what effort goes into achieving the performance. Conant’s Harvard case studies performed precisely this role.84 Kuhn, as will be indicated, fully appreciated this. Many of his education readers appreciated it less fully.
Nancy Davis and colleagues, and indeed many others, make a direct, but mistaken, link between Kuhn’s theory of science and pedagogy. They write that they used ‘Thomas Kuhn’s (1970a)work as a basis to support change in guiding epistemological paradigms’, whereby they endorse constructivism and reject objectivism (Davis et al., 1993, p.627). They then move easily from constructivist epistemology to constructivist pedagogy:From a constructivist perspective, the individual learner has a primary role in determining what will be learned. Emphasis is placed on providing students with opportunities to develop skills and knowledge which they can connect with prior knowledge and future utility. … The learner decides with others what learning is important to him or her and means of learning are explored. While working with others, the student solves problems and examines solutions. This view of curriculum is closer to the actual work of scientists. (Davis et al., 1993, p. 629)
No practising scientist, and certainly not Kuhn, could identify any of this in their own formation as scientists. Notwithstanding, constructivism was adopted as the official education theory in numerous provinces, states, and countries. In the USA:… the current teaching standards in the USA call for teachers to embrace a social constructivist view of learning and teaching in which science is described as a way of knowing about natural phenomena and science teaching as facilitation of student learning through science inquiry … In particular, the reform emphasizes teacher education by promoting social constructivist teaching approaches … These sophisticated epistemological perspectives are promoted in the US science education reform documents as both learning goals and teaching approaches. (Kang, 2008, pp. 478, 480).
Jerome Bruner (1915–2016), who was a Harvard colleague of Kuhn (professor of psychology 1945–1972), when speaking of his famous Process of Education (Bruner, 1960) that presented a constructivist alternative to didactic, transmissionist, behaviourist-informed ‘banking’ pedagogy, wrote:Its ideas sprang from epistemology and the sciences of knowing … all of us were, I think, responding to the same “epistemic” malaise, the doubts about the nature of knowing that had come first out of the revolution in physics and then been formalized and amplified by philosophy. (Bruner, 1983, p.186)
For Bruner, it might have been his colleague, Kuhn, who amplified the purported ‘epistemic malaise’ of modern times.
The early twentieth-century revolution in physics understandably fuelled a range of philosophical responses. Some are productive, others are unproductive and misguided. Not all philosophers were moved by the revolution to ‘formalized doubts about the nature of knowing’. Among the best philosophers, the revolution prompted epistemological refinement, not scepticism. This was documented in the 1930s by Susan Stebbing (Stebbing, 1937/1958) and subsequently by philosopher-physicists such as Abner Shimony (Shimony, 1963/1993), Mario Bunge (Bunge, 1967b, 1979/2001), and many others. Mario Bunge, in discussing Einstein’s two relativity theories, observed:In sum, the two relativities, just like classical mechanics, electrodynamics, and thermodynamics before them, and the quantum theory shortly thereafter, have given rise to a number of ontological and epistemological problems. Whereas some of these are legitimate and still worth discussing, others are pseudo problems generated by the attempt to cast science into an inadequate philosophical mould. Moral: Any mismatch between science and philosophy is bound to harm both. (Bunge, 1979/2001, p.243)
Pedagogical Tension
There was a tension, seldom addressed, between the liberal, humanistic science education of Conant and Kuhn’s General Education case studies programme, and the dogmatic, unquestioning science education that Kuhn identifies as required for the practice of normal science. Indeed, for Kuhn, such ‘closed minded’ education was a sign that proto-science or pre-science was finally progressing along the normal science trajectory and so preparing the scientific community to identify an anomaly and deal with a crisis. It is resolution of the latter that precipitates scientific revolutions. If there is a multitude of diverse scientific beliefs, then there is no paradigm, and there cannot be a crisis. Anomalies can only be recognised against a detailed, established, ‘taken for granted’ background. Something forged in science classrooms.
Kuhn, notoriously in many quarters, described normal scientists as conservative, uncreative, closed-minded, and dogmatic. Their education made them this way. And it had to so make them. Many have said that Kuhn is describing not the cut and thrust of normal science but sub-normal science. His 1959 address ‘The Essential Tension’ (Kuhn, 1959a) was his first substantial discussion of the characteristics of effective pedagogy and the cognitive mechanisms involved in learning scientific concepts. His linkage of normal science to distinctive, authoritative science pedagogy is further laid out in an essay, ‘The Function of Dogma in Scientific Research’ (Kuhn, 1963) that was presented at a 1961 conference organised by A.C. Crombie. Kuhn noted:Yet even a cursory inspection of scientific pedagogy suggests that it is far more likely to induce professional rigidity than education in other fields, excepting, perhaps, systematic theology. (Kuhn, 1963, p.350)
In summary:… scientific education remains a relatively dogmatic initiation into a pre-established problem-solving tradition that the student is neither invited nor equipped to evaluate. (Kuhn, 1963, p.351)
Educators, and others, saw Kuhn’s eye-catching scientific revolutions, paradigm changes, incommensurability, rejection of truth, and other such putative features of science. Passed over was his account of grinding normal science and the tunnel-visioned pedagogical requirements for its practice. For many, he has been identified with progressive, student-centred, inquiry-based teaching (Matthews, 2021b). This is an association from which he would run.
Kuhn’s little-known 1990 essay ‘On Learning Physics’ (Kuhn, 1990) is a careful and valuable contribution to the science of learning. 85 It gives due recognition to science teachers in the communicating, embedding, and development of science:The vocabulary in which the phenomena of a field like mechanics are described and explained is itself a historical product, developed over time, and repeatedly transmitted, in its then-current state, from one generation to its successor. (Kuhn, 1990/2000 p.11)
For Kuhn, if a society wants, or needs, normal science to be conducted, then it requires a rigid science education. Other systems, worldviews, and understandings can be taught, but not as science and not in the science programme. The conceptual apparatus of science needs to be internalised. Much of this needs to be done ‘on faith’ as school laboratories and equipment are never ideal, and they fall well short of clinical standards. Friction, impurities, and everything else will always be present. Balls do not fall as they should, current does not flow in the quantity it should, pendulums do not swing as they should, and tall plants do not occur in Mendelian ratios. Hanne Andersen noted:Kuhn’s early interest in science education centers around two claims: (1) the empirical claim that science education as it actually takes place does lead to convergent thought, and (2) the normative claim that the development of convergent thought through rigorous training is necessary for the progress of science. (Andersen, 2000, p.91)
This is at stark odds with the pedagogical constructivism so often associated with Kuhn’s name. The abject failure of unguided inquiry, and discovery teaching and learning, is especially well documented in mathematics, but also in science programmes. This pedagogy is oft-referred to as ‘inquiry’, ‘discovery’, ‘problem-based’, ‘student-centred’, ‘open classroom’, ‘open-ended’, ‘real-world’, and other such synonyms.86
A Case Study
Ken Tobin is a noteworthy example of Kuhnian impact on education. He is one of the most influential, highly awarded, and most-cited researchers in science education.87 Appraising the impact of Kuhn on so substantial a researcher provides an informative case study from which to draw some wider conclusions about Kuhn’s impact on science education. As for so many others, Ernst von Glasersfeld was Tobin’s self-acknowledged conduit to Kuhn (Tobin, 2007, p.292). Tobin acknowledged, and then dismissed, Suchting’s critique of von Glasersfeld writing:Too often the critiques [by philosophers] were based on analyses of the use of single words and sentences from one text … word-by-word and line-by-line analyses were not convincing when the [constructivist] authors regarded the meaning as constituted in entire texts or collections of texts. (Tobin, 2000, p.242)
The comment is noteworthy because it so clearly displays a disciplinary difference between philosophy and science education: philosophers were schooled to be attentive to, not impatient with, clarity and consistency. In 1991, after his embrace of, or in Kuhn’s term ‘conversion’ to, constructivism Tobin cautioned:To become a constructivist is to use constructivism as a referent for thoughts and actions. That is to say when thinking or acting, beliefs associated with constructivism assume a higher value than other beliefs. For a variety of reasons, the process is not easy. (Tobin, 1991, p.1)
This is a big claim calling out for elaboration: What parcel of beliefs, policies or practices can be trumped by constructivist commitment? On the face of it, everything. A year later, Tobin, with a co-author, wrote:… constructivist epistemology asserts that the only tools available to a knower are the senses. It is only through seeing, hearing, touching, smelling, and tasting that an individual interacts with the environment. With these messages from the senses the individual builds a picture of the world. Therefore, constructivism asserts that knowledge resides in individuals. (Lorsbach & Tobin, 1992, p.5)
This is, of course, pure empiricism; it is almost a caricature of individualist, subjectivist, looking-out-at-the-world-and-acquiring-knowledge empiricism. But because HPS was not part of education programmes, this similarity between constructivism and its self-proclaimed foe was little noticed.88 To their credit, social constructivists, who took their lead from Lev Vygotsky, did urge the inclusion of society, culture, language, dialogue, and interactions with others, to be added to the sources of an individual’s knowledge. For social constructivists, knowledge did not result merely from individuals walking around, looking at the world and having sense impressions.89
In the Introduction to his AAAS-sponsored and published anthology, The Practice of Constructivism in Science Education, Tobin utilised, as did millions of others, Kuhnian imagery to announce:there is a paradigm war waging in education. Evidence of conflict is seen in nearly every facet of educational practice. … [but] there is evidence of widespread acceptance of alternatives to objectivism, one of which is constructivism. (Tobin, 1993, p. ix)
An itemised deficiency of objectivism is that: ‘it seeks to identify causal relationships among salient variables’ (ibid). For many, of course, it is indeed the aim of education research.
Tobin did, early on, recognise one problem with embracing ‘Kuhnian’ philosophy, namely, its soft-focused, undisciplined, ambiguous formulation. These ills were not just Kuhnian, but they were, to a degree, there in Kuhn’s own writing. In Tobin and Deborah Tippins’ words:As we have thought about constructivism, we have come to realize that it is not a unitary construct. Every day we learn something new about constructivism. Like the bird in flight, it has an elusive elegance that remains just beyond our grasp. (Tobin & Tippins, 1993, p. 20)
The imagery is poetic, but how anything that remains permanently ‘beyond our grasp’ can be a useful learning, teaching, or curricular theory in education, or give philosophical guidance in epistemology, ontology, or methodology, is not explained. But, like the bird in flight to nowhere in particular, Tobin pushed on with his advocacy and 22 years later announced his refined position:In contrast to the mainstream of research in science education, I advocate a multilogical methodology that embraces incommensurability, polysemia, subjectivity, and polyphonia as a means of preserving the integrity and potential of knowledge systems to generate and maintain disparate perspectives, outcomes, and implications for practice. In such a multilogical model, power discourses such as Western medicine carry no greater weight than complementary knowledge systems that may have been marginalized in a social world in which monosemia is dominant. (Tobin, 2015a, p.1)
He explains polysemia as: ‘many meaning systems, hence truths’. And elsewhere:Polysemia is a powerful construct that acknowledges people’s social positioning in the world as primary frames for what is regarded as socially true. Having accepted a polysemic stance it behooves us not to judge from outside a framework, but to endeavour to step inside to understand what is happening … that is, to adopt an emic perspective. (Tobin, 2015b, p.4)
This is the most common interpretation of Kuhn’s philosophy. Tobin not only adopts polysemia and polyphonia, but also polyontology:However, since we accept poly-ontology (i.e., the co-occurrence of multiple realities/many ways to answer the question: What happened?), we acknowledge that the frameworks we use, with and without awareness, illuminate and obscure what we experience as researchers. That is, our research frameworks are subjectivities that orientate and inform, but are not unique and should not be privileged to justify inequalities and social harms. (Tobin, 2015a, p.3)
Although it sounds pollyanna-ish, it is a faithful Kuhnian echo. Polyontology prepares the ground for a philosophically seamless segue into Tobin’s, website-announced, current occupations:Tobin began formal studies of Jin Shin Jyutsu in 2014 and continues to learn through practice of the art of JSJ, undertaking research on use of JSJ and disease such as diabetes 2, and participation in classes offered by Jin Shin Jyutsu (Scottsdale, AZ). As part of his focus on different complementary modalities, Tobin also has studied Integrated Iridology with Toni Miller. Presently he uses both JSJ and iridology in ongoing studies of wellness, mindfulness, and more broadly, contemplative inquiry.90
Many Kuhn-influenced science educators had taken the same path. Wolff-Michael Roth, a major figure having 47,000 + Google Scholar citations, and a Tobin collaborator, wrote in a co-authored piece:What remains here is the question how to de-privilege science in education and to free our children from the “regime of truth” that prevents them from learning to apply the current cornucopia of simultaneous but different forms of human knowledge with the aim to solve the problems they encounter today and tomorrow. (Van Eijck & Roth, 2007, p.944)
This ‘research programme’ transition can be tied to Kuhn who, in his ‘Afterwords’ contribution, wrote:The fact that experience within another form of life another time, place, or culture might have constituted knowledge differently is irrelevant to its status as knowledge. (Kuhn, 1993, p.332)
So, there can be alternative, stand-alone knowledge systems such as JSJ, Iridology, Q-Anon, Feng Shui, and whatever else might appear on the scene. The epistemic status of one system has no bearing on the others; they are not competitive; they merely co-exist, and, for some, cannot even be compared. And this is just what Tobin is committed to in with his ‘multilogical’ methodology whose very purpose is to maintain disparate perspectives, not to compare or adjudicate between them. This is fine, provided nothing serious is at stake. But when there is national research money to allocate, science curricula to write, hospitals and doctors to fund, COVID viruses to find, then comparative judgement is required, and the separation of genuine from bogus science is required.
Kuhn’s Influence on Education III: Science-Technology-Society (STS) Studies
Kuhn had an impact on Science and Technology Studies (STS) and, as a flow-on, on the new field of Cultural Studies of Science. Since at least Robert Merton and John Bernal in the 1930s (Bernal, 1939; Merton, 1938/1973), there have been comprehensive social studies of science. Since the 1960s, STS has been institutionalised.91
Naomi Oreskes,92 an historian and philosopher, surveyed Kuhn’s work and gave a very constrained account of his contribution to HPS:Scholars generally agree that the largest impact of Kuhn’s work – besides adding the term paradigm shift to the general lexicon – was in helping to launch the field of science studies. (Oreskes, 2020, p.66)
She is correct. Structure was the basic text in the Edinburgh course titled ‘A Philosophical Approach to Science’. It speaks volumes that the text of a self-confessed ‘amateur’ in philosophy, who had never learnt the subject, was chosen in Edinburgh as the way to give students a philosophical understanding of science. Barry Barnes, a co-founder of the Strong Programme, wrote in 1982:Kuhn has made one of the few fundamental contributions to the sociology of knowledge. It fell to him to provide, at the time it was most needed in the 1960s, a clear indication of how our own forms of natural knowledge could be understood sociologically. This encouraged the empirical studies of scientific culture. (Barnes, 1982, p.x)
Not long after Kuhn’s death in 1996, Clifford Geertz, the preeminent US social anthropologist, stated that Kuhn’s Structure ‘opened the door to the eruption of the sociology of knowledge’ into the study of science (Weinberg, 1998). This is not disputed.
Three STS scholars acknowledged Kuhn as the founder of their discipline and went on to say in their Editorial Introduction to an STS anthology:In the wake of STS research, philosophical words such as truth, rationality, objectivity, and even method are increasingly placed in scare quotes when referring to science – not only by STS practitioners, but also by scientists themselves and the public at large. (Brante et al., 1993, p.ix)
Recurrent Idealism
Kuhn never renounced his anti-realism, he held on to youthful Kantian notions of investigators creating the world, and scientists who worked in different paradigms (later those utilising different lexical structures) lived in different worlds. This ontological idealism flowed through to STS studies. This is on plain view in the classic Laboratory Life (Latour & Woolgar, 1986).93 Latour had earlier claimed that nothing extraordinary, indeed nothing ‘scientific’, was happening in research laboratories (Latour, 1983, p.141). In Laboratory Life, the authors conclude of science, after Latour’s two years of field work in Roger Guillemin’s laboratory in the Salk Institute, that:Each text, laboratory, author and discipline strives to establish a world in which its own interpretation is made more likely by virtue of the increasing number of people from whom it extracts compliance. (Latour & Woolgar, 1986, p.285)
And further:The “out-there-ness” [of the external world] is the consequence of scientific work rather than its cause … science is a form of fiction or discourse like any other, one effect of which is the ‘truth effect’, which (like all literary effects) arises from textual characteristics. (Latour & Woolgar, 1986, pp.182, 184)
As with so many Kuhn-influenced scholars, they were seriously idealist and avowedly anti-realist. It was human discourse, language, which brought the ‘thing’ into existence:the thing and the statement correspond for the simple reason that they come from the same source. Their separation is the final stage in the process of their construction. (Latour & Woolgar, 1986, p.183)
In case the idealism was not fully grasped, Woolgar subsequently wrote:There is no sense in which we can claim that the phenomenon … has an existence independent of its means of expression … There is no object beyond discourse … the organisation of discourse is the object. Facts and objects in the world are inescapably textual constructions. (Woolgar, 1988, p.73)
David Bloor had the good sense to describe Latour’s procedure as ‘obscurantism raised to the level of a general methodological principle’ (Bloor, 1999, p.97). Unfortunately, science educators did not share Bloor’s opinion. Peter Fensham, in his landmark study of the formation of leading science education researchers, reports: ‘One book stood out as an influence about the culture of science and that was Latour and Woolgar’s Laboratory Life: The construction of scientific facts’ (Fensham, 2004, p.58).
STS programmes were widely promoted as a way of making science teaching contextual, meaningful, and avoiding the dogmatism, abstractness, and personal irrelevance of orthodox, disciplinary science courses. Surveying UK education in the time since Snow’s ‘Two Cultures’, David Edge observed:The pedagogical context created by such moves gave considerable scope for the incorporation of STS scholarship (especially the humanistic insights of SSK and its derivatives) into the syllabuses of budding scientists and technologists. (Edge, 1994, p.9)
Harry Collins, a leader of the sociology of science programme that claimed Kuhn as its founder, wrote a paper on ‘Stages in the Empirical Programme of Relativism’ in which he made the head-turning claim that: ‘ … the natural world has a small or non-existent role in the construction of scientific knowledge’ (Collins, 1981, p.3). And a few years later:It is not the regularity of the world that imposes itself on our senses, but the regularity of our institutions and beliefs that imposes itself on the world. (Collins, 1985, p.148)
So, it is not just nature that goes missing in the creation of science but, seemingly, the individual researcher who functions merely as a conduit for different social regularities that impose themselves on our knowledge of the world. Or in Marxist historiography, as a conduit for class divisions.94 If taken literally and seriously, Collins’ position re-directs the search for, and understanding of, laws of nature and causal relations: We do not look outside at the world; we look inside at our belief systems or around us at our social structures. Of course, this has to be done, as Bacon long ago advised when detailing his ‘Idols of the Mind’,95 but at some point, the world has to be looked at, measured, experimented upon, taken into account.96
The same influences were at play in the USA, Canada, Europe, Australia, and New Zealand.97 The NSTA yearbooks of 1984 (Bybee et al., 1984) and 1985 (Bybee, 1985) deal with the rationale and content of such STS school programmes. The NSTA publication The Science, Technology, Society Movement (Yager, 1993) reviewed their implementation. The US National Science Teachers Association (NSTA) endorsed the STS orientation to science in its 1971 statement School Science Education for the 1970s (NSTA, 1971). This view was repeated in its 1984 and 1985 yearbooks. All of this sounds good and progressive. But, of course, a great deal of the good, if not the entire deal, hinges on what is taught as the ‘humanistic insights of SSK’. That is, how accurate is the sociology of scientific knowledge (SSK) account of the nature, methods, and status of scientific knowledge?
Glen Aikenhead, a leading Canadian science educator, summed up STS scholarship when he informed readers that contemporary social studies of science reveal science as:mechanistic, materialist, reductionist, empirical, rational, decontextualized, mathematically idealized, communal, ideological, masculine, elitist, competitive, exploitive, impersonal, and violent. (Aikenhead, 1997, p.220)
As with nearly all prominent science educators, Aikenhead acknowledges Kuhn’s formative influence on him:Thomas Kuhn’s Structure of Scientific Revolutions is one of the few books I’ve reread several times … It was extremely helpful in my thinking with all sorts of implications for teacher education and everything I did. (In Fensham, 2004, p.56)
Considering the supposed findings of STS, science should not be taught in schools. But before banishing science, the first task is to unpack and then appraise Aikenhead’s claims, and the comparable claims of so many other SSK proponents. But this requires that science teachers, administrators, and curriculum writers have some grasp of HPS. What science is being described? Where? When? At different times and places, all of these ills have been manifested in science as practised: Maoist science, Nazi science, Soviet science, Islamic science, military-industrial-complex science, Christian science, Feng Shui science, Vedic science, and creation science. The list can go on. Whether indigenous science should be added to the list is a much debated and very consequential question.98 There has been consistent effort to show that these are inadequate and failed, if not corrupt, sciences. Aikenhead’s proffered summary of HPS scholarship if off the mark.
HPS-informed teachers, administrators, and curriculum writers can strive for putting the best of science, and its history, into school programmes while also point to corruptions, detours, and pseudosciences. Examples can be given and fleshed out. The importance of such HPS competence is manifested in an Editorial published in a 2022 issue of The Journal of Science Teacher Education. The editorial was titled: ‘Challenging the Hegemony of Western Scientism in Science Teacher Education’ (Melville et al., 2022). The editorial was to be: ‘both a mea culpa and a call to recognize and challenge the hegemony of Western scientism in the science education literature’. Readers are warned: ‘the power of scientism is often just below the surface, ready to reassert itself in our lives’ (ibid., p.706). A prerequisite for any intelligent engagement in this question is some knowledge of HPS, minimally the ability to separate scientism from pseudoscientism.
Scientism began with Newton who proposed extending the methods of natural philosophy to the subject matter of the moral sciences. This was the core programme of the Enlightenment. Contrary to the impression given in the editorial, many philosophers have extended and defended that core programme.99 They are not mentioned in the editorial, rather readers are advised: ‘we can all renegotiate our identities in relation to scientism’ (Melville et al., 2022, p.707). This is another missed opportunity for promotion of HPS in science education. Without solid HPS training, teachers are just moved by faddism, in this case about what scientism is and is not.
Peter Fensham documented how the bulk of science educators have zero formal training in philosophy, psychology, sociology, or history—the education foundations subjects—yet have to teach courses related to those fields.100 His conclusion is sobering:science educators borrow psychological theories of learning … for example Bruner, Gagne and Piaget …The influence of these borrowings is better described as the lifting of slogan-like ideas. (Fensham, 2004, p.105)
The sorry picture applies even more to philosophical theories. There, educators are even more susceptible to faddish views and the lifting of slogans.
Kuhn’s Influence on Education IV: Cultural Studies of Science
Just as Kuhn-influenced STS studies found a home in education, so too did Kuhn-influenced cultural studies of science find a home.101 In the early 1990s, the journal Science as Culture was published in order to provide ‘research space’ for anthropological studies of science of the kind promoted by the Edinburgh ‘Strong Programme’ and exemplified in Bruno Latour and Steve Woolgar’s above-mentioned Laboratory Life (Latour & Woolgar, 1979). Just as the anthropology of religion is not concerned with the truth or falsity of religious claims, or even the strength or weakness of specific religious arguments, so too this approach to studying science was consciously ‘truth neutral’; it was to be ‘naturalistic’, meaning that truth, better evidence, or good warrant could not be appealed to as the explanation of scientific consensus, much less scientific progress. Claims were not believed because they were true, or positions adopted because there were epistemically good reasons for so doing. It was external pressures or, at best, personal interests that shaped, powered, or caused belief and change of belief.
Pierre Bourdieu (1930–2002), a French philosopher and sociologist of education, utilised this naturalistic methodology in appraising the philosophical, historical, and sociological arguments occasioned by Structure:The reactions provoked by Thomas Kuhn’s book, The Structure of Scientific Revolutions, show this very clearly, and would provide high-quality experimental material for an empirical analysis of the ideologies of science and their relationship with their authors’ positions in the scientific field. (Bourdieu, 1999, p.44)
There are not ‘better’ arguments, just more compelling personal and social pressures.
Many adopted this position. David Bloor titled one article: ‘The Sociology of Reasons: Or Why “Epistemic Factors” are really “Social Factors”’ (Bloor, 1984, pp.295–324). Steven Shapin proposed a thorough-going sociological account of the history of science (Shapin, 1982). The research avenues and questions for the new field were sign-posted in the 15-chapter landmark anthology Science as Practice and Culture edited by Andrew Pickering, a founder of the discipline (Pickering, 1992).
The Pickering anthology appeared the same year that the journal Science & Education: Contributions from History and Philosophy of Science was launched. The first editorial of this journal stressed the need for clear communication and the avoidance of jargon in scholarly writing. As if to show the relevance of the editorial, three years later, Pickering published a book, The Mangle of Practice: Time, Agency and Science (Pickering, 1995). This contained many challenging sentences, including the following:The dance of agency, seen asymmetrically from the human end, thus takes the form of a dialectic of resistance and accommodation, where resistance denotes the failure to achieve an intended capture of agency in practice, and accommodation an active human strategy of response to resistance, which can include revisions to goals and intentions as well as to the material form of the machine in question and to the human frame of gestures and social relations that surround it. (Pickering, 1995, p.22)
These 80 words constitute more than a purple passage, it is an incomprehensible sentence. The sentence suggests that a better title for the book would have been The Mangle of Language. However, it was a trailblazer, and it set the tone for writing in the new field. If this sentence gets through review, copyediting, and into print, what can be kept out?
In 2006, Kenneth Tobin and Wolff-Michael Roth co-founded the Springer journal Cultural Studies of Science Education. The journal’s first editorial announced:The journal encourages empirical and non-empirical research that explores science and science education as forms of culture … It was anticipated that the forms of dissemination will make visible the non-linearity of doing research and the recursive nature of delineating problems. (Tobin & Roth, 2006, p.1)
From the foundational 2006 editorial, the journal has been home to, one might charitably say, less than clear writing.102
The journal’s founding editors, in the Introduction to an anthology of ‘Sociocultural and Cultural-Historical [Research] Perspectives’, write:If, on the other hand, we begin with the ontological assumption of difference that exists in and for itself, that is, with the recognition that A↓A (e.g., because different ink drops attached to different paper particles at a different moment in time), then all sameness and identity is the result of work that not only sets two things, concepts, or processes equal but also deletes the inherent and unavoidable differences that do in fact exist. This assumption is an insidious part of the phallogocentric epistemology undergirding science as the method of decomposing unitary systems into sets of variables, which never can be more than external, one-sided expressions of a superordinate unit. (Roth & Tobin, 2007, pp.99-100)
Comment is not needed, and could not be made anyway. Except to note that the passage was composed by the two most-cited, and probably most-awarded, researchers in the discipline of science education.103
Earlier Roth had laid out clearly his multi-world, idealist ontology:according to radical constructivism, we live forever in our own, self-constructed worlds; the world cannot ever be described apart from our frames of experience. This understanding is consistent with the view that there are as many worlds as there are knowers. (Roth, 1995, p.13).
And then proceeds:Radical constructivism forces us to abandon the traditional distinction between knowledge and beliefs. This distinction only makes sense within an objective-realist view of the world (Roth, 1995, p.14).
And concludes, for those who could not draw the lesson:Through this research [sociology of science], we have come to realize that scientific rationality and special problem-solving skills are parts of a myth. (Roth, 1995, p.31).
The effect of Kuhn’s idealism is apparent. It is of some note that the claims were published in a book part-titled: Authentic School Science. Is that really the understanding of science that any decent society wants its citizens to have? It is unfortunate that promotion of these claims does local harm in a graduate classroom. But when countries are trying to deal with pandemics, climate change, environmental degradation, and other pressing real issues, promotion of such views does national harm; they consistently erode trust in science and open doors to countless alternatives.
In 2011, two researchers asserted, in a Cultural Studies article, the now disciplinary commonplace:Recent scholarship in science studies [STS] has opened the way for more thoughtful science education discourses that consider critical, historical, political, and sociocultural views of scientific knowledge and practice …. Increased attention to the problematic nature of western science’s claims to objectivity and universal truth has created an educational space where taken-for-granted meanings are increasingly challenged, enriched, and rejected …Thus, science’s long accepted claim to epistemological superiority has now become bound to the consideration of cultural codes, social interests, and economic imperatives. (Bazzul & Sykes, 2011, p.268)
Each sentence is either false or lacks supporting argument. The first completely ignores the 150 + years of HPS scholarship that has richly documented the ‘historical, political and sociocultural views of science’. And this scholarship has, for the same length of time, been utilised in European, UK, and US science education (Matthews, 1994, chaps.4, 5). Consider, for instance, the rich understanding of science displayed in the writings of even the much-maligned archetypical positivists Ernst Mach, Philipp Frank, and Herbert Feigl.104
The authors of a 2020 CSSE paper maintain:we highlight the post-critical curricular perspectives to problematize discursive demands and articulations as part of processes of struggle for the fixation of particular meanings in the field of science education. With emphasis on discourse theory and categories such as discourse, articulation, hegemony and antagonism, we sought to identify hegemonic and counter-hegemonic discourses defended in the struggle for curricular proposals of science education and teacher training in Brazilian scholarship and some international examples. (Rezende & Ostermann, 2020, p.1047)
In case the project was not clear, they followed with a clarifying elaboration:Traditional curricular and teacher-training projects were seen as products of discursive articulations in defence of the universalism of Western Modern Science (knowledge itself) and of the technical rationality. (ibid)
Although the enormously influential, social-constructivist Edinburgh programme was, beginning 30 years ago, convincingly criticised,105 confidence about universal science has been widely diminished. Kuhnianism has been a significant factor in the rise of relativism (all views are equally good) and scepticism (we cannot know anything) concerning knowledge of the natural, social, cultural, and moral worlds (Barnes & Bloor, 1982; McIntyre, 2018, 2019). Such relativism and scepticism are depressingly common in science education.106 To be a sensible fallibilist (there is no perfect, cannot-be-improved knowledge) is not to be a relativist. A point oft not appreciated.
As with many writers, Kuhn is more cited than read. The mere citation of Kuhn is considered to constitute an argument, or to provide evidence, for some philosophical view. Marilyn Fleer, a senior Australian science educator, writes:In recent years, the rational foundations of Western science and the self-perpetuating belief in the scientific method have come into question …. The notion of finding a truth for reality is highly questionable. (Fleer, 1999, p.119)
No evidence is adduced for these sweeping claims; no argument is provided for why ‘finding a truth for reality is highly questionable’. The one piece of supposed evidence is an unpaginated reference to Kuhn.
The practice of having an unpaginated Kuhn reference substitute for evidence, or argument, is widespread in science education. It is almost the disciplinary norm. Merely putting the name ‘Kuhn’ in brackets after some claim is widely regarded as sufficient warrant for making the claim, no matter how outrageous, self-contradictory, or ill-supported it might be. Cathleen Loving and William Cobern, in a study of science education citations of Structure, found, staggeringly and to the disgrace of the discipline, that only 1.5% (144 out of 9715) provided a page reference. The rest were ‘generic’ references, and the Kuhn’s name was good enough (Loving & Cobern, 2000, p.194). Needless to say, those citing Kuhn paid no attention to the published arguments that challenge or refute the claim made on his behalf, even when the claims were refuted by Kuhn himself!
Sal Restivo, a sociologist and former president of the Social Studies of Science Society (4S), identified this, to put it overly kindly, academic malaise:By the early1980s ‘T.S. Kuhn’ had become a cultural resource more or less detached from T.S. Kuhn, his writings, and the social contexts of his arguments. ‘Kuhn’ has served the interests of left, right, and center across the entire spectrum of intellectual discourse. (Restivo, 1994, p.99)
Conclusion
Kuhn deserves credit for taking the history and philosophy of science into the education, academic, and cultural domains. Unfortunately, what went into these public domains was, at best, Kuhn I or ‘radical’ Kuhn, not Kuhn II or ‘mature’ Kuhn. The vehicle for Kuhn I was his monumental 1962/1970 Structure. This had a, so to speak, four-cylinder engine: physics, philosophy of science, history of science, and sociology of science. But, as has been shown, the latter three of these cylinders progressively gave up as Kuhn drove the vehicle down the research road. Many key elements of radical philosophy were, under the weight of criticism, gradually abandoned. But he held on to enough—relativism and idealism—to cause trouble. His revolutionary apparatus for history of science turned out not be used even by himself in his major historical study on the early twentieth-century quantum revolution. He conducted no research in sociology of science to support his claims about decisive processes within the scientific community.
Philosophers cannot be entirely responsible for the writings and arguments of their followers. But, given the deleterious impact of Kuhn-inspired philosophy in educational constructivism, in STS studies, in Cultural Studies of Science, in fuelling post-modernism in education, and in misdirecting debates about inclusion of indigenous knowledge in science programmes, he should have been more considered and careful in his writing. Cultivating a more orthodox philosophical ‘cast of mind’ would have done no harm, and would have done considerable good, both inside and outside the academy. Kuhn had ample opportunity at Harvard and beyond to acquire a good philosophical education, but he declined. And he half-thought he would be better off without it, avowedly saying that getting a philosophical education would have been at the cost of writing Structure.
But if Kuhn is to be blamed for writing purple passages and so carelessly affirming relativist and idealist positions, then surely the science education community (and others) needs to be blamed for their uncritical and ill-informed reading of his work. With enthusiasm, they embraced Kuhn I and ignored his own re-making of himself into Kuhn II. And they ignored pretty much all critics of Kuhn. The community en masse mistakenly thought Kuhnian pedagogy was constructivist, child-centred, inquiry-powered pedagogy. Kuhn was as clear as can be that the pedagogical preparation for normal science was the antithesis of this. These failings of the science education community were disciplinary rather than an individualist; individuals are not to be blamed. The failings will not be rectified until philosophy and philosophical thinking returns, in some degree, to undergraduate and graduate programmes in education.107
The following are some steps that could be taken:Inclusion of some education-related HPS course in the preparation of science teachers is a necessity. Ideally, it means the creation of specific courses that pick up tangible theoretical, curricular, and pedagogical topics in science teaching that teachers can identify and recognise as genuine classroom and curricular problems; then, elaborate how HPS considerations can contribute to the better understanding and resolution of the issue. There is a massive ‘engagement’ difference between sending trainee teachers off to a philosophy department to do a HPS unit and providing an education orientated HPS course for them (Matthews 2014). One-day, multi-presentation, in-service workshops for teachers conducted by scientists, historians, philosophers, and sociologists are one small way this can be done.108
Encourage science teachers doing higher degrees in education to undertake one or more formal courses in HPS. Even dissuade them from a higher degree in education in favour of an undergraduate degree in HPS; after that, do a PhD in Education. This is good for their personal growth, and it is ultimately beneficial to whatever education research programme with which they might engage.
Ensure that PhD committees in science education have foundations faculty on them. The participation of a psychology, philosophy, history, or sociology researcher on thesis committees, along with a science professor, would contribute to raising candidate and supervisor awareness of past, and current, issues and literature in the relevant disciplines. It is noteworthy that in all the contemporary literature on activist and social justice science education, there is very little attention to how easy indoctrination could be, and has been, substituted for education.
Notoriously, promoting a ‘mature’ or ‘informed’ NOS position is simply taken to be promoting the NOS position of the instructor or examiner (Matthews, 1998b). Indoctrination replaces education. Without some grounding in philosophy of education, it is difficult to even recognise the distinction, let alone weigh up appropriate responses in programmes where it is practiced.109
Try as much as possible to ease publication pressure so that new faculty can effectively pursue their own reading and scholarship. Far better for newly appointed science educators to spend a semester attending a philosophy, psychology, linguistics, or history course, and reading substantial books, than conducting yet another study of misconceptions or the impact of talking on classroom learning. Better that a few things be done well than a hundred things be done poorly.
Work towards a system of joint appointments between education and foundation disciplines. Encouragingly, this happens to a small extent between education schools and science departments; if other faculty could be cross appointed to philosophy or HPS or psychology, this would assuredly lift the quality of scholarship and research in education and broaden scholarship and social utility in the foundation field.110
Declarations
Conflict of Interest
The author declares no conflict of interest.
1 David Treagust has 100 + publications, 36,000 citations, and has supervised scores of doctoral theses. He is not a minor or peripheral figure in international science education. His quoted words indicate how normalised Kuhn’s ‘picture of science’ has become among educators.
2 A collection of educational responses to Kuhn, and associated philosophical, educational, and psychological issues, can be seen in Matthews (2000b).
3 For an overview of the history and rationales of NOS in science education, see McComas and Clough (2020) and contributions to Flick and Lederman (2004) and McComas (2020). Also references in Khishfe (2022).
4 Structure sold over a million copies in 24 + languages. And they were just the authorized, or recorded, sales. So, talk of ‘millions of readers’ is not hyperbolic or rhetorical. And if the Edinburgh sociologists misinterpreted Kuhn, assuredly others also did.
5 Kuhn was awarded physics degrees at Harvard: B.S. (1943), M.A. (1946), and Ph.D. (1949). His dissertation thesis was ‘The Cohesive Energy of Monovalent Metals as a Function of Their Quantum Defects’, supervised by J.H. Van Vleck, and subsequently a Nobel laureate. He quickly published two thesis-related papers in Physical Review.
6 A 2000 listing of his publications, beginning in 1945, runs to ten pages (Conant & Haugeland 2000, pp.325–335).
7 The encyclopedia was founded in 1937 by scientifically minded, left-wing, US and European émigré philosophers and published by University of Chicago Press. From the beginning, like its Vienna Circle forebears, it was enveloped in political and philosophical controversy. Two days after the commencement of WWII, James Conant, the Harvard President, hosted the group’s conference at the university. He shared the group’s conviction that science was central to a free and democratic society and to this end, he did his utmost in the following decades to advance both science and science education. See Reisch (2019, chap.2) and Rudolph (2002).
8 For some explanations, see Fuller (2000b) and Reisch (2019, chap.16).
9 Gary Gutting’s 1980 book has a partial bibliography that lists, by academic discipline—philosophy, history of science, sociology of science, sociology, political science, economics, psychology, history, theology, art, literature, and education—320 works on Kuhn: (Gutting 1980, pp.321–339).
10 See at least the Introduction to Nickles (2003) and the interview with Kuhn in Baltas et al. (1997) reproduced in Conant and Haugeland (2000, pp.255–321).
11 Just in English, there have been hundreds of substantial philosophical books and anthologies devoted to Kuhn and Kuhnian themes. Many praising and explicating him, others criticising.
12 Proceedings of some major English celebratory conferences are Devlin and Bokulich (2015), Kindi and Arabatzis (2012), and Richards and Daston (2016). In reviewing the published proceedings of one such conference, the philosopher Howard Sankey commented ‘Still, I am not prepared to ignore the critical objections of an earlier generation of commentators on Kuhn. … the inclusion of dissonant voices would have strengthened the collection and provided a more balanced treatment of Kuhn’ (Sankey 2014, p.47).
13 Kuhn was born in 1922 and Structure was published in 1962. So, the conference was both a centenary and a 60-year celebration. The conference was jointly sponsored by the Aristotelian Society and the British Society for the Philosophy of Science. There were, disappointingly, no presentations on Kuhn and science education.
14 See major studies of Kuhn by Hoyningen-Huene (1993) and Bird (2000, 2013), and contributions to Gattei (2003), Horwich (1993), Mizrahi (2017), and Nickles (2003). And contributions to the celebratory conferences mentioned above.
15 See minimally Matthews (1992, 1993, 1994 chap.7).
16 Variously labelled the ‘Standard View’ (Grandy 2003) or the ‘Received View’ (Suppe 1977).
17 For then-contemporary appraisals of Nagel’s work, see contributions to Morgenbesser et al. (1969). For current appraisals of his work, see contributions to Neuber and Tuboly (2022).
18 This point is developed at length, with texts, in Matthews (1989).
19 Some of this history of separate development is discussed in Matthews (1994, chap.2). An exception to ‘silo’ research in philosophy and education was the work of Harvey Siegel (1978, 1979, 1985, 1989).
20 He writes in the second edition’s Postscript: ‘For this edition I have attempted no systematic rewriting, restricting alterations to a few typographical errors’ (Kuhn 1970a, p.174).
21 On the use of Kuhnian arguments in debate about inclusion of indigenous knowledge in science curricula, see Matthews (2022b).
22 Succinct overviews are in Bird (2012, 2013).
23 See Kuhn’s repeated acknowledgements of scholars-of-influence in his autobiographical interview (Baltas et al., 1997).
24 On the development of logical empiricism, see Giere and Richardson (1996); for appraisals, see contributions to Parrini et al. (2003).
25 See Conant’s autobiography (Conant 1970). For Conant’s direct influence on Kuhn, see Wray (2016) and Reisch (2017, 2019 chap.4).
26 Holton travelled much the same early professional path as Kuhn but came to a very different philosophical destination. They were born the same year, 1922, both completed Harvard physics PhDs in 1947, both taught in Conant’s General Education programme, and both produced important books arising from those experiences.
27 and Holton’s ‘themata’, it would have been a valuable contribution to philosophy, and informative for science educators.
28 On Holton’s reminiscences of Kuhn, and the latter’s ‘struggles’ with philosophy, see Holton (2018).
29 Hence, his later co-authored book, The Web of Belief (Quine & Ullian 1970).
30 There might well have been, of course, private corridor or common-room engagement, but if so, none of it made it beyond the Harvard Yard.
31 Kuhn’s connections with Carnap, and the overlooked similarities of their positions, are laid out by Friedman (2002), Irzik and Grunberg (1995), Reisch (1991), and Uebel (2011). This has been called a ‘revisionist’ reading of the Carnap-Kuhn relation.
32 Jonathan Tsou has argued for the deep-seated divergence between their two programmes in philosophy of science. For him, Carnap’s being traditional top-down philosophy of science, Kuhn’s being new bottom-up, case-study, or particularist philosophy of science (Tsou 2015).
33 See, for instance, Abner Shimony, whose philosophy PhD was supervised by Carnap (Shimony 1947, 1963/1993, 1977, 1978); Mario Bunge (1959/1979, 1967a, b, 1969, 2016); Robert S. Cohen (1970, 1975); and Gerald Holton (1952/1985, 1973/1988). For appraisal of Shimony, see contributions to Myrvold and Christian (2009); for Bunge, see contributions to Matthews (2019c); for Cohen, see contributions to Gavroglu and Wartofsky (1995).
34 On metaphysics in science, see at least Agassi (1964), Wartofsky (1968), Amsterdamski (1975), and Dilworth (1996/2006).
35 See Kuhn’s essays in his The Essential Tension (Kuhn 1977b) and essays included in The Road Since Structure (Conant & Haugeland 2000).
36 For foundation texts, see Barnes (1974, 1977) and Barnes et al. (1996). For evaluations, see contributions to Brown (1984).
37 See at least Bird (2000), Devlin and Bokulich (2015), Gutting (1980), Horwich (1993), Nickles (2003), and Sharrock and Read (2002),
38 Brad Wray has documented the citation patterns of Structure (Wray 2015).
39 The derivative quality of the book was largely the reason the Harvard History department did not offer Kuhn tenure. Subsequently, he did conduct careful and archival studies of the early history of quantum theory (Kuhn 1978).
40 Shimony’s first PhD was in philosophy at Yale with Rudolf Carnap as his advisor. His second PhD was in physics at Princeton supervised by Eugene Wigner.
41 The interview originally appeared in a Greek philosophy of science journal and was then reproduced in Conant and Haugeland (2000).
42 See, especially, Kuhn (1970b, 1977c, 1982, 1990, 1991, 1993).
43 On this, see Matthews 2021a, chap.8.
44 An informative review of the critics and their arguments is Sanbonmatsu and Sanbonmatsu (2017).
45 On the impact of Kuhn across academic, and other fields, see ‘Introduction’ and contributions to Gutting (1980).
46 The Google Ngram is a measure of the proportion of a given word among the total of all words published in books during a year. ‘Paradigm’ was stable and very low between 1800 and 1950; it barely moved off the zero base line. It began to move up in 1960 and then dramatically took off the year the first edition of Structure was published. See here.
47 In the early 1950s, Kuhn had been invited by Philipp Frank to join a group researching the sociology of science (Reisch 2017, p.241). Some correspondence is cited above.
48 See at least Brown (2001) and contributions to McMullin (1988), Brown (1984), and Gross et al. (1996).
49 Recent US, Brazilian, British, and Russian history well testifies to the reality and power of ‘mob psychology’. For a ‘long view’ of the phenomena, see Kurt Andersen’s Fantasyland. He devotes two of 450 + pages to Thomas Kuhn, describing Structure as ‘one of the most influential books of the age’ (Andersen 2017, pp.191). And adds: ‘it fed the new skepticism about science and scientists and, by extension, about rationality as propounded by elites, the mainstream, the Establishment’ (ibid).
50 The central text is Kant’s 1786 Metaphysical Foundations of Natural Science. For its preface and commentary, see Matthews (2022a, chap.VIII).
51 There are many sophisticated accounts of Kant’s contribution to understanding of science. See at least Friedman (1992) and contributions to Watkins (2001).
52 For philosophical analysis of perception and observation, see at least Mandelbaum (1964), Shapere (1982), Dretske (1969), and Kosso (1992, chap.6). Of particular relevance is the philosopher-physicist Abner Shimony (1977).
53 For issues and literature concerning object and propositional perception, see Matthews (2015, pp.250–253).
54 This episode is discussed and documented in Matthews (2019a, chap.6).
55 The shape of the earth debate, and its dependence on accurate timekeeping, is canvassed in Matthews (2000c, chap.6).
56 For literature, and arguments on this distinction, see Curd et al. (2013, section I) and Matthews (2019a, chap.13).
57 On Kuhn’s problems occasioned by eliminating truth from science, see Devlin (2015).
58 The Galilean episode is discussed, with texts, in Matthews (1989, chap.II).
59 For elaboration of realism, see Bunge (1993), Devitt (1991), Kukla (1998), Harré (1986), Sankey (2009), and Psillos
(1999, 2000) and contributions to Leplin (1984), Agazzi (2017), and Lyons and Vickers (2021).
60 For accounts of the episode see Conant (1948, chap.2), Jackson (2005), and Musgrave (1976).
61 Details of the history of the book are in Marcum (2015, pp.125–126) and Hoyningen-Huene (2015, pp.190–191).
62 This ontological idealism has serious consequences when gender equality, human rights, or political systems are being appraised. So, ‘Such and such group might have human rights in your reality, but not in our reality’, and so on.
63 See Hoyningen-Huene (1993, pp.206–222), Marcum (2015), and Sankey (1993). There is an abundance of technical literature on incommensurability: see contributions to Hoyningen-Huene and Sankey (2001) and Sankey (1994). On Kuhn’s own account, and critique of it, see Sankey (1993) and Mizrahi (2015).
64 Gerald Doppelt described Kuhn’s final position as ‘moderate relativism’ and defended it (Doppelt 2001).
65 On such an approach to incommensurability, see Bunge (1999, pp.253–254).
66 The term ‘Kuhnian’ rather than ‘Kuhn’s’ is deliberate as many positions were advanced in his name that he did not accept.
67 See Doran (1972), Driver and Easley (1978), Novak (1987), and the 2,000 + entries in Reinders Duit’s 2009 bibliography (Duit 2009).
68 Having 9000 + citations (April 2022).
69 This claim is elaborated in Matthews (2020)
70 Exceptions can be found in the 1991 thematic issue of Journal of Research in Science Teaching devoted to the subject (vol.28 no.9). See especially Duschl and Gitomer (1991).
71 Proponents of ‘naturalistic epistemology’ are more comfortable with accepting such work as epistemology, but that is an in-house philosophical debate.
72 See Piaget (1970, 1972) and Kitchener (1986, 1993).
73 See Nersessian (1989, 2003).
74 On this tradition, see contributions to the three volume Dearden et al. (1972).
75 See Hirst (2008) and contributions to Colgan and Maxwell (2020).
76 For an account of the influence of constructivism in science education, see Matthews (2000, 2015 chap.8, 2021b). For wider views of the matter, see contributions to Matthews (1998a) and Phillips (2000).
77 Pfundt and Duit (1994) contain a cumulative index of the 2000 + constructivist articles published to the early 1990s.
78 Joseph Novak guided much work at Cornell University where in the decade after 1977, over 100 graduate students were enrolled (Novak 1977, p.7), and over his whole career he supervised, or contributed to, theses of 300 + graduate students (Novak 2018, p.138).
79 As of September 2022, the paper has 2880 citations.
80 See Glasersfeld (1984, 1993, 1995) and Steffe and Thompson (2000).
81 For critical appraisal of von Glasersfeld’s positions, see Matthews (1994, pp.148–158) and contributions to Matthews (1998b).
82 The canonical statement was Rosalind Driver’s book The Pupil as Scientist (Driver 1983). See also Kitcher (1988).
83 See Bybee (2000), DeBoer (2004), Duschl and Grandy (2008), and National Research Council (2000).
84 Conant established the Natural Science 4 course, titled ‘Research Patterns in Physical Science’. For some years, Kuhn taught this course (as did Gerald Holton). On the General Education programme, see Fuller (2000a), Rudolph (2002, pp.48–51). On the utilization of the case studies in schools, see Klopfer (1964).
85 The essay is contained in ‘Dubbing and Redubbing: The Vulnerability of Rigid Designation’ in C.W. Savage (ed.) Scientific Theories, University of Minnesota Press, 1990, pp.302–308. And reproduced in Science & Education 9(1–2), 2000.
86 The debate is laid out in contributions to Tobias and Duffy (2009). On the pedagogical failure of constructivist methods, see Kirschner, Sweller and Clark (2006), and Sweller (2009). The literature and arguments are traversed in Matthews (2021a, pp.169–173).
87 He has authored or edited over 400 books, anthologies, chapters, and papers in science education. He has supervised scores of PhD theses. Google Scholar, as of September 2022, records 25,000 + citations of his work.
88 On the empiricist foundations of constructivism, see Matthews (1992, 1993, 1994 chap.7).
89 The educational wing of social constructivism took inspiration from the 1920s writings of the Soviet social psychologist Lev Vygotsky that had been translated into English in the 1960s and 1970s (Vygotsky 1962, 1978).
90 Wikipedia entry: https://en.wikipedia.org/wiki/Kenneth_Tobin
91 David Edge, a leading STS researcher, provides an informative history (Edge 1994). The full gamut of STS studies is laid out in contributions to Jasanoff et al. (1995).
92 She is co-author of Merchants of Doubt: How a Handful of Scientists Obscured the Truth on Issues from Tobacco Smoke to Global Warming (Oreskes & Conway 2010) and currently a regular contributor to Scientific American.
93 The book is widely, and approvingly, cited in science education having 21,500 + citations to October 2022. Peter Slezak provided a withering critique (Slezak 1994b).
94 The classic statement was Boris Hessen’s 1931 ‘The Social and Economic Roots of Newton’s Principia’ (Hessen 1931/2009). It was oft enough said that Darwinian ‘Survival of the Fittest’ was just Victorian England transferred to the animal world.
95 New Organon, 1620, Aphorisms 31–46.
96 One critical account of STS studies is Maxwell (2015).
97 See at least Bybee (1977) and Solomon and Aikenhead (1994).
98 For how the issue has played out in New Zealand, see Corballis et al. (2019).
99 See Ross et al. (2007) and Ladyman (2018) and contributions to Boudry and Pigliucci (2017).
100 Fensham says that when he was appointed to Monash University in 1967, as Australia’s first professor of science education, a master’s degree in one of the foundations of education—history, philosophy, psychology, or sociology—was a prerequisite for doctoral studies. But he removed the requirement (Fensham 2004, p.23). Monash’s foundation-free pattern is now the norm for science education doctoral programmes in Australia, and internationally.
101 An authoritative insider’s account of how this happened is given in Tobin (2015b). See also contributions to Milne et al. (2015).
102 For a philosophical review of the cultural studies research genre, with an abundance of illustrative quotations, see McCarthy (2014).
103 Wolff-Michael Roth 47,004 citations (September 2022), Ken Tobin 25,173 citations (September 2022).
104 For texts and elaboration on Mach, see Matthews (1990, 2019b); for Frank and Feigl, see Matthews (2004b).
105 See minimally Bunge (1991, 1992) and Slezak (1994a, b).
106 The unhealthy reach of relativism and idealism in science education is described in Matthews (2015, chap.8, 2021a, chap.7).
107 On philosophy in teacher education programmes, see contributions to Colgan and Maxwell (2020) and Matthews (2015 chap.12, 2020). On ways to incorporate HPS into classrooms, see substantial studies in McComas (2020).
108 For programmes of three such annual in-service workshops, and teacher evaluations, see Matthews (2021a, pp. 264–268).
109 See Hannson (2018) and discussion in Matthews (2021a, pp. 277–279).
110 Israel Scheffler (Harvard) and Denis Phillips (Stanford) had appointments in both education and philosophy with manifest benefit to their institutions and graduate programmes. Harvey Siegel, for instance, was an education student whose thesis was supervised by Scheffler. And there are other such exemplars.
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| 0 | PMC9745714 | NO-CC CODE | 2022-12-15 00:02:40 | no | Sci Educ (Dordr). 2022 Dec 13;:1-70 | utf-8 | Sci Educ (Dordr) | 2,022 | 10.1007/s11191-022-00408-1 | oa_other |
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Wetlands (Wilmington)
Wetlands (Wilmington)
Wetlands (Wilmington, N.c.)
0277-5212
1943-6246
Springer Netherlands Dordrecht
1647
10.1007/s13157-022-01647-2
Wetland Ecology
Macroinvertebrate Community Composition in Wetlands of the Desert Southwest is Driven by wastewater-associated Nutrient Loading Despite Differences in Salinity
http://orcid.org/0000-0002-0630-1811
Piña Anna Elisa [email protected]
http://orcid.org/0000-0002-6091-1151
Lougheed Vanessa L. [email protected]
grid.267324.6 0000 0001 0668 0420 Department of Biological Sciences, University of Texas at El Paso, 79968 TX El Paso, USA
13 12 2022
2022
42 8 12827 7 2022
28 11 2022
30 11 2022
© The Author(s), under exclusive licence to Society of Wetland Scientists 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
The relatively rare freshwater ecosystems in the arid southwestern United States serve as biodiversity hotspots, yet they remain among the most threatened systems in the world due to human impacts and climate change. Globally, arid region wetlands remain understudied with respect to their ecology, making assessments of quality or restoration efforts challenging. To address these needs, this project aims to better understand the factors that drive water quality and macroinvertebrate community composition of wetlands of the US desert Southwest. Water quality and macroinvertebrate data were collected over three years from 14 different wetland and riparian sites spanning across West Texas, New Mexico and Arizona. Principal Component Analysis (PCA) indicated that salinity related variables such as chloride, sulfate and conductivity were the greatest drivers of environmental variance (32%) among sampled desert wetlands. Nutrients such as nitrate and phosphate described a second axis, with 22% of variation in environmental data explained, where we found a clear distinction between wastewater and non-wastewater wetlands. Nutrients were shown to have the greatest impact on macroinvertebrate communities with wetlands receiving wastewater showing more uneven distribution of functional feeding groups and lower Simpson Index scores. These sites were dominated by filter feeders and had lower relative abundances of predator and collector-gatherer taxa. There was also a significant decrease in metrics related to diversity and environmental sensitivity such as % Ephemeroptera-Odonata-Trichoptera (EOT) within high nutrient sites. Increased salinity levels were also shown to correlate with lower Simpson Index scores indicating that increased salinity resulted in a decline in macroinvertebrate diversity and evenness. Overall, the nutrients within effluent water have shown to significantly alter community composition especially in desert wetlands where macroinvertebrates may be more adapted to high salinity. Though macroinvertebrate communities in wastewater sites may not fully resemble those of natural wetlands over time, creation of these sites can still benefit landscape level diversity.
Supplementary Information
The online version contains supplementary material available at 10.1007/s13157-022-01647-2.
Keywords
Arid region
Desert
US Southwest
Metrics
Biotic indices
Department of EducationP031C160235 http://dx.doi.org/10.13039/100000199 U.S. Department of Agriculture 2015-68007-23130 issue-copyright-statement© The Author(s), under exclusive licence to Society of Wetland Scientists 2022
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pmcIntroduction
The loss of global biodiversity is occurring at an exceedingly rapid rate due to climate change and overexploitation by humans (Dawson et al. 2011). While terrestrial ecosystems are often in the spotlight, aquatic ecosystems surpass their rate of loss of biodiversity due to declines in water quality, changes in nutrient availability and increasing temperatures (Van De Waal et al. 2010; Woodward et al. 2010rösmarty et al. 2010). Arid region wetlands are especially vulnerable due to altered precipitation patterns related to climate change and declining groundwater flow as a result of overuse (Burkett and Kusler 2000; Taylor et al. 2013; Richey et al. 2015). As biodiversity hotspots, these oases are habitat for many organisms and provide critical habitat connectivity within the desert landscape (Dinerstein et al. 2001; Bogan et al. 2014; Drake et al. 2017). While freshwater habitats are known to support ~ 10% of all species, including many endangered and endemic species, arid region wetland ecosystems worldwide remain understudied and under-recognized when it comes to wetland ecology and conservation (Walsh et al. 2009; Strayer and Dudgeon 2010; Hershler and Liu 2010; Minckley et al. 2013; Murphy et al. 2013; Nieto et al. 2017; Stanislawczyk et al. 2018). Due to the rapid loss of habitat, there has been a recent push to protect and restore these rare freshwater ecosystems.
In the southwest United States, many wetlands have been restored or created to replace those wetlands that have been lost. Some wetland sites use the delivery of treated wastewater to mitigate or restore water flow to areas that were previously drained or degraded due to river channelization or agricultural use (O’Geen et al. 2010; Rodriguez and Lougheed 2010). These sites create new habitats for migrating birds and aquatic organisms as well as areas of cultural value such as city parks (Andrade et al. 2018; Hamdhani et al. 2020; Bogan et al. 2020). These habitats are often used to further purify effluent water through the uptake of nutrients (i.e. nitrogen and phosphorus) and contaminants by wetland macrophytes and microalgae before replenishing groundwater sources (Whitton et al. 2016; Matamoros et al. 2017; Zhuang et al. 2019). While studies have shown these wetlands to be effective at reducing excess nutrients and contaminants from wastewater, the initial presence of these byproducts may have lasting effects on freshwater biota (Brooks 2000). In some non-arid created wetlands, increased nutrients cause shifts in community composition with an increase in pollution-tolerant macroinvertebrate taxa (Pinto et al. 2014). However, due to variables relatively unique to arid regions (i.e. extreme heat, irregular and rare precipitation), it is unknown if macroinvertebrates in arid wastewater wetlands respond the same way as those in non-arid regions.
In freshwater ecosystems, macroinvertebrates have historically been used as indicators of water quality and wetland health (Hilsenhoff 1987; Mandaville 2002). As bioindicators, aquatic macroinvertebrates serve as a low-cost and useful tool for monitoring wetland health and function due to their constant contact with water and sediment (Hilsenhoff 1987; Cairns and Pratt 1993; Bartell 2006; Siddig et al. 2016; McIntosh et al. 2019). By monitoring the abundance, diversity, and reproductive success of these organisms we can determine habitat response to change or disturbance (Foote and Rice Hornung 2005; Siddig et al. 2016; Wu et al. 2017). While these biotic indices are easily applied to non-arid region habitats, it should not be assumed that macroinvertebrates in arid habitats will respond the same way to environmental stressors. Recent studies have even highlighted the possible disparities of using the same biotic indices across differing systems (Mazor et al. 2016; Serrano Balderas et al. 2016).
When examining wetlands in non-arid regions the differences in macroinvertebrate community composition have often been attributed to vegetation community composition (Balcombe et al. 2005; Stewart and Downing 2008; Becerra Jurado et al. 2009; Swartz et al. 2019) and water quality associated with development (Carew et al. 2007; Lougheed et al. 2008; Kobingi et al. 2009). In contrast, studies assessing arid region ponds and springs in the Chihuahuan and Sonoran deserts have pointed to hydroperiods and desiccation cycles (Esposito 2012) or wetland isolation and dispersal limitations (Stanislawczyk et al. 2018) as the driving factor of macroinvertebrate community composition. While both these arid region studies identified differences in nutrient chemistry or salinity among sites, neither identified water chemistry as a predictor of macroinvertebrate community structure, perhaps because of the limited number of sites sampled, or small gradients examined. Salinity, in particular, may be elevated in arid region water bodies due to high evaporation rates and inconsistent water availability (Williams 1999; Nielsen et al. 2003) and may increase in importance during dry periods (Lahr 1997). In addition, many permanent water bodies in the southwest are fed by groundwater, which are known to be high in salts and minerals (Borrok and Engle 2014). Furthermore, it is largely unknown what gradients of water quality organisms in desert wetlands of the US southwest are exposed to as there have been no broad scale studies to examine these environmental gradients.
The primary objective of this study was to determine how water chemistry varies among wetlands of the US desert southwest, and how this may drive macroinvertebrate community composition within these rare habitats. In particular, we assess whether metrics of macroinvertebrate diversity, tolerance and functional feeding groups are related to water source (i.e. wastewater sites vs. non-wastewater sites) or salinity. We expect that wastewater effluent and highly saline water sources of many desert wetlands will negatively affect sensitive taxa due to their sensitivity to anthropogenic factors (Ocon and Capítulo, 2004) and lead to homogenization of functional feeding groups as shown in similar studies in non-arid regions (Lougheed et al. 2008).
Study Sites
Fourteen wetlands in the US desert southwest were sampled during the summers of 2018–2020 (Fig. 1). Most sites were found in the Chihuahuan Desert, where rainfall averages 247 mm annually and occurs primarily during the summer months (June-September) when peak ambient temperatures average 36 °C (Matthews 2014). However, several sites were found in the Sonoran Desert, which receives between 75 and 380 mm of rain per year and has peak summer temperatures reaching up to 49 °C (Britannica 2020). During 2018 and 2019, the southwest received near-below to below average precipitation and experienced above average temperatures (NOAA 2019; NOAA 2020). Sites sampled in 2020 experienced near average precipitation with much above average temperatures (NOAA 2021).
Fig. 1 Map of all sites sampled in Arizona, New Mexico and Texas during the summer months of 2018–2020
Wetlands varied in their water sources, coming from either wastewater (effluent water from treatment plants) or non-wastewater (i.e. Rio Grande river, spring-fed or stormwater) (Table 1). Wastewater sites generally received continuous amounts of effluent water throughout the growing seasons. Non-wastewater sites included those that were flooded with water from the Rio Grande (Las Palomas, La Mancha, Rio Grande 1, Rio Grande 2); however, these were floodings and not considered riverine wetlands. Ascarate and Crossroads differed by additionally receiving stormwater inflow sporadically throughout the year, especially during the summer monsoon season. Water depths for the sites ranged from 0.3 m to greater than 1.5 m, however areas sampled were in wadable depths (< 0.5 m).
Table 1 Sample sites, location of site, water source and area for 14 wetlands sampled in the Chihuahuan and Sonoran deserts. Sites 1–12 were visited in 2018 and 2019. Sites 13–14 were added in 2019 help elucidate patterns. Only sites located in El Paso, Texas were also sampled in 2020 due to travel restrictions. Code names appear in Fig. 1b. * Indicates ephemeral wetlands
# Name Location Code Name Water Source Area (ha)
1 Tres Rios Wetlands Phoenix, AZ TR1, TR2 wastewater 91.49
2 Sweetwater Wetlands Tucson, AZ SW1, SW2 wastewater* 5.54
3 Las Palomas Marsh Las Palomas, NM LP non-wastewater* 2.86
4 Rio Grande 1 Las Palomas, NM RG1 non-wastewater 0.22
5 La Mancha Wetlands Las Cruces, NM LM non-wastewater* 0.26
6 Rio Grande 2 Las Cruces, NM RG2 non-wastewater 0.53
7 Keystone Wetlands El Paso, TX KS non-wastewater 1.05
8 Crossroads Pond El Paso, TX CR non-wastewater* 3.25
9 Ascarate Lake El Paso, TX AS wastewater 15.73
10 Rio Bosque Wetlands El Paso, TX RB1, RB2 wastewater* 11.30
11 Sandia Springs Balmorhea, TX SS1, SS2, SS3 non-wastewater* 1.15
12 BJ Bishop Wetlands Presidio, TX BJ wastewater* 1.09
13 Cattail Falls Big Bend National Park, TX CF non-wastewater* < 1
14 Manzanita Springs Guadalupe Mountains National Park, TX MS non-wastewater < 1
Most sites were sampled twice, once a summer in two different years, however, Cattail Falls and Manzanita Springs were only sampled once due to being added later in the project and COVID-19 travel restrictions. Sites located in El Paso, TX were sampled once every summer during the three sampling years. Some sites, such as the Rio Bosque, were sampled in more than one area, as indicated in by multiple code names in Table 1 (i.e. RB1, RB2). Different areas sampled within one wetland were usually associated with separate ponded areas.
Methods
Macroinvertebrate Sampling
Prior to sampling, we qualitatively identified the three dominant macrophyte types in each wetland. Macroinvertebrate samples were then collected with three successive dips using a 250 μm d-frame kick net from each of these three habitats. Contents from all dips were pooled into 1 composite sample. Because all sites were sampled with the same effort (3 dips in 3 different habitats for a total of nine dips per wetland), abundances are reported as catch per unit effort (CPUE) and are directly comparable. Macroinvertebrates were counted and identified in the field with some specimens kept for further identification in the lab. Specimens were preserved in 70% ethanol, stored at room temperature, and identified to the order and family level (Merritt and Cummins 1996; Smith 2001).
Using these data, a variety of metrics of macroinvertebrate community composition were calculated, including those that summarized taxonomic richness, composition, and functional feeding groups. A full list of taxa with designated functional feeding guilds can be found in supplementary materials. Ephemeroptera, Odonata and Trichoptera (EOT) composition was used as measure of diversity and water quality (Mereta et al. 2013). Similar metrics including Plecoptera (i.e. EPT) were not included due their absence in our study areas. Using abundance data, Simpson’s Diversity Index (λ) was calculated for each sampling visit as a measurement of macroinvertebrate diversity (Simpson 1949). Both λ scores and the percentages of functional feeding groups were computed for each site visit, then averaged for sites that were sampled more than once (Anderson and Davis 2013).
Water Quality Sampling
At the time of macroinvertebrate collection, physicochemical conditions such as pH and conductivity were collected in the field using a YSI® 556 multi-probe (YSI Incorporated Yellow Springs, OH, USA). Dissolved organic carbon (DOC) and total dissolved nitrogen (TDN) samples were determined after filtration through pre-ashed GF/F filters and stored in precombusted amber glass bottles at 4 °C until analysis (APHA 1998). Both were determined using a Shimadzu TOC-L analyzer with TMN module. Water samples for additional water chemistry were collected from an open water location using acid washed HDPE bottles. Anion concentrations (Cl−, SO42−, NO3−, PO43−) were measured on a Dionex 2100 ion chromatograph. Alkalinity was measured using a Mettler Toledo G20 auto-titrator. Turbidity was measured in triplicate using a Hach 2100 turbidimeter. Percent organic matter was determined using a “loss on ignition” method in which a subsample of the sediment was dried at 100°C for one hour. The sample was then weighed and heated in a muffle furnace at 550°C for fifteen minutes and reweighed (APHA 1998). Percent organic matter was calculated from the mass lost after ashing.
Chlorophyll-a concentration, as an estimate of algal biomass, was quantified for both phytoplankton and periphyton. To measure phytoplankton, a known volume of water (between 150 and 1000 mL) was collected from open water and filtered through a GF/C filter to collect algae floating in the water column. Filters were frozen until analysis. Periphyton was collected from pond sediment surfaces at three haphazard locations in each pond using a spatula and an inverted petri dish. All three periphyton samples were combined into one composite sample. Algae were separated from the sediment by rinsing with distilled water, pouring off and retaining the algal-rich supernatant solution and repeating ten times, at which point the solution typically became clear. A subsample of the resulting algal suspension was stored in a test tube, wrapped in foil and frozen until the analysis for chlorophyll. Chlorophyll a (CHLa) was extracted into 90% acetone for 24 h in the freezer. Absorbance of the extract was measured with a Genesis 10 UV spectrophotometer (APHA 1998). Concentrations were calculated on a volumetric basis for phytoplankton (µg L− 1) and by area sampled for periphyton (µg cm− 2). Phytoplankton CHLa was corrected for turbidity and phaeopigments by acidification (Wetzel and Likens 2002).
Data Analysis
All statistical analysis and graphing were performed in R (Version 4.1.2). A Principal Component Analysis (PCA) was used to describe underlying gradients in the environmental data. All environmental data, including physicochemical properties and algal biomass were entered into the analysis. The PCA analysis was conducted using the “princomp” function and data were transformed and standardized as required, to approximate a normal distribution (McCune and Grace 2002). Graphing of the PCA was performed with the “factoextra” package (Kassambara and Mundt 2020). Simpson Diversity Indices were calculated using the “vegan” package (Oksanen et al. 2022). Water quality and macroinvertebrate metrics were compared between wastewater and non-wastewater sites using Wilcoxon rank-sum tests, due to non-normality of data. Pearson correlation co-efficients were determined to relate Simpson’s Diversity Index scores and PCA scores for all sites. Normality of residuals was confirmed for all regression analyses.
Results
Environmental Gradients
Environmental conditions ranged from nutrient-poor (non-detectable levels of N and P) to nutrient-rich, with relatively high levels of water column chlorophyll (maximum 352 ug/L), DOC (maximum 75ppm) and nutrients (Table 2). There was also a large gradient of salinity-related variables such as Cl− and SO42− ranging from non-detectable amounts to 828.5 and 5309 ppm, respectively. Water clarity ranged from clear (1.8 NTU) to highly turbid (208.3 NTU). Sites generally had largely inorganic sediments with the highest percentage of organic matter only 9%.
Table 2 Median, standard deviation and range of water physio-chemical variables for wetlands sampled in the Chihuahuan and Sonoran deserts. Phytoplankton CHLa was corrected for turbidity and phaeopigments by acidification (Wetzel and Likens 2002); Total CHLa refers to uncorrected CHLa values
Median SD Min Max
Conductivity (mS/cm) 3.30 3.89 0.21 16.40
DOC (ppm) 13.84 17.46 0.29 75.04
Alkalinity (meq/L) 200.11 130.80 21.98 457.62
Corrected CHL a (µg L − 1 ) 21.82 60.63 0.00 146.68
Cl − (ppm) 281.84 290.23 0.00 828.53
SO 4 2− (ppm) 536.38 1073.27 0.00 5309.00
TDN (ppm) 2.84 3.85 0.00 7.00
NO 3 − (ppm) 1.62 2.79 0.00 9.00
PO 4 3− (ppm) 2.63 4.97 0.00 26.00
Periphyton (µg cm − 2 ) 0.00 0.01 0.00 0.02
Organic Matter % 1.29 2.93 0.00 8.97
pH 7.40 0.76 6.25 9.29
Turbidity (NTU) 24.29 38.26 1.80 208.30
The PCA yielded two dimensions explaining more than 50% of variation in the environmental data: PCA 1 accounted for 31.9% of the variability, and PCA 2 accounted for 22.1%. For PCA1, DOC was the greatest driver of variance, along with salinity-related variables such as Cl−, SO42−, alkalinity and conductivity. Both total and corrected phytoplankton CHLa were also related to this axis (Fig. 2a; Table 3). This axis contrasted urban ponds with high salinity, such as Keystone and Crossroads, to more remote sites, such as Manzanita Springs and Cattail Falls, with relatively low salinity levels. Nutrients such as NO3−, PO43− and TDN, as well as soil organic matter, were the greatest drivers of variance along PCA 2 (Fig. 2a; Table 3). This axis contrasted sites flooded with effluent water (Rio Bosque, Sweet Water, Tres Rios and BJ Bishop) to all other sites. Wetland sites flooded with water from the Rio Grande (Rio Grande 1 and 2, Las Palomas, La Mancha) were shown to have relatively low levels of nutrients (Table 4). Differences based on sites flooded with wastewater versus those flooded with non-wastewater is especially apparent, as they occupied distinct groups on the PCA plot (Fig. 2b).
Fig. 2 Plots of PCA scores of environmental data collected from 14 wetlands in the Chihuahuan and Sonoran deserts with (a) environmental vectors, where longer arrows indicate stronger correlations with the axis scores, and (b) sites grouped by water source. Sites codes are listed in Table 1 and appear with the last two digits of the year they were sampled
Table 3 Correlation coefficients (r) of water physiochemical parameters with PCA1 and PCA2 scores from wetlands sampled in the Chihuahuan and Sonoran deserts. Significance: ***p < 0.0001, **p < 0.01, *p < 0.05
PCA1 PCA2
Conductivity (mS/cm) -0.8250*** 0.1259
DOC (ppm) -0.8855*** -0.1917
Alkalinity (meq/L) -0.6148** -0.2793
Corrected CHL a (µg L − 1 ) -0.6981** -0.1450
Cl − (ppm) -0.8052*** -0.0884
SO 4 2− (ppm) -0.8586*** 0.1127
TDN (ppm) -0.4484 -0.7393***
NO 3 − (ppm) 0.2392 -0.8511***
PO 4 3− (ppm) 0.0374 -0.8458***
Periphyton (µg cm − 2 ) 0.0318 -0.5853*
Organic Matter % 0.2686 -0.5627*
pH -0.5632* 0.5456*
Turbidity (NTU) -0.2529 0.1949
Table 4 Means and Standard Error of water quality parameters grouped by water type. Wilcoxon rank sum difference between groups ***p < 0.0001, **p < 0.01, *p < 0.05, without asterisks indicate non- significance
Non-wastewater Wastewater
Conductivity (mS/cm) 4.76 (0.98) 2.28 (0.49)
DOC (ppm) 15.45 (4.65) 7.75 (1.23)
Alkalinity (meq/L) 223.65 (24.55) 245.60 (32.32)
Corrected CHL a (µg L − 1 ) 28.76 (15.94) 21.28 (11.72)
Cl − (ppm) 358.51 (71.29) 155.86 (23.76)
SO 4 2− (ppm) 951.65 (285.07) 122.31 (12.97)
TDN (ppm) 1.39 (0.40) 5.20 (1.33) **
NO 3 − (ppm) 0.23 (0.06) 4.64 (0.89) ***
PO 4 3− ppm) 0.15 (0.05) 7.34 (1.72) ***
Periphyton (µg cm − 2 ) 0.001 (0.0003) 0.008 (0.002) **
Organic Matter % 0.02 (0.003) 0.05 (0.005) **
pH 7.74 (0.15) ** 6.89 (0.14)
Turbidity (NTU) 30.52 (9.61) 14.05 (4.39)
Macroinvertebrate Metrics
In total, 13,760 macroinvertebrate individuals were collected over the time of the study. Total abundances ranged from 15 to more than 1000 per unit effort, the latter being sites that were dominated by mostly Ostracods and Cladocera, while the number of taxa found at each site ranged from 2 to 10, depending on the site.
When grouped by water type, many metrics were significantly higher in sites that were fed with non-wastewater, including both tolerant and sensitive taxa (Table 5). % EOT, which was used as a measure of both diversity and water quality, was also high in site receiving non-wastewater, as were the percentage of predators and collector-gatherers (Table 5). Non-wastewater sites also had a more even representation by functional feeding groups, notably collectors, predators and filterers, while wastewater sites were largely dominated by filterers (Fig. 3). Similarly, within the non-wastewater sites (low nutrients), we found multiple taxa with relatively even percent abundances (10–15%), including Ephemeroptera, Odonata, Hemiptera, Coleoptera and Amphipoda (Table 5). Conversely, wastewater fed sites were dominated by filterers (Fig. 3; Table 5), largely represented by significantly more ostracods (62%) and cladocerans (12%).
Table 5 Means and Standard Error of macroinvertebrate metrics from wetlands in the Chihuahuan and Sonoran deserts grouped by non-wastewater and wastewater source type. Wilcoxon rank sum significant difference between groups ***p < 0.0001, **p < 0.01, *p < 0.05, + <0.10, without asterisks indicate non- significance
Non-Waste Waste
Total taxa 7.16 (0.46) 9.78 (1.12)+
No. of orders 6.76 (0.42) 8.50 (0.81)
No. of families 6.76 (0.42) 8.50 (0.81)
Simpson Diversity Index 0.57 (0.20)* 0.39 (0.22)
% Ephemeroptera 13.56 (3.16) 3.17 (1.56)
% Odonata 10.86 (2.40)+ 3.67 (1.12)
% Amphipoda 11.49 (23.07) 11.05 (20.19)
% Gastropoda 7.56 (9.7) 4.06 (7.96)
% Hemiptera 11.05 (3.59)* 1.55 (0.93)
% Coleoptera 12.54 (4.10)** 0.30 (0.15)
% Diptera 5.75 (1.30)* 2.00 (0.60)
% Chironomidae 4.49 (6.79) 1.70 (2.14)
% Cladocera 5.84 (11.7) 12.26 (26.55)+
% Decapoda 1.34 (3.71) 0.11 (0.33)
% Ostracoda 20.33 (5.62) 61.75 (7.64)**
% EOT 24.46 (3.93)** 6.85 (2.34)
% Predators 32.51 (4.98)** 5.53 (1.43)
% Scrapers 8.91 (11.58) 4.18 (8.16)
% Filterers 25.77 (6.00) 74.02 (5.78)***
% Collector-gatherers 29.38 (4.58)+ 15.93 (5.35)
All figures were created using RStudio (Version 2022.02.0 + 443), with the exception of Fig. 1 which was created in ArcMap 10.6.1
Fig. 3 Relative abundances of functional feeding groups from wetlands in the Chihuahuan and Sonoran deserts grouped by water source types: non-wastewater and wastewater
λ scores were found to be positively associated with both PCA1 (r2 = 0.11, p = 0.04) and PCA 2 (r2 = 0.16, p = 0.01) axes (Fig. 4) indicating that increased salinity and nutrient levels resulted in a decline in macroinvertebrate community diversity and evenness. When comparing the λ scores of wastewater sites and non-wastewater sites, there was a significant difference with non-wastewater sites displaying higher macroinvertebrate diversity scores (Table 5; Fig. 5). There were no significant correlations between percent abundances of taxa or functional feeding groups and either of the PCA axes after corrections for multiple comparisons.
Fig. 4 Regression plots depicting significant associations (p < 0.05) of Simpson Diversity Index scores with (a) PCA1 and (b) PCA2 axes scores for all 14 wetlands in the Chihuahuan and Sonoran deserts
Fig. 5 Boxplot depicting average Simpson Index Scores for wetlands in the Chihuahuan and Sonoran deserts grouped by water source type: non-wastewater and wastewater. Letters indicate statistical differences (p = 0.02)
Discussion
Wetlands in this study tended to vary along a gradient of either salinity or nutrient enrichment, with salinity appearing to explain more among-site variability. While salinity exhibited the greatest environmental variation amongst sites, nutrient loads from wastewater appears to be the greatest driver of variation within macroinvertebrate communities. Overall, our predictions correctly indicated that increased levels of nutrients, such as those found in wastewater from treatment sites has negative effects on macroinvertebrate diversity and abundances in sensitive taxa. Furthermore, this has shown to cause changes in distribution of functional feeding groups, specifically leading to communities dominated by filter feeders. While salinity also led to reduced diversity of macroinvertebrate taxa, we were unable to show an effect of elevated salinity on any taxonomic group or functional feeding group.
Salinity
The salinity gradient contrasted permanent and isolated spring sites such as Cattail Falls and Manzanita Springs, with low chloride, sulfate and conductivity levels, to known naturally high saline sites within El Paso, TX city limits, such as Keystone and Crossroads. The relatively high levels of salinity within these two sites are likely due their location. These arid region wetlands are both highly dependent on the regional, saline water table to maintain water levels. Groundwater is known to have high levels of salts and sulfate in the region (Hiebing et al. 2018). Irregular influx of water and rising temperatures could lead to high evaporative conditions, which could contribute to the high levels of salinity within these sites (Jolly et al. 2008; Borrok and Engle 2014).
DOC and chlorophyll-a were also shown to vary along the salinity gradient. Sites that are highly saline have been shown to have suppressed microbial activity (including those which take up DOC) which may explain the higher levels of available DOC within these sites (Straathof et al. 2014; Yang et al. 2018). In some studies, the increase in chlorophyll-a levels within highly saline sites was related to SO42− and salt-induced aggregation of suspended matter, which can lead to increase light penetration of the water column and thus, high rates of photosynthesis (Donnelly et al. 1997; Nielsen et al. 2003). However, given we saw no effect of water clarity in our study, this is unlikely.
While the salinity gradient explained most of the environmental variability among sites, there were relatively few significant associations between salinity and metrics of macroinvertebrate community composition. Sites that were higher in salinity tended to have lower Simpson Index Scores, thus lower macroinvertebrate diversity and evenness. This remains consistent with similar studies showing negative relationships between macroinvertebrate taxonomic richness and functional evenness with increasing levels of salinity and related parameters (Kefford et al. 2004; Chemers et al. 2011; Ordonez et al. 2011; Cuthbert et al. 2020; Muresan et al. 2020). Although other studies within Chihuahuan desert freshwater systems have found that Amphipoda are adapted to high levels to salinity (Gervasio et al. 2004; Dinger et al. 2005; Cuthbert et al. 2020) and coleopterans, in general, are tolerant of high salinity within freshwaters (Lancaster and Scudder 1987; Garrido and Munilla 2008; Sharma et al. 2019; Colombetti et al. 2020), we were unable to verify these trends with our data.
Nutrients
Not surprisingly, there was a distinct difference in physiochemical features between sites flooded with wastewater and those flooded with non-wastewater. The sites flooded with wastewater were significantly higher in nutrients such as NO3−, PO43−, and TDN, typical of effluent water (Zhuang et al. 2019; Hamdhani et al. 2020). Periphyton was also significantly higher in the wastewater sites, likely due to the high levels of nutrients, which are often a limiting factor of benthic algal communities (Power 1992; Francoeur et al. 1999).
Sites with lower nutrient levels had more diverse and even macroinvertebrate communities. Lougheed et al. (2008) found that wetlands in less developed, nutrient-poor locations had increased diversity of multiple taxonomic groups. This is consistent with multiple studies finding homogenization of macroinvertebrate communities with increased nutrient levels, some stating total phosphorus as the main driver of decline in diversity (Spieles and Mitsch 2000; Hsu et al. 2011; Ouyang et al. 2018; Qu et al. 2019). Along the nutrient gradient, we saw a clear contrast in macroinvertebrate community structure between wastewater sites and non-wastewater sites. The presence of multiple taxa with relatively even percent abundances (10–15%) agrees with findings of increased evenness in non-wastewater or low nutrient sites compared to wastewater wetlands, specifically with the increase in more sensitive taxa such as Ephemeropterans (Becerra Jurado et al. 2009; Hsu et al. 2011). The percent EOT increased significantly within non-wastewater sites, likely due to their sensitivity to anthropogenic impacts (Ode et al. 2005; Kutcher and Bried 2014). The increase in predators in the absence of wastewater was also found by other studies relating declines in predators as a result of increased nutrients and anthropogenic disturbances (Fu et al. 2016; Zhang et al. 2019). Corixidae, in particular, have been commonly observed in other studies in Rio Grande habitats (Bain et al. 2011, Burdett et al. 2015), which we found were generally lower in nutrients than wastewater fed sites.
Functional feeding groups were also evenly represented in the absence of wastewater, with collectors, predators and filterers each forming approximately one-third of the composition. In contrast, filterers (ostracods in particular) dominated the community in wastewater sites, representing more than 60% of the total abundance, and increased in abundance along the PCA nutrient gradient. Increased relative abundance of filter feeders in high nutrient sites could be due to increased periphyton algae levels within these sites (Hillebrand and Kahlert 2001). There was, however, less of difference in phytoplankton CHLa levels among site types; this could be related to overgrazing by abundant filter feeders in wastewater-fed wetlands. Another difference found between wetland types was size, with wastewater sites being larger and having more open water. While smaller filter feeders may sometimes be more abundant in open water areas (Lougheed and Chow-Fraser, 2001), all our collections were done from vegetated zones, so we are unable to make conclusions regarding the effect of open water in this case.
Other studies indicated plant diversity as being the main driver of diversity and habitat selection in macroinvertebrates (Hsu et al. 2011; Perron and Pick 2020; Perron et al. 2021). Although we did not quantitatively evaluate plant species richness, there appeared to be a similar trend with macroinvertebrate richness increasing within sites that tended to have higher plant diversity, many of which are non-wastewater sites.
Results from this investigation could be an important consideration for maintaining or restoring biodiversity to macroinvertebrates in arid region wastewater wetlands. More research is needed to confirm whether prolonged nutrient inputs in wastewater fed wetlands leads to further homogenization of macroinvertebrate communities, or whether this becomes an alternative stable state for these sites. Recent work has shown that the creation of wetland habitats fed by wastewater can substantially alter and improve aquatic macroinvertebrate community composition in a desert site relative to non-wetland aquatic habitats (Piña 2022). Thus, while wastewater sites are substantially different than their more natural counterparts, creation of these sites can benefit landscape level diversity (Stanislawczyk et al. 2018). We suggest that, where possible, managers of these valuable created habitats might try to find less nutrient-rich water sources, such as groundwater, to enhance the water quality in their sites. With reduced nutrient levels, we would expect to see an increased proportion of EOT, predators and collectors, among others. Further investigation is required to determine if other trophic levels are equally impacted by salinity and nutrient levels within these arid wetland ecosystems.
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Supplementary Material 1
Acknowledgements
This research was funded by STEMGrow (Dept of Education P031C160235) and the USDA (2015-68007-23130). The National Park Service granted access to sample at Big Bend National Park (BIBE-2019-SCI-0030) and Guadalupe Mountains National Park (GUMO-2019-SCI-0019). Thank you to Elizabeth Walsh for site location suggestions, to Lixin Jin for assistance with nutrient chemistry, and to John Sproul and all other wetland managers for allowing us to collect at their sites. This project would not have been possible without the help from STEMGrow project managers Paul Hotchkin and Helen Geller and undergraduate research assistants: Viridiana Orona, Christy Adame, Jovannie Gomez, Bryan Yu, Alyssa Calderon and Carlos Vargas. Special thanks to volunteer field assistant, Emmanuel Jacquez.
Tables.
Author Contributions
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Anna Elisa Piña. The first draft of the manuscript was written by Anna Elisa Piña and Vanessa Lougheed commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
This work was supported by Department of Education Hispanic Serving Institution STEMGROW (P031C160235) and the United States Department of Agriculture Water Resources Project Summer Internship (2015-68007-23130).
Data Availability
The datasets generated and analyzed during the current study are available in the Environmental Data Initiative repository, 10.6073/pasta/f42ad76f0562e27544d1bb0b56f19fb6.
Statements and Declarations
Competing Interests
The authors have no relevant financial or non-financial interests to disclose.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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| 0 | PMC9745719 | NO-CC CODE | 2022-12-15 00:02:41 | no | Wetlands (Wilmington). 2022 Dec 13; 42(8):128 | utf-8 | Wetlands (Wilmington) | 2,022 | 10.1007/s13157-022-01647-2 | oa_other |
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J Prev (2022)
J Prev (2022)
Journal of Prevention (2022)
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Springer US New York
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10.1007/s10935-022-00718-8
Policy
Measuring Impact of Climate Change on Indigenous Health in the Background of Multiple Disadvantages: A Scoping Review for Equitable Public Health Policy Formulation
Sahu Monalisha 1
http://orcid.org/0000-0002-7940-378X
Chattopadhyay Biswadip [email protected]
1
Das Ranjan 1
Chaturvedi Sakshi 2
1 grid.413616.7 0000 0001 2325 7296 Department of Preventive and Social Medicine, All India Institute of Hygiene and Public Health, 110, Chittaranjan Avenue, Kolkata, 700 073 India
2 grid.440551.1 0000 0000 8736 7112 Faculty of Nursing, Banasthali Vidyapith, Tonk, Rajasthan 304022 India
13 12 2022
136
24 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
How climate change is uniquely affecting Indigenous health remains a very less explored area in the existing research literature. The imperative of inclusive climate action to protect indigenous health multiplies manifolds due to their unique vulnerabilities owing to predominant dependence on natural resources and multiple disadvantages faced. The current article attempted to add to the evidence pool regarding climate change impacts on the indigenous population by systematically collecting, processing, and interpreting data as a scoping literature review for effective and inclusive climate policymaking. Twenty-Nine articles of varied study designs were identified employing a systematically organized search strategy using PubMed (Field, MeSH, and advanced search) and Google scholar; relevant data were extracted for further analysis. The Preferred Reporting Items for Systematic Review and Meta-Analysis for Scoping Reviews (PRISMA-ScR) guidelines were followed. Changing climate scenarios had both direct and indirect health-related impacts on indigenous health, and altered the epidemiological triad for various health-related events, causing the emergence and re-emergence of infectious diseases, and increased prevalence of chronic diseases and mental disorders. An expanded framework was developed showcasing the variability of climate change events, multiple disadvantages, and its impacts on indigenous populations. Few studies also reported a wide range of adaptation responses of indigenous peoples towards climate change. It was substantiated that any climate-change mitigation policy must take into account the trials and tribulations of indigenous communities. Also, due to the complexity and large variability of the impacts and differences in mitigation capabilities, policies should be contextualized locally and tailored to meet the climate need of the indigenous community.
Keywords
Climate change
Indigenous community
Health
Policy
Multiple disadvantage model
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pmcIntroduction
Humanity’s impact on the Earth has been profoundly leading to the Anthropocene epoch. The striking acceleration since the mid-twentieth century of carbon dioxide emissions and the transformation of land by deforestation and development has marked change in climate by effects like a rise in earth’s average temperature, sea level rise, and increased episodes of drought change in global average precipitation over land areas and increased incidences of natural disasters. The term “Climate change” refers to changes in climate properties (temperature, precipitation, extreme events, and wind patterns) that persist for a long period (decades or longer). (Liang & Gong, 2017) It is a powerful determinant of current and future health for all human populations. Though its far-reaching impact is on all parts of society; the impact of climate and ecosystem change has a direct impact on local livelihoods and sustenance of Indigenous people. Indigenous peoples are descent from populations, who inhabited the country or geographical region at the time of conquest, colonization, or establishment of present state boundaries. They retain some or all of their own social, economic, cultural, and political institutions, irrespective of their legal status. (Who Are the Indigenous & Tribal Peoples, 2016) The territories of the world’s 370 million indigenous peoples cover 24% of land worldwide and contain 80% of the world’s biodiversity. (The Role of Indigenous Peoples in Combating Climate Change | Humanities and Social Sciences Communications, 2022) Due to their subsistence economies and spiritual connection to lands and territories, most indigenous peoples suffer disproportionately from loss of biological diversity and environmental degradation resulting from climate change. (Indigenous Peoples & the Nature They Protect, 2020) Climate change presents substantial risks to their health and well-being.
Indigenous peoples also face multiple disadvantages and intersecting inequalities in terms of their economic situation (e.g., income), social support (e.g., social networks), and personal characteristics (e.g., health and educational attainment). (Research_summary_no1_2004_-_multiple_disadvantage)They are among the poorest of the poor; though they make up just 6 percent of the global population, they account for about 19 percent of the extreme poor. (Indigenous Peoples, 2022) They often lack formal recognition over their lands, territories, and natural resources, are often last to receive public investments in basic services and infrastructure, and face multiple barriers to participating fully in the formal economy, and participating in political processes and decision-making. (Indigenous Peoples, 2022) This legacy of inequality and exclusion has made Indigenous peoples the most threatened segment of the world’s population in terms of social, economic, and environmental vulnerability and hence at the receiving end of the impacts of climate change and impending natural hazards. This also highlights an important and difficult challenge in achieving the 2030 Agenda for Sustainable Development, which was adopted with the pledge that “no one will be left behind”. (Social Development for Sustainable Development | DISD, 2022) Surmounting this challenge will require focusing on indigenous peoples with inclusive policies. In particular, protecting Indigenous health now and into the future with rapid, equitable, and effective policies and practices.
It is thus imperative that climate mitigation policies and practices are designed to maximize positive impacts and minimize adverse outcomes for Indigenous health. However, evidence on which to base these decisions is limited.
Research Question: This scoping review sought to explore the current evidence for important potential impacts of climate change on Indigenous health in the background of multiple disadvantages and how it engages with Indigenous perspectives and experiences.
Methodology
We identified scoping review, as the most appropriate review method for mapping the impacts of climate change on Indigenous health as scoping reviews are useful for bodies of research that have cross-disciplinary and methodological boundaries, which is undoubtedly the case with the indigenous health and climate change literature. Scoping reviews are also helpful for identifying research gaps and emerging research priorities. We utilized standard scoping review methods for this study according to the relevant sections of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-ScR guidelines. (Tricco et al., 2018).
Information Source and Search Strategy
The review was undertaken conforming with the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping review (PRISMA-ScR) statement. (Tricco et al., 2018) We searched three major electronic databases of MEDLINE/PubMed (https://www.ncbi.nlm.nih.gov), Google Scholar (https://scholar.google.com), and Cochrane Library for pre-print and published literature from January 1, 2000, until May 31, 2022. Initial database search was done through field search using Boolean Operators with a combination of the following text words: “Indigenous people*”, “indigenous population*”, “indigenous health”, “indigenous communit*”, “tribal population”, “native peoples”, “climate change”, and “global warming”. A search strategy was formulated following a detailed analysis of the keywords and index terms (Medical Sub-Headings or MeSH terms for MEDLINE) based on their presence in the title and text of the articles. (Refer to Appendix A) Furthermore, reference lists from the identified articles selected through electronic databases were searched manually (backward chronological search).
Eligibility Criteria and Study Selection
The selection of articles was restricted to human studies published in the last 20 years. Original research findings based on both primary and secondary data were explored and included if found suitable. After completing the literature search with various databases with the search strategy discussed, the data for the found articles were transferred to Zotero 5.0 software (AGPL). In the next step, the duplicate articles in different databases were identified and merged. All titles and abstracts were examined to remove irrelevant studies or documents. In the next step, the available full texts of the selected studies were retrieved by filtering the abstract-only papers, and then the full texts were screened in detail.
Article entries were included in the review based on the following criteria:(i) Description of the impact of climate change, in its various form, on the health and well-being of indigenous communities
(ii) Perspective of the indigenous population towards climate change,
(iii) Association of disruption of health services in the indigenous community due to climate change.
Articles that were protocols and methodological studies were further excluded, and after reading the full texts, articles that did not fulfill the research question, or included any specific population or health-related outcomes were also excluded.
The search strategy was first developed and completed by MS & BC independently. To validate the process, RD and SC independently reviewed a random sample of 10% of the documents included for full-text review, and any discrepancies concerning inclusion were discussed by MS, BC, RD, and SC to reach consensus.
Data Extraction and Charting
Data extraction was done from individual full-text studies in two separate structured extraction sheets in Microsoft Excel. The following data items were collected during the data charting process:Publication characteristics: title, author name, journal, year of publication, country of origin.
Contextual characteristics of the study: Study design (e.g., review study, intervention study, qualitative or mixed-methods design study), study setting, sample characteristics including sampling design, source of data
Relevant output data from each full-text study were extracted for further analysis. Namely,Nature of climate change and its influence on the indigenous population. (e.g., unexpected weather changes, reduction of ice levels, heatwaves, bushfires)
Health outcomes (e.g., mortality, morbidity, risk factors, various determinants of health affected)
Few additional outcomes were extracted from articles, whenever applicable and necessary, such as the perspective of the indigenous community about climate change and its effect on their health and adaptive measures if taken any.
Results
From the 506 unique citations identified in the initial database search; the screening and eligibility assessments resulted in a final set of 29 (See Fig. 1).Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-ScR) flow diagram for study inclusion
In the following sections, we summarize the reviewed literature in terms of general characteristics and our research questions.
General Characteristics of Papers
Our review included empirical studies, non-empirical review studies, and some editorial/ commentaries/ perspectives that examined a range of climate change events, with health-related outcomes and analyzed by ethnicity. The search identified 518 articles. After, removing duplicates, and applying exclusion criteria detailed full-text search was done for 134 articles. On full-text screening it was found that 60 articles did not discuss climate change impacts; 10 were not related to health; 22 of them were not discussing Indigenous peoples, five articles were an editorial call for data collection and another five were protocols. Hence, finally, twenty-nine publications remained eligible for inclusion. Out of these 29 articles, five articles were incorporating qualitative research (Bryson et al., 2021; Keatts et al., 2021; Kowalczewski & Klein, 2018; Rautela & Karki, 2015; Westoby et al., 2020), two articles incorporated Mixed Method Research (Chatwood et al., 2017; Durkalec et al., 2015); case studies, time series, community-based project and symposium report were one piece each(Amstislavski et al., 2013; Galway et al., 2022; Huber et al., 2020b; Rahman & Alam, 2016); Seven review articles (1 systematic review, 2 Scoping Review, 4 narrative review) (Ellwanger et al., 2020; Galway et al., 2019; Jones et al., 2020; Lansbury Hall & Crosby, 2022; Lebel et al., 2022; Schramm et al., 2020; Standen et al., 2022); 6 commentaries (Hernandez et al., 2022; Leal Filho et al., 2021; Lewis et al., 2020; Redvers et al., 2022; Richards et al., 2019; Zavaleta-Cortijo et al., 2020); 4 perspectives (Callaghan et al., 2020; Houde et al., 2022; Redvers et al., 2020; Timler & Sandy, 2020) and 1 editorial was included in the final analysis. (Pollock & Cunsolo, 2019) We did not find any meta-analyses, randomized controlled trials, cohort, or case–control studies.
The studies examined a diverse set of both direct and indirect adverse effects of climate change on indigenous health worldwide. Out of these articles, most of them concentrated on physical health; five articles emphasized mental and psychosocial aspects of health (Galway et al., 2019; Huber et al., 2020b; Kowalczewski & Klein, 2018; Lebel et al., 2022; Standen et al., 2022); One article had discussed majorly on the access to health care system (Amstislavski et al., 2013); and another one discussed in detail about Health stewardship for indigenous peoples. (Chatwood et al., 2017) A few articles also discussed adaptive measures against climate change undertaken by various tribes and some community-based projects on climate-ready tribe initiatives. (Schramm et al., 2020) One article particularly discussed Gardening as an important solution to overcome climate change-led food insecurity. (Timler & Sandy, 2020) One article discussed how youth are being affected by climate change and how they can play a role in mitigation measures. Another article discussed how vulnerable groups like pregnant mothers are being affected by climate change. (Bryson et al., 2021) Tables 1, 2, and 3 have summarized the findings and spatial distribution of included reviews, empirical studies, and editorial/comments/perspectives respectively. Table 1 Summarized findings and spatial distribution of included reviews (n = 8)
SN Author, Year, Title, Source Study methodology Spatial distribution (Indigenous Population) Nature of climate change Impact on health outcomes and adaptation/response mechanism
1 Lebel et al. (2022)
Climate change and Indigenous mental health in the Circumpolar North: A systematic review to inform clinical practice
Transcultural
Psychiatry
Systematic review The Indigenous community of the circumpolar north:
Canada: Nunatsiavut, Nunavut, Northwest Territories
US: Alaska
Russia: Sakha Republic
Sweden: Sapmi
Environmental changes like:
The unpredictability of weather, extreme weather, decreased thickness and extent of the ice, changes in animal behavior, changes in wildlife
Immediate impacts of climate change on mental health were felt through restricted mobility and disrupted livelihoods
Effects on mental health were further felt through changes in culture and identity, food insecurity, interpersonal stress and conflicts, and housing problems
The mental health outcomes reported:
Anxious reactions, including chronic stress
Depressive reactions (i.e., grief, sadness, boredom, hopelessness, suicidal ideations)
Anger and frustration
Concerns about the future
2 Galway et al (2019)
Mapping the Solastalgia Literature: A Scoping Review Study
Int J Environ Res Public Health
Scoping Review Mostly Australia and United States Emotional, mental, and spiritual health dimensions of climatic and environmental change Solastalgia experiences often come “on top of other economic and social stressors”, thereby exacerbating health disadvantages and inequities
3 Jones et al. (2020)
International Journal of Environmental Research and Public Health
Scoping Review Global distribution:—Indigenous communities of Canada, the Dominican Republic, Ecuador, India, Mexico, New Zealand, Venezuela, the United States, Brazil, Australia, Peru, Cameroon, Tanzania, Indonesia, and Vietnam Climate change mitigation policies were evaluated through various methodologies according to the impact on Indigenous health Co-benefits and co-harms on indigenous health were detected
Intergenerational knowledge transmission, strengthening community resiliency, reduced energy use and fuel poverty, reduced air pollution, increased physical activities
Economically regressive impacts like job losses, and negative impacts on the diet
4 Standen et al (2022)
Aboriginal Population and Climate Change in Australia: Implications for Health and Adaptation Planning
Int. J. Environ. Res. Public Health
Review Australian Aboriginal populations Current evidence on the health risks of climate change for Aboriginal populations in New South Wales
Increased Temperatures and Heatwaves
Rainfall Variability and Risks of Flooding and Drought
Fire Danger
Pre-existing health sensitivities (such as chronic diseases and psychosocial distress) and factors limiting adaptive capacity (such as socioeconomic disadvantage and political environments) already put Aboriginal populations in NSW at greater risk of the impacts of climate change, and this will continue unless significant challenges are addressed
5 Schramm et al. (2020)
Current Environmental Health Reports
Review of Three case studies Swinomish Indian Tribal Community, which is located in present-day Washington State, US Climate-related warming and other changes, including storm surges, flooding, erosion from wind and wave actions Negative physiological (contamination, infectious disease) and non-physiological health impacts like, fishing and hunting resources initiated the policy of ‘Indigenized BRACE framework’ which incorporates a complex definition of health considering mental, social, cultural, and environmental facets and reflecting non-physiological priorities with the local context
BRACE =
Anticipate climate impacts and assess vulnerabilities
Project the disease burden
Assess public health interventions
Develop and Implement a Climate and Health adaptation plan
Evaluate impact and Improve the quality of activities
6 Lansbury-Hall et al. (2020)
International Journal of Environmental Health Research
Narrative Review Remote Indigenous people of Australia Extreme weather events like:
Storms, cyclone
Heavy rainfall
Heatwaves, bushfires
Droughts
Increased ozone formation in warmer weather and increased air-borne allergens
Food safety and security are compromised—food-borne diseases and malnutrition
Vector-borne diseases:
Warmer temperatures and increased rainfall are the main drivers of providing breeding conditions for mosquitoes
Water-borne diseases like bacterial gastroenteritis, Cryptosporidium, Giardia, Salmonella, and Hepatitis A incidence has increased over a few years due to climate change
7 Ellwanger et al. (2020)
Annals of the Brazilian Academy of Sciences
Narrative review Indigenous community in Amazon Rainforest Climate change, deforestation, rainfall, flooding, water contamination, human agglomeration, urbanization Habitat loss and pathogen spillover, and changes in vector dynamics lead to an increase in infectious diseases
Increased incidence of Leishmaniasis cases
Emergence and re-emergence of Arboviral diseases
High prevalence of Malaria and Hantavirus pulmonary syndrome among gold miner community of Amazon
Increase in Rabies attack
Higher density of Chagas disease
8 Keatts et al. (2021)
Implications of Zoonoses from Hunting and Use of Wildlife in North American Arctic and Boreal Biomes: Pandemic Potential, Monitoring, and Mitigation
Frontiers in Public Health
Qualitative Literature Review North American Arctic and Boreal Biomes Arctic and boreal ecosystems are undergoing rapid changes through climate warming, habitat encroachment, and development All of these can change the host and pathogen relationships, thereby affecting the probability of the emergence of new (and re-emergence of old) zoonoses
Table 2 Summarized findings and spatial distribution of included empirical studies (n = 9)
SN Author, Year, Title, Source Study methodology Spatial distribution (Indigenous Population) Nature of climate change Impact on Health Outcomes and Adaptation/ response mechanism
1 Amstislavski et al (2013)
Effects of increase in temperature and open water on transmigration and access to health care by the Nenets reindeer herders in northern Russia
Int Journal of Circumpolar Health
Correlational and time series analyses Nenets reindeer herders in northern Russia Autumn temperature anomalies and increases in open water on health care access and transmigration of reindeer herders on the Kanin Peninsula Later arrival of freezing temperatures in the autumn followed by the earlier spring thaws and more open water delay transmigration and reduce herders’ access to health care. The recently observed delays in arrival to the clinic are likely related to the warming trend and concomitant hydrologic changes
2 Chatwood et al (2017) Indigenous Values and Health Systems Stewardship in Circumpolar Countries
Int. J. Environ. Res. Public Health
Embedded, Transformative, Emergent Mixed Methods Design First Nations, Inuit, Métis, Sámi, and non-indigenous To understand indigenous values that underlie and direct effective health systems stewardship in circumpolar countries including the Nine values were identified and described: humanity, cultural responsiveness, teaching, nourishment, community voice, kinship, respect, holism, and empowerment
3 Durkalec et al. (2015)
Social Science and Medicine
Sequential mixed-methods design Inuit Community (sea ice users) of Arctic Canada Changing sea and freshwater ice, Physical health:
Strain and discomfort from physical exertion, hypothermia from falling off the ice, impact from cold exposure, injuries from unintentional impacts
Mental, emotional, and spiritual health impacts
Social well-being
4 Galway et al (2022)
"Land is everything, the land is us": Exploring the connections between climate change, land, and health in Fort William First Nation
Social Science & Medicine
Community-based Project Fort William First Nation, which is an Anishinaabe community in Northern Ontario Understanding the links between climate change and physical, mental, emotional, and spiritual health Five themes at the intersection of climate change, land, and health, with theme three- Healthy lands, healthy people describing the pathways through which knowledge holders spoke to the physical, mental, emotional, and spiritual health implications of climate change. a central idea that emerged is that when the land is sick, and when Mother Earth is sick, people are sick
5 Rahman et al. (2016)
Climate
Case-study Four indigenous communities living in and around Lawachara National Park located in North-eastern Bangladesh:
Khasi, Tripura, Garo, Manipuri
Increasing temperature, variation in rainfall, irregularity in rainfall, landslide, soil erosion, flash flood, drying up of streams and well, natural calamities, heavy fog, and cold Increased water-borne diseases (diarrhea, dysentery, skin diseases)
Malaria and allergies
6 Kowalczewski et al. (2018)
International Journal of Circumpolar Health
Qualitative study Youths of the Sami community from Kautokeino, Norway Climate change like thinning of the ice, altered ice stability, and decreased snow cover Youths are particularly susceptible to being negatively impacted by climate change through increased safety issues (unstable snow routes traversed during Reindeer herding) or anxiety
7 Rautela et al. (2015)
American Journal of Environmental Protection
Qualitative research Bhotiya tribe of Johar, Byans, Niti Valley in the Northern frontier of Uttarakhand state, India Perception of climate change among the indigenous population was: -
Increased temperature, glacial retreat, early melting of snow, less snowfall, increased winter precipitation (rain), change in duration and timing of rain
Impact on livelihood, reduced agro-diversity, food insecurity, scarcity of drinking water, increased workload for women and children, and thus, being vulnerable to a plethora of diseases
8 Bryson et al (2021)
Seasonality, climate change, and food security during pregnancy among indigenous and non-indigenous women in rural Uganda: Implications for maternal-infant health
PLOS One
Community-based research approach, we conducted eight focus group discussions— Indigenous Batwa communities Pathways through which climate change influenced food security during pregnancy among Indigenous and non-Indigenous women in rural Uganda Women indicated that food insecurity was common during pregnancy and had a bidirectional relationship with antenatal health issues. Food security was thought to be decreasing due to weather changes including extended droughts and unpredictable seasons harming agriculture. Women linked food insecurity with declines in maternal-infant health over time, despite improved antenatal healthcare. While all communities described food security struggles, the challenges Indigenous women identified and described were more severe
9 Westoby et.al. (2020)
From community-based to locally-led adaptation: Evidence from Vanuatu
Ambio
focus group discussions, formal
interviews and conversations about the projects
Four Ni-Vanuatu Communities Adaptation response of community towards climate change Pacific Islanders in situ are the best judge of their own agendas, needs, aspirations and futures and in the best position to make decisions for themselves about what and how they might become more resilient. Rather than adaptation being ‘community-based’, it needs to be ‘locally led’, and should take place across different entry points and incorporate, as appropriate, elements of autonomous/Indigenous peoples ownership
Table 3 Summarized findings and spatial distribution of included editorial/ commentaries/ perspectives. (n = 12)
SN Author, Year, Title, Source Study methodology Spatial distribution (Indigenous Population) Nature of climate change Impact on Health Outcomes and Adaptation/ response mechanism
1 Huber et al., (2020a), (2020b) (Huber et al., 2020a)
International Journal of Circumpolar Health
Symposium report Yakutia indigenous community in the Republic of Sakha, Russia Extreme weather changes, prolonged heat periods, smoke, exposure to ultraviolet radiation, thawing of permafrost Increased cases of zoonotic diseases:
Diphyllobothriasis
Echinococcosis
Yersiniosis
Lyme Disease
Brucellosis
Mental health deterioration due to inadequate coping strategies
Asthma due to increased air pollution
2 Filho et al., (2021) (Impacts of Climate Change to African Indigenous Communities and Examples of Adaptation Responses | Nature Communications, n.d.)
Impacts of climate change on African indigenous communities and examples of adaptation responses
Nature Communication
Commentary Five African Indigenous communities
(Afar, Borana, Endorois, Fulani, and Hadza)
Increased frequency and intensity of extreme weather events such as droughts, floods, storms, cyclones, as well as heatwaves, among others The scarcity of drinking water, reduction of fresh crops, and the emergence of zoonotic diseases led to the formulation of climate-change mitigation strategies, like livestock destocking and diversification, rainwater harvesting, and mixed cropping
3 Redvers et al., (2022) (Redvers et al., 2022)
Lancet Planet Health
Commentary/ personal view Global distribution of Indigenous Peoples from around the world (Kenya [Ogiek], Canada [Denésuliné, Sahtu’ot’ine, and Haudenosaunee], USA [Blackfeet and Tsimshian], Australia [Gamilaraay, Nyikina Warrwa, and Wangkumara], Mexico [Yaqui, Nahua, and Maya], El Salvador [Nahua], and Nicaragua [Miskita]) Global Environmental changes within indigenous communities, including climate change and pollution Planetary Health Determinants: Indigenous people’s health is considered a determinant of planetary health as global climate change affects indigenous people’s health. The indigenous people’s health must be approached from a holistic lens that acknowledges cultural and land-based practices
4 Lewis et al (2020)
A radical revision of the public health response to the environmental crisis in a warming world: contributions of Indigenous knowledge and Indigenous feminist perspectives
Canadian Journal of Public Health
Commentary Indigenous peoples living in the colonial nation-states of Canada and Aotearoa New Zealand How public health policy and discourse fails Indigenous peoples living in the colonial nation states of Canada and Aotearoa New Zealand Addressing these systemic failures requires the incorporation of Indigenous knowledge and Indigenous feminist perspectives beyond superficial understandings in public health-related climate change policy and practice, and that systems transformation of this nature will in turn require a radical revision of settler understandings of the determinants of health
5 Pollock et al. (2019)
Collaborative approaches to wellness and health equity in the Circumpolar North: Introduction to the Special Issue
International Journal of Circumpolar Health
Editorial Circumpolar North To help bridge local insights, innovations, and varied forms of evidence from the Circumpolar North, with global conversations about health equity, health system transformation, and the rights of Indigenous peoples Indigenous self-determination in health care and health research; access to traditional medicines; language and identity; youth engagement; mental health; climate change; and health technology
6 Redvers et al. (2020)
Molecular Decolonization: An Indigenous Microcosm Perspective of Planetary Health
Int. J. Environ. Res. Public Health
Perspective US & Australia Need for Indigenous self-determination and the formal recognition of Indigenous pieces of knowledge, including micro-level molecular and microbial knowledge, as a critical foundation for planetary health is in urgent need The planet’s health is a reflection of our health and well-being right down to the molecular level. When Mother Earth is sick and unbalanced, we are also sick and unbalanced. Due to the interconnected web of our existence, there is a great need to reconsider our daily practices and thought processes through the lens of reciprocity, responsibility, and relationality to Mother Earth
7 Timler et al., (2020)
Gardening in Ashes: The Possibilities and Limitations of Gardening to Support Indigenous Health and Well-Being in the Context of Wildfires and Colonialism
Int. J. Environ. Res. Public Health
Perspective Indigenous Peoples in Canada Gardening as a relationship with nature and an ongoing process to support Indigenous health and well-being in the context of the climate crisis and increasingly widespread forest fires The concept of gardening as both a Euro-Western agricultural practice and as a longstanding Indigenous tradition—wherein naturally occurring gardens were tended in the relationship—and the influences of colonialism and climate change on both. The foundational importance of reciprocity and relationship in the context of foodways to support holistic health and well-being will be outlined
8 Callaghan et.al. (2020)
Improving dialogue among researchers, local and indigenous peoples, and decision-makers to address issues of climate change in the North
Ambio
Perspective Circumpolar North (Eurasian Arctic and Siberia) Climate change impacts Siberian and global weather systems, increasing the frequency and intensity of extreme weather events. Examples are local scale hurricanes, tornados, extremely dry/wet periods (e.g. Forbes et al. 2016), and increased frequency of tundra and forest fires (Bret-Harte et al. 2013). Another example is the rapid methane release from below-ground reservoirs that can cause explosions, creating craters in the physical landscape (Kizyakov et al. 2017). This is potentially dangerous if future explosions occur under oil and gas pipelines Understanding and adapting to both types of changes are important to local and indigenous peoples in the Arctic and for the wider global community due to transboundary connectivity
9 Cortijo et al., (2020)
Climate change and COVID-19: reinforcing Indigenous food systems
The Lancet Planetary Health (2021)
Commentary The nature and extent of the effects of COVID-19 on Indigenous food systems are still largely unknown, but the direct results include mortality from severe illness, reduced access to food, changes in the local diet, and economic losses resulting from lockdowns Effects of climate change undermine Indigenous food security, in turn compromising the resilience of Indigenous populations to pandemics. At the same time, disruptions to food and nutrition security and the resulting health implications for Indigenous populations during pandemics exacerbate their vulnerability to climate change
10 Richards et al., (2019)
The Climate Change and Health Adaptation Program: Indigenous Climate Leaders' Championing Adaptation Effort
Health Promotion and Chronic Disease Prevention in Canada
Commentary First Nations Inuit Needs of climate change and health in First Nation and Inuit communities to support resiliency and adaptation to a changing climate both now and in the future through its emphasis on youth and capacity building Engaging youth and Elders to respectively learn and pass along Indigenous Knowledge from generation to generation strengthens communities’ resiliency and helps ensure that the projects and initiatives are sustainable as capacity within the community and amongst youth is built. Through both peer and professional training each project builds capacities in different areas, such as research and interview skills, technological skills, and skills on the land
11 Houde et al., (2022)
Contributions and perspectives of Indigenous Peoples to the study of mercury in the Arctic
Sci Total Environ
Perspectives Arctic Indigenous Peoples Overview of the contributions of Indigenous Peoples to Hg monitoring in the Arctic, and discuss approaches that could be used, and improved upon, when carrying out these activities In recent years, Indigenous communities often have chosen to participate in, or initiate contaminant research projects because they were, or are, worried about the health of the ecosystem and the safety of their traditional country foods. During the early stages of contaminant research in the Arctic (i.e., starting in the late 1980s in Canada), the finding of high contaminant levels in the remote Arctic environment rattled researchers and led to fear-inducing communication and messages directed toward public
12 Hernandez et al., (2022)
Prevent pandemics and halt climate change? Strengthen land rights for Indigenous peoples
The Lancet Planetary Health
Commentary USA Indigenous, pastoralist, and rural farming communities are especially dependent on land, which is widely recognized by conservation organizations. Such communities are often uniquely vulnerable to the effects of ecosystem destruction while simultaneously having strong social norms and cultural values that support ecosystem preservation Planetary health and “One Health” researchers should make explicit the links between land rights and health. This includes the marginalization, exclusion, and forced displacement of Indigenous peoples, which have been shaped by colonial and postcolonial politics and economics. Such groups are often at the margins of state control and experience state incursion through systems of taxation, isolation, monetization, commodification, and deculturation
Spatial Distribution of the Articles
Concerning geographic distribution among the papers in our final sample, there is a clear predominance of circumpolar countries underlying the imminent impact of climate change that the indigenous population of those countries is facing. Of these 29 articles, nearly half had a focus on the Canadian region; and another 11 (38%) had a focus on the United States; seven studies (24%) focused on Russia; Australia (five articles) and the Scandinavian countries (Sweden five, Norway and Finland and Denmark three apiece) were next for the most-focused countries in the review. Very few articles studied the indigenous communities of Asia (India, China) and Africa (Uganda, Kenya, Tanzania, Ethiopia). The Global South was underrepresented in the review as a whole. Figure 2 provides the geographic distribution of articles within the globe.Fig. 2 Choropleth Map showing the geographical distribution of the indigenous population within the articles included in the review
Temporal Distribution of the Articles
There was an increasing trend in the number of articles published over the last twenty years’ time, especially after 2015–May 2022 (Fig. 3). The number of Indigenous health research articles has been increasing over time with a few notable drops and peaks. In 2020, there was a steep increase in, which had 11 published articles. A potential reason for the increase in publications may be attributed to the COVID-linked lockdown and increased overall publication frequency of research papers that may have contributed to the increased publications during that year.Fig. 3 Number of included studies by years of publication (n = 29)
How Climate Change is Affecting Indigenous Health?
To better understand the impacts of climate change on Indigenous health, we focused on the subset of studies with empirical data, specifically (n = 20). Study populations were quite varied and ranged from geographically based residents of specific regions and culturally identified subpopulations such as Pregnant Batwa women of Uganda, Sami youths in Norway, Swinomish tribes in Washington, and Bhotia Tribe in India, etc. It was found that Indigenous health is impacted by climate change in three main stages (primary, secondary and tertiary impacts):
Firstly, climate change can directly or primarily cause injury and death from extreme weather events including heat waves and droughts, violent storms, cyclones, flooding, landslides, bushfires increasing sea levels, and rising infectious disease. It was reported that extreme weather events and decreased thickness and extent of ice lead to increased safety hazards. Among the Inuit community in northern Canada, the changing nature and increasing variability of environmental hazards are predicted to increase the frequency and severity of physical health impacts from environmental exposure reporting increasing injuries related to changing ice and weather conditions (ACIA 2005, 2022; Prowse & Furgal, 2009). The Yakutia indigenous community in the Republic of Sakha, Russia has reported increased illness resulting from extreme weather events. (Kowalczewski & Klein, 2018). Indigenous remote settlements in Australia suffer from various physical health impacts due to the severity and frequency of extreme weather events—namely heatwaves, bushfires, floods, cyclones, and drought. (Lansbury Hall & Crosby, 2022) In indigenous communities from Bangladesh (Khasia, Tripura, and Garo) changes in temperature and rainfall patterns, have led to increased frequency of landslides, soil erosions, flash floods, heavy cold, and fog, increasing injuries, diseases, and deaths. (Rahman & Alam, 2016) Productivity and other workforces also get impacted by hotter/colder working conditions, and damage to infrastructure from extreme events, such as on housing and healthcare systems further devastating for the indigenous people.
Secondly, indirect or secondary impacts are triggered through environmental and ecosystem changes and manifest as impacts on water quality and availability, food quality, security, and sovereignty. For example, it was reported that extreme weather events and decreased thickness and extent of ice lead to decreased access to country food and result in impaired food security and sovereignty. In the higher Himalayan Region increase in average temperatures and abrupt changes in the precipitation regime have resulted in water scarcity, food insecurity due to crop failure, increased incidences of pest infestations, and animal attacks affecting the indigenous people adversely. (Rautela & Karki, 2015). In-utero exposure to climate change effect like food insecurity also leads to poor maternal and child health.
Impact on air quality secondary to climate change leads to a rise in associated respiratory health and other chronic diseases, and on distribution and breeding/propagating conditions for vector-borne diseases and pathogens of various infectious diseases. Climate change is also altering the epidemiological triad resulting in ‘the epidemiological transition’ through a changing climate and a resulting change in the environmental component of the triad. (Lansbury Hall & Crosby, 2022) Also, the interaction between hosts and pathogens is regulated in part by highly synchronized temperature and photoperiod changes during seasonal transitions. (Casadevall & Pirofski, 2000) With a warming climate and altered humidity, these key biological cues are undergoing drastic changes, resulting in drastic consequences on host–pathogen interactions especially on indigenous populations as they have a greater dependence on environmental resources for their basic needs. The Yakutia indigenous community in the Republic of Sakha, Russia has reported increased incidences of zoonotic diseases resulting from extreme weather events. (Kowalczewski & Klein, 2018). In Amazonia, deforestation and climate change have become the major drivers of emerging diseases in the indigenous population. (Ellwanger et al., 2020) In forest-based indigenous communities, namely, Khasia, Tripura, and Garo from Bangladesh changes in temperature and rainfall patterns, and natural calamities have increased pests, diseases, and the attack by wild animals. (Rahman & Alam, 2016).
Finally, impacts can be tertiary or indirect through changes to social systems; affecting socio-economic, mental, emotional, and spiritual well-being. Indigenous peoples have a deep sense of their place and belongingness which gets perturbed due to climate-related changes compelling them to migrate resulting in solastalgia. It was also reported that extreme weather events and decreased thickness and extent of ice that adversely affects food security and sovereignty, indirectly bring changes in culture and identity, accentuating interpersonal stress and conflicts.
Impacts of climate change on mental health happen due to restricted mobility and disrupted livelihoods and are further accentuated through changes in culture and identity, food insecurity, interpersonal stress and conflicts, and housing problems. (Lebel et al., 2022). In the Inuit community in northern Canada which has deep cultural connections with sea ice, the changing ice and weather conditions have been reported to result in anxiety-related episodes (ACIA 2005, 2022; Prowse & Furgal, 2009).
Indigenous People and the Multiple Disadvantages
In addition, Indigenous people across the world tend to suffer multiple types of socioeconomic disadvantages, including extreme poverty, poor living conditions, low educational attainment, unemployment due to failure of traditional livelihoods, racism, and limited access to various healthcare services which are important determinants of Indigenous health. Living on marginal land with poorer infrastructure, socioeconomic deprivation, various inequities, and political marginalization; they are doomed to suffer from a greater burden of disease, and poorer access to quality health care.
In this review we analyzed the data from a vast body of heterogenous literature and synthesized an expanded framework with the background of multiple disadvantages, depicting the effects of climate change on Indigenous health through various direct and indirect pathways.
Figure 4 proposes an expanded framework of climate change impacts on indigenous health.Fig. 4 Expanded Conceptual framework of climate change impacts on indigenous health
How does the Literature on Climate Change and Health Impacts Engage with Indigenous Perspectives and Participation?
The indigenous peoples (especially those relying on natural resources) have an experienced and inherited knowledge of their environments, ecosystems, and local society. Therefore, their perspectives have an important role in determining and mitigating the impacts of climate change on local societies. Indigenous Peoples in the Arctic and Boreal have expressed concerns about potential effects on Indigenous rights and food sovereignty as a result of policy initiatives focused on hunting, consumption, sharing, and local trade of wildlife. These populations are frequently at the forefront of protecting wild food systems, livelihoods, and cultural values. When the socioeconomic, cultural, and nutritional aspects of Indigenous subsistence methods were not taken into account, negative effects resulted. For instance, prior culturally insensitive and inadequately developed communication outreach efforts regarding health and traditional and country foods (on contaminants) resulted in adverse health effects for the affected populations from avoiding traditional foods altogether, given the dearth of healthy alternatives. For local communities of hunters, trappers, and fishermen throughout the area, zoonotic health hazards have also risen (Keatts et al., 2021). From the perspectives of indigenous peoples of Circumpolar North, the changing environmental conditions have led to a decrease in the abundance of lichens and other forage plants such as horsetails, resulting in reduced reindeer weight and has forced the herders to move to new areas resulting into the instability of reindeer husbandry livelihoods. (Callaghan et al., 2020) Similarly, among Nenets reindeer herders from Russia, the later arrival of freezing temperatures in the autumn followed by the earlier spring thaws and more open water, delay in transmigration, and reduced access to health care are major concerns (Amstislavski et al., 2013). There are also concerns about how public health policy and discourse fail Indigenous peoples living in the colonial nation-states of Canada and Aotearoa New Zealand especially not taking into account Indigenous knowledge and Indigenous feminist perspectives (Lewis et al., 2020). Indigenous Women of the Batwa tribe in Uganda indicated that food insecurity was common during pregnancy and had a bidirectional relationship with antenatal health issues. (Bryson et al., 2021).
Paetnerships with Indigenous people: Within the twenty-nine studies, included in the review eleven studies were conducted in partnership with Indigenous communities namely, the Swinomish Indian Tribal Community (Swinomish)- a Coast Salish nation located in present-day Washington State (Schramm et al., 2020); Khasia, Tripura, Garo, and Manipuri are living in and around Lawachara National Park (LNP) located in North-eastern Bangladesh (Rahman & Alam, 2016), Bhotiya tribe of Johar, Byans, Niti Valley in the Northern frontier of Uttarakhand state, India (Rautela & Karki, 2015), Youths of Sami community from Kautokeino, Norway, Yakutia indigenous community in the Republic of Sakha, Russia (Kowalczewski & Klein, 2018), Inuit Community of Arctic Canada (Durkalec et al., 2015), Fort William First Nation—an Anishinaabe community in Northern Ontario, Indigenous Batwa Communities from Uganda, Ni-Vanuatu Communities, and five indigenous African communities (Afar, Borana, Endorois, Fulani, and Hadza). (Leal Filho et al., 2021) Out of the 29 studies around half of them studied the local climate adoption methods also.
The Swinomish Tribe had adjusted the CDC’s BRACE framework in a more local, indigenized context where several needs and activities of the community which were affected by climate change (for example, traditional hunting, fishing, and harvesting practices) along with community-held perceptions of climate change were incorporated in the ‘value-based’ decision-making for key adaptation strategies (Schramm et al., 2020). Focus group discussions on three indigenous communities of LNP revealed a handful of community-based adaption strategies through local knowledge and perceptions, such as, using medicinal plants, organic and compost fertilizers, lime oil, and cake to tackle rising temperature and low rainfall, storing extra firewood for high rainfall, early harvesting of crops and livestock rearing for tackling natural calamities, etc. Increasing temperature and drying up of streams and wells were the highest priority climate risk from the perspective of the indigenous tribes (Rahman & Alam, 2016). The Bhotiya tribe of the Higher Himalayas, Uttarakhand perceived a decline in agricultural productivity and reduced agro-biodiversity as the major impacts of climate changes like reduced rainfall on livelihood. The indigenous perspective of coping and adaptation measures comprised improvising with cash crops, delayed sowing, shifting to smaller livestock, etc. (Rautela & Karki, 2015). The Health of the Sami community has been impacted by climate change, for instance, an increase in safety issues and anxiety due to less stable ice and snow routes. Health-seeking process for people from the Sami community exhausts beyond individual and family-level coping strategies towards professional aid (conventional Norwegian medicine and traditional Sami medicine) as per the severity of climate change impact; which are separated by social norms and health-seeking behavior (Kowalczewski & Klein, 2018). African indigenous communities (Afar, Borana, Endorois, Fulani, and Hadza) have been observed to use their local knowledge and perception in climate-change adaptation strategies (e.g., temporary migration, livestock diversification, a shift in settlement patterns, mixed cropping) as it is seen that traditional knowledge and local perception on climate change could help in, apart from mitigating it, sustainable management of the ecosystem, bolstering food security, benefit livelihood, and promote socio-economic resilience. (Leal Filho et al., 2021).
Discussion
In this review, we assessed the potential size and scope of available research literature on climate change impacts on Indigenous health. We observed that globally, many Indigenous Peoples face higher exposure to climate change risks due to close relationships and dependence on livelihoods associated with natural resources, and the location of communities in remote areas that are exposed to natural hazards of cyclones, fires, and droughts. (Natural Hazards & Disaster Risk Reduction, 2015) For indigenous communities from arctics and circumpolar north, rising temperatures and reduced ice cover are causing serious impacts on both the physical and mental health of the various Indigenous communities (Kowalczewski & Klein, 2018). Increased heatwaves, droughts, floods, storms, and other extreme weather phenomena on the African continent led to a shortage of fresh produce and drinking water as well as the spread of zoonotic diseases.
Similarly in other parts of the world, extreme weather changes, prolonged heat periods, smoke, and exposure to ultraviolet radiation, causes poor physical health, strain, and discomfort from physical exertion, episodes of heat stroke, as well as poor mental, emotional, and spiritual health. Their vulnerability is also increased manifold due to wide prevalent inequity and multiple disadvantages faced by the indigenous communities. They are suffering from a ‘triple burden of disease’, due to the combined effect of chronic diseases, infectious diseases and climate change impacts where climate change impacts further exacerbate existing health inequalities. (Kumar et al., 2020).
In our study, out of the 29 studies around half of them studied the local climate adoption methods also. The majority of the response mechanisms consist of impact measurement, assessment of the health system in the community, and bringing out resilient community action through capacity building and resource management, which were context-specific. In an earlier review conducted only three studies reported being conceived, designed, or conducted in partnership with Indigenous communities or informed by Indigenous pieces of knowledge and values. (Lebel et al., 2022) In our study, we found that in eleven studies there was an involvement of indigenous peoples in the climate mitigation and adaptation process.
Research Gap
The climate change impacts on health and its examination through indigenous perspectives has been a less explored area. The lack of studies on the health impacts of climate change on indigenous people worldwide has resulted in a lack of understanding and failure to comprehend the related domains. Also, despite the clear implications of climate change on indigenous health and the associated multiple disadvantages, there were strikingly few studies examining the possible pathways and mechanisms. Though in the past few years this topic has seen an accelerated momentum, most of the studies were done in a piecemeal manner lacking holistic treatment. Importantly, a comprehensive understanding of how Indigenous people’s health could be affected by climate change holistically, with the identification of strengths, weaknesses, and gaps in the literature to guide future research, policy, and practice is urgently needed. Promising trends like the increase in research on the adaptation and mitigation efforts for Indigenous health, along with an increase in studies that are seeking Indigenous partnership and participatory methods of research are the call of the hour.
In response to this challenge, the present paper attempts to contribute to the existing body of knowledge by systematically mapping the various climate factors influencing indigenous health with diverse methodologies based on the multiple disadvantage model.
Policy Implications
In drawing attention to the impact of changing climate on indigenous health with the backdrop of multiple disadvantages, this review provides a powerful argument for the need for policymakers to have an indigenous approach in decision-making and acknowledge their differing needs.
The variety of sources considered in this study allows the identification of major principles that can inform policymakers on the topics of climate mitigation and adaptation efforts to contribute to Indigenous health equity. As per our review findings, the climate mitigation policy formulation must be done with keeping in mind the specific features and contextual factors for the particular indigenous community for generating impacts. This will also require a deliberate, carefully planned approach to community engagement. Genuine climate solutions must seek to disinvest from institutions and systems that are complicit in fuelling the climate crisis, and instead must be grounded in different ways of knowing, doing, and being that reflect Indigenous values to fully account for the unique realities of Indigenous peoples. Indigenous communities’ contributions are essential in designing and implementing solutions for changing ecosystems.
Strengths and Limitations
The majority of the evidence that currently exists on climate change and its impact on health is limited to a colonial/western perspective and is from generic equity analyses. Very few studies have tried exploring climate change impacts using an indigenous lens. Our review with its particular emphasis complements existing literature and also adds some fresh insights on relevant outcomes, which can have serious implications for informing future climate policy and their translation into action. However, it only captures information included within the identified articles. Also, given the wide scope of the review and the heterogeneity of terminology used in article titles, abstracts, and keywords, our search might have missed a few relevant studies. The review also had an emphasis on publications in the peer-reviewed literature, which may further have decreased the number of articles. Also, the authors did not reach out to authors individually to gather further information nor did infer or extrapolate what the authors of these articles may or may not have done in their research processes.
What the Scoping Review Adds
Drawing on the review of the previous studies, the authors synthesized the determinants from the literature review to frame the: Expanded Conceptual framework of climate change impacts on indigenous health (Fig. 4). This framework sought to synthesize the complex interplay of factors across the physical, mental, social, and spiritual health of Indigenous people directly or indirectly because of climate change and multiple disadvantages.
Conclusion and Recommendations
Climate change has a significant impact on the health of indigenous people and multiple disadvantages were found to have a ‘compounding’ effect on their vulnerabilities that appears to be much more prominent for Indigenous people than for others. Hence adaptation and mitigation policies and practices should be inclusive of the indigenous communities to address this growing threat. Because of large geographic variations in climate impacts, and differences in vulnerability and adaptation capabilities of different indigenous populations; policies and programs must be tailored to cater to specific health needs at a local scale utilizing local data and expertise. Despite the complexity of this field of research, it is possible to improve the quality of evidence about co-impacts on Indigenous health to inform pro-equity climate mitigation. This will require partnership with Indigenous communities, recognition and privileging of indigenous pieces of knowledge, and study design that fully embeds Indigenous values, realities, and priorities. Fundamentally, sharing of power, both in the research process and in the conception, design, and implementation of climate policy and interventions, will be essential for Indigenous rights and health equity.
Appendix A: Sample Search Strategy (MEDLINE)
Search Strategy (PubMed/MEDLINE):
"Indigenous Peoples"[MeSH Terms] OR "native people*"[Title/Abstract] OR "indigenous population*"[Title/Abstract] OR "first nation people*"[Title/Abstract] OR "trib*"[Title/Abstract] OR "indigenous communit*"[Title/Abstract] OR "indigenous group"[Title/Abstract] OR "aboriginal people*"[Title/Abstract] OR "aboriginal communit*"[Title/Abstract] OR "primitive communit*"[Title/Abstract] OR "primitive group"[Title/Abstract]
"climate change*"[Title/Abstract] OR "climate variabilit*"[Title/Abstract] OR "climatic variabilit*"[Title/Abstract] OR "climatic change*"[Title/Abstract] OR "climate uncertaint*"[Title/Abstract] OR "climatic uncertaint*"[Title/Abstract] OR "global warming*"[Title/Abstract] OR "Global Warming"[MeSH Terms] OR "Climate Change"[MeSH Terms]
1 AND 2
Limit 3 to full-texts, Publication date from 01.01.2000 to 31.05.2022, and studies on human.
Author’s Contribution
M.S. conceived the study and M.S. and B.C., contributed to the development of the research methods and conducted the literature searches, screening and selection of studies, data charting and analysis, and prepared the first draft of the manuscript. R.D. & S.C. undertook the independent review of study selection and. M.S., B.C, R.D. & S.C. advised on the literature search strategy, data analysis, and interpretation of findings. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding. No funding was received to assist with the preparation of this manuscript.
Declarations
Conflict of Interest
We declare no other competing interests. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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| 36512184 | PMC9745731 | NO-CC CODE | 2022-12-15 00:02:41 | no | J Prev (2022). 2022 Dec 13;:1-36 | utf-8 | J Prev (2022) | 2,022 | 10.1007/s10935-022-00718-8 | oa_other |
==== Front
Pediatr Nephrol
Pediatr Nephrol
Pediatric Nephrology (Berlin, Germany)
0931-041X
1432-198X
Springer Berlin Heidelberg Berlin/Heidelberg
5835
10.1007/s00467-022-05835-4
Review
Vaccines and nephrotic syndrome: efficacy and safety
http://orcid.org/0000-0002-6121-5326
Angeletti Andrea [email protected]
Lugani Francesca
La Porta Edoardo
Verrina Enrico
Caridi Gianluca
Ghiggeri Gian Marco
grid.419504.d 0000 0004 1760 0109 Division of Nephrology, Dialysis and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy
13 12 2022
114
14 6 2022
9 11 2022
14 11 2022
© The Author(s), under exclusive licence to International Pediatric Nephrology Association 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Vaccines represent the most important medical evolution in the last two centuries allowing prevention and formally eradication of a wide number of infectious diseases. Safety and effectiveness are main issues that still require an open discussion. A few clinical reports described a critical temporal relationship between vaccination and acute nephrotic syndrome, indirectly suggesting an association. For this review, the literature was reviewed to identify articles reporting associations of nephrotic syndrome with vaccines against a vast array of infectious diseases (including bacteria, virus and Sars-Cov-2). As specific aims, we evaluated effectiveness and safety in terms of occurrence of either “de novo” nephrotic syndrome in health subjects or “relapse” in those already affected by the disease. In total, 377 articles were found; 166 duplicates and 71 non-full text, animal studies or non-English language were removed. After excluding another 50 articles not containing relevant data on generic side effects or on relapses or new onset nephrotic syndrome, 90 articles met the search criteria. Overall, studies reported the effect of vaccines in 1015 patients, plus 4 nationwide epidemiologic investigations. Limited experience on vaccination of NS patients with measles, mumps, and rubella live attenuated vaccines does not allow any definitive conclusion on their safeness. VZV has been administered more frequently without side effects. Vaccines utilizing virus inactivated, recombinant, and toxoid can be utilized without risks in NS. Vaccines for influenza reduce the risk of infections during the pandemic and are associated with reduced risk of relapse of NS typically induced by the infection. Vaccines for SARS-CoV-2 (all kinds) offer a concrete approach to reduce the pandemic. “De novo” NS or recurrence are very rare and respond to common therapies.
Keywords
Children
Idiopathic nephrotic syndrome
Relapse
Infectious diseases
Vaccine
==== Body
pmcIntroduction
The use of vaccines in nephrotic syndrome (NS) is a timely topic, discussed over many years. Patients with NS are, in fact, at high risk of developing serious infectious complications based on immune-depression arising from hypogammaglobulinemia, urinary loss of complement factors, and immunosuppressive agents [1, 2]. Vaccines are the adequate answer to prevent infections provided that they achieve a sufficient titer of specific antibodies in circulation.
Safety and effectiveness are main issues that still require an open discussion. This is particularly true after the COVID pandemic that has re-proposed these questions in relation to the new anti-COVID mRNA formulations. Safety is particularly relevant to live attenuated preparations since patients may be exposed to the risk of developing viral infection from the vaccine strains [3]. A second concern is about the possibility that post-vaccine serum conversion is limited by the presence of proteinuria and/or for the concomitance of immune suppressive therapies [4, 5]. Finally, vaccines have been proposed as triggers of idiopathic NS, either de novo episodes or recurrence based on case reports and association studies, a possibility that is critical in children for the intuitive reason that most vaccines are administered in childhood. Unfortunately, we lack a numerically comparable control population of children who did not receive vaccination since common vaccinations usually involve about 90–95% of children in Western countries.
We here present results deriving from a comprehensive review of the literature on effectiveness and safety of vaccines, including the previous suggested association with de novo or relapses of NS. A description of vaccine categories, types of production, or their administration precedes the analysis of data. The limited world-wide indications by deputed national organizations of public health for vaccination are presented at the end.
Vaccine categories
Vaccines may be classified in relation to the status of the antigen administered and include live, live attenuated, and inactivated virus/bacteria. They are prepared from purified crude or recombinant virus pool and may be conjugated with proteins or polysaccharides. Live vaccines (mycobacterium) should not be considered for their toxicity.
The live attenuated category includes Varicella, Measles, Mumps, rubella, Polio-Sabin, Typhoid, Yellow fever. They are produced by attenuating the power of living strains and are available as monovalent preparations or as part of combined formulations: measles–mumps (MM), measles–mumps–rubella (MMR), measles–mumps–rubella–varicella (MMRV).
Inactivated vaccines are simple killed virus/bacteria and include Hepatitis-A, Polio-Salk, Influenza, Papilloma virus, Rabies; a few of these are available as conjugated with proteins or polysaccharides (Haemophilus influenzae, Pneumococcal and Typhoid). Vaccines for Streptococcus pneumoniae are the most representative of this category since infections induced by Streptococcus pneumoniae represent the major cause of morbidity and mortality in children under 5 years [6]. Vaccines for pneumococcus exist as protein conjugated (PPV) and more recently as polysaccharide conjugated (PCV). PCV7 was first introduced in 2000 and then substituted by the PCV13 that immunizes against the 13 prevalent serotypes, covering 80–90% of all Streptococcus pneumoniae subtypes.
Vaccines for Tetanus and Diphtheria are toxoid and derive from inactivation with formaldehyde and purification of anatoxins from Clostridium tetani and Corynebacterium diptheria respectively. They are usually administered in combination with pertussis antigens, in a vaccination form (Diph–Te–Per) widely utilized around the word. In a different formulation, the two inactivated toxins are used in combination with Poliomyelites (REVAXIS).
Vaccines for Hepatitis B are produced starting from recombinant proteins. The mono-antigenic yeast-derived alum-adjuvanted hepatitis B vaccines (MAVs), containing a small HBsAg fragment, date back more than 35 years [7–9]. New tri-antigenic hepatitis B vaccines (TAV) containing HBV surface antigens resembling the HBV envelope are now in phase 3 clinical studies in neonates and children [10].
Vaccines for Neisseria meningitides Group C and B and for papilloma virus (HPV) are produced utilizing purified proteins. The former is of particular importance being responsible for cases of meningitides with poor clinical outcome [11]. The sero-group C meningitides vaccine conjugate (MCC) was first introduced in Europe in 1999 and offered to the whole pediatric population. Starting from 2014, the new 4CMenB vaccine was developed and introduced in many countries, soon covering more than 85% of the population of children under 12 months of age. A significant protection against the infection was soon reported [12]. Vaccines for HPV are multivalent and assemble capside proteins purified from several recombinant HPV types, including the most frequent virus variants implicated in pathologies of the genital apparatus (from warts to cervical dysplasia and cancer) and oro-pharyngeal cancer [13].
Finally, new anti-Sars-CoV-2 vaccines use different technologies: the EMA approved four vaccines, two composed of non-replicating mRNA (Pfizer-BioNTech BNT162b2 and Moderna mRNA1273) [14–18] and two others based on recombinant adenovirus vectors (Astrazenica ChAdOx1 and Jansen Ad26.COV2.S) [19, 20]. The former vaccines deliver nanoparticles of encapsulated single-strand non-replicating mRNA encoding for the spike antigen of the virus, the other two utilize adenovirus vectors, modified to express the SARS-CoV-2 spike protein on the cell surface. In Europe, only mRNA vaccines have been authorized for pediatric use so far.
Methods of research
Papers published up to July 2022 were selected utilizing the MEDLINE (via PubMed) database. We searched articles about vaccinations of any kind in patients with NS without limits of age. We crossed titles and key words through the MesH motor “Nephrotic Syndrome” OR “Idiopathic Nephrotic Syndrome” AND “vaccin*” (that includes vaccine/s and vaccination/s) or “COVID-19 vaccine” or “SARS-CoV-2 vaccine”. We excluded animal experiments and articles not available in English or that did not provide quantitative data. Case reports were included. Two independent researchers read papers and selected those considered of interest. The list was then merged and discussed.
Results
A total of 377 articles were obtained using the search criteria: 166 duplicates and 71 non full text, animal studies or not English languages were removed (see the PRISMA PICO diagram in Fig. 1). We removed another 50 articles not containing relevant data on generic side effects nor on relapses or new onset NS. The final result was a list of 90 records (14 for live attenuated, 26 for inactivated, 17 for recombinant, 3 for toxoid and 30 for SARS-CoV-2) overall reporting the effect of vaccines in 1015 patients, plus 5 nationwide epidemiologic investigations. The absence of any reported side effects following vaccinations was considered a surrogate for no relapse or “de novo” events in the included study. When possible, the incidence rate of relapse (Inc.) in any specific cohort of patients was calculated (Fig. 2).Fig. 1 PRISMA PICO flow diagram
Fig. 2 Recommendations for the use of vaccines in patients with NS: a practical scheme
Live attenuated virus
With the exception of Varicella-zoster, safety and recurrence of NS following live attenuated vaccines has been investigated in only a few recent studies, which utilized vaccination for single Mumps/Measles or for multiple strains, i.e., MR and MMR. In the year following vaccinations, authors reported seroconversion and adverse events for each vaccine type, including vaccine-associated infection and recurrence of NS. The results are reported separately in the sections below (Table 1).Table 1 Summary of studies on live attenuated vaccines
Reference Study type (n of subjects) Diagnosis pre-vaccine Type of vaccine Rec./de novo* Comments
Measles
Kuzemko et al. [22] Case report (2) NS Live attenuated 2/0 This was the first report on association between measles vaccine and NS
Kamei et al. [21] Observational study (2) NS Live attenuated 0/0 Patients were receiving immunosuppression agents. Immunization resulted effective
Measles-Rubella
Kamei et al. [21] Observational study (31) NS Live attenuated 0/0 Patients were receiving immunosuppression agents. Immunization resulted effective
Ajay et al. [23] Observational study (76) SSNS/FSGS Live attenuated NA SSNS were in active treatment with steroids and FSGS with ciclosporin/tacrolimus
Measles-Mumps-Rubella
Ahuja and Wright [24] Case report (1) Healthy Live attenuated 0/1 Steroid was effective in the treatment of NS, with no more relapse
Varicella-zoster
Alpay et al. [26] Case series (20) SSNS Live attenuated 1/0 Relapse of NS in three weeks after vaccination
Furth et al. [27] Prospective multicenter clinical trial (29) SSNS Live attenuated 0/0 All patients developed adequate VZV antibody levels
Kamei et al. [21] Observational study (42) NS Live attenuated 2/0 Recurrences were reported at 16 and 22 day after vaccination
N/A not available, NS nephrotic syndrome, SDNS steroid-dependent nephrotic syndrome, SSNS steroid-sensitive nephrotic syndrome, VZV: Varicella-zoster virus
Mumps
Kamei et al. [21] vaccinated 24 children with NS utilizing two vaccines prepared with different mumps strains (Torii and Hoshino): they reported seroconversion in the 50 and 42% of patients respectively, which decreased to 20% after 1 year (Table 1). No side effects were observed.
Measles alone/Measles–Rubella
Two children presenting an association of measles vaccine and NS were described in 1972: the first was a 21-month-old girl who developed “de novo” NS 9 days after vaccination, the second was a 4-year-old boy affected by NS who developed recurrence of the disease 4 days after measles vaccination [22]. In the Kamei study [21], 2 patients were vaccinated for measles alone and 31 received measles–rubella (MR). Seroconversion after MR was high for either measles (95%) and rubella (100%) and was maintained after 1 year. No side effects were observed. A good seroconversion following measles single vaccination has been confirmed in a recent report by Ayaj et al. [23], who vaccinated 76 children with NS (40 were steroid sensitive NS (SSNS), 36 had focal segmental glomerulosclerosis (FSGS)) and were in active treatment with steroids (SSNS) or with ciclosporin/tacrolimus (FSGS). The study did not furnish any details on either the time of the follow up or the occurrence of side effects, including recurrence of NS.
Measles–Mumps–Rubella
The unique case of NS following measles–mumps–rubella (MMR) has been reported in the literature in 1989. A 13-month-old girl developed “de novo” NS 6 days after vaccination and rapidly responded to steroids [24] (Table 1).
Varicella-zoster
Effectiveness and safety of varicella vaccines in NS have been more widely investigated than other live attenuated vaccines (Table 1). Data published in 1997 in a small group of 7 children with NS, demonstrated that a two-phase vaccination program is required in the majority of NS patients to obtain a satisfactory protection, and that the vaccine was safe [25]. Alpay et al. [26] compared 20 NS children vaccinated with the attenuated Varicella-zoster virus (VZV) vaccine (Varilrix, SmithKline Beecham) and 20 healthy, age-matched controls. Seroconversion was obtained after 8 weeks in 85% and 86% of NS and controls respectively, most of whom had positive antibody titers at 2 years of follow up. Recurrence of NS was observed in one child 20 days after vaccination (Inc. 5%). In 2003, the Southwest Pediatric Nephrology Study Group published the results of an open-label, multicenter clinical trial in 29 children who received 2 doses of VZV attenuated vaccine (Varilrix, Merck) and were followed for 2 years [27]. The study included patients on chronic steroid therapy and excluded other immunosuppressive regimens. All patients and controls demonstrated immunity after the first dose of vaccine and 91% maintained antibodies at 2 years of follow up. Seventeen children with NS relapsed during the 2 years of follow up and 6 within 2 weeks after vaccination (overall Inc. 62%). The study did not provide data on pre-vaccine relapse except for the early relapsers, all of whom had already relapsed in the 2–10 months (mean 3) before vaccination. The study by Kamei et al. [21] reported data on VZV in 42 children with NS: only 61.9% seroconverted after 1 vaccination and 76% after 2–3; NS recurred in 2 patients after 16 and 22 days from vaccination (Inc. 4.8%).
Conclusions
Single mumps and composite vaccinations for measles of NS patients seem safe but only a few reports are available in both cases. Considering the risk of infectious diseases induced by the vaccine itself, live attenuated should generally be avoided, at least in immunocompromised children and in those receiving immunosuppressive drugs. Their use in SSNS could be evaluated considering the context.
Regarding VZV vaccination in children with NS, we can conclude that this is a safe practice and produces sufficient seroconversion to guarantee protection over years. While a few cases of NS relapses following VZV vaccination have been reported, the pre/post vaccination incidence seems similar, not supporting a clear link between the two phenomena.
Inactivated bacteria/virus
Pneumococcal
Several studies have addressed either efficacy and side effects of PPV [28–37] and, more recently, of PCV in subjects affected by NS treated with both one dose [38, 39] and booster [40]. In the former case (PPV), vaccination was performed in 302 patients with SSNS and 13 with SRNS without side effects or recurrence of NS (reviewed by Goonewardene et al. [41]). PCV vaccines were found to be safe in 62 children with NS who received the first dose and booster [38, 40]; PCV13 [39] was given to 42 patients with NS without side effects (see Table 2).Table 2 Summary of studies on inactivated vaccines. In the case of vaccines for Pneumococcus, only studies on conjugated vaccines (PCV) are reported
Reference Study type (N of subjects) Diagnosis pre-vaccine Type of vaccine Rec./de novo Comments
Pneumococcal
Liakou et al. [38] Observational study (33) NS PCV7 0/0 15 patients were on low dose oral prednisolone or no therapy and 18 were receiving additional treatment of Mycophenolate mofetil or ciclosporin A for a minimum of 6 months prior to enrolment
Liakou et al. [40] Observational study (29) NS PCV7 0/0 PCV7 was not associated with increased risk of INS relapse and serotype-specific antibodies increased in all subjects at 1 month
Pittet et al. [39] Observational study (42) NS PCV13 0/0 Vaccination was performed at disease onset or at regular follow up, during remission
Influenza
Kielstein et al. [43] Case report (1) Healthy Inactivated H1N1 0/1
Poyrazoğlu et al. [48] Case series (19) NS Inactivated H1N1 0/0 The first relapse was reported in one subject at three months after vaccination
Gutierrez et al. [44] Case report (1) Healthy Inactivated H1N1 0/1 Histology showed severe acute tubular injury and interstitial inflammatory infiltrate. The immunofluorescence was negative. Ultrastructural examination showed diffuse foot-process effacement, microvillus transformation and cytoplasmic vacuolization
Fernandes et al. [42] Case report (1) Healthy Inactivated H1N1 0/1 Patient developed NS one week after receiving vaccine. Oral steroid therapy was started, and proteinuria returned to the non-nephrotic range
Kutlucan et al. [45] Case report (1) Healthy Inactivated H1N1 0/1 Histological findings were consistent with membranous glomerulonephritis
Tanaka et al. [49] Observational study (15) NS Inactivated H1N1 NA No side effects including NS were reported
Klifa et al. [50] Monocentric retrospective investigation (14) SSNS Inactivated H1N1 0/0 Relapse rate differed but without statistical significance between vaccinated and unvaccinated subjects
Ishimori et al. [51] Multicenter observational study (306) NS Inactivated H1N1 NA Risk of relapse was lower in vaccinated than non-vaccinated. Moreover, in vaccinated, risk of relapse was lower in post-vaccine time than in pre-vaccine time
Kamei et al. [21] Observational Study NS Live attenuated NA Patients were receiving immunosuppression agents. Immunization resulted effective
NA not available, NS nephrotic syndrome, PCV polysaccharide vaccines, SSNS steroidsensitive nephrotic syndrome
In conclusion, PCV vaccines are safe and can be utilized in patients with NS.
Influenza
Annual influenza outbreaks significantly impact the clinical outcome of children with all types of NS, who are at high risk of severe infections and of possible relapses of NS secondary to the infection. Vaccines for influenza have also been associated with both relapse [42] and “de novo” NS [43, 44]; one case of “de novo” NS was characterized as membranous nephropathy [45]. Based on the H1N1 experience, many physicians indicate prophylaxis in children and their caregivers prior to the start of the influenza season, with vaccines that are timely produced each year after isolating virus strains [46, 47]. Studies have reported an adequate immunologic response to vaccines for influenza in children with NS [47], which was associated with reduced complications and relapses [48–51]. Angeletti et al. [52] followed for 24 months 9 children/young patients with NS who had received purified influenza vaccines and found an incidence of recurrence not different from the control group of NS not receiving influenza vaccines. A large study published in 2021 [51] recruited 306 children with NS: 102 were vaccinated, 204 were the control group who did not receive the vaccine. Recurrence of NS was much higher in the latter group compared to vaccinated children (Inc. 0.74% vs. 0.25%). As expected, vaccinated children presented fewer flu episodes compared to non-vaccinated (Inc. 12.7% vs. 25.4%), which corresponded to a markedly reduced risk of getting the disease. In parallel, vaccinated children also had a reduced risk of NS relapse (Inc. 0.22%), indirectly confirming that flu infection may be correlated with NS relapse. Consistently, during the year following the vaccination the 102 children vaccinated for influenza had fewer episodes of NS relapse compared to the year before vaccination, with a reduced risk of recurrence of NS in the post-vaccine versus the pre-vaccine period (Inc. 0.31%).
In conclusion, observational studies demonstrate that influenza vaccines are safe and reduce the risk of infections during the seasonal pandemic. Moreover, vaccines for influenza are also associated with a reduced risk of relapse of NS due to fewer influenza episodes typically related to NS relapse, without any additive risk linked to the vaccine itself.
Poliomyelites
See section on Diphteria–Tetanus (REVAXIS).
Vaccines containing recombinant and purified antigens
HBV
The interest in MAVs vaccines in NS, and more generally in glomerulonephritis, is related with the known association of HBV infection with membranous glomerulopathy, an autoimmune condition causing NS where HBV is deposited along the basal glomerular membrane and functions as an antigen. The development of MAVs and its use in clinical practice has produced a drastic decrease of HBV determined membranous glomerulopathy [53].
Studies in other forms of NS are scanty and, despite the wide utilization of MAVs in the whole population, reports on their association with idiopathic NS in children are limited to case reports describing “de novo” NS in three healthy children and a case of proteinuria recurrence in a patient with MCD [54–57] (Table 3). The unique observational study reported in the literature was performed in 41 children (age 1–10 years) with SSNS, some of whom (24/41) were on steroid therapy [58]. Seroconversion was higher in those patients not on therapy (76.5% vs. 37.5%). Early recurrence of NS (within 1 month after vaccination) was observed in 14 patients (5 on steroids and 9 not on any treatment, for an overall Inc. 34).Table 3 Summary of studies on vaccines containing recombinant and purified antigens, toxoid or anatoxin
Reference Study type (N of subjects) Diagnosis pre-vaccine Type of vaccine Rec/de novo or I* Comments
Hepatitis B
Macario et al. [54] Case report (1) MCD Recombinant hepatitis B vaccine 1/0 –
Pennesi et al. [57] Case report (1) Healthy Recombinant hepatitis B vaccine 0/1 The immunohistochemical examination shows the presence of hepatitis B surface antigen in renal tissue. Remission was reported after 3yrs of treatment with RAASi
Ozdemir et al. [56] Case report (1) Healthy Recombinant hepatitis B vaccine 0/1 NS developed 17 days after second inoculation. Complete remission was observed after 20 days of steroids (2 mg/kg/day). Kidney biopsy was not performed because subject was 3yo
Işlek et al. [55] Case report (1) Healthy Recombinant hepatitis B vaccine 0/1 After the first diagnosis, at 4yo, he had three relapses in the following years. Each relapse developed after vaccinations of polio, pneumococcal, and flu vaccine, respectively. All relapses had been easily treated by prednisolone
Yıldız et al. [58] Observational study (41) SSNS Recombinant hepatitis B vaccine 0/14 Relapse rates after the vaccination were higher than those in the pre-vaccination period (p = 0.002)
Meningococcal
Abeyagunawardena et al. [59] Observational Study
(106)
SSNS Meningococcal C conjugate vaccine 0/0 Risk of relapse was significantly higher in the 6 months post-vaccination, than the 6 months pre-vaccination
Taylor et al. [60] Observational Study
(52)
SSNS Meningococcal C conjugate vaccine – Overall risk of relapse was not associated with vaccination (I 0.35)
De Serres et al. [61] Epidemiologic investigation (49,000) Healthy 4-component meningococcal serogroup B 0/4 8.3-fold increased risk of relapse
Andrews et al. [62] National epidemiologic investigation Healthy 4-component meningococcal serogroup B – No more risk of relapse related to vaccination
Diphteria-Tetanous-Polio
Clajus et al. [66] Case report (1) Healthy Cleaned tetanus and diphtheria toxoid, inactive poliomyelitis virus 0/1 Subject was 82 years old. Kidney biopsy revealed minimal change disease
NS nephrotic syndrome, RAASi rennin angiotensin aldosterone system inhibitor, SSNS steroid-sensitive nephrotic syndrome. n of relapses or de novo cases of NS are reported in case of single observation. In case of observational studies, the overall incidence (I) I of relapses plus de novo is given when available
In conclusion, data on a potential association between HBV vaccines and NS are limited and refer to vaccines that are not currently administered as a first option. Data on recurrence or on new episodes of NS following TAV are not available yet, but considering the high number of children treated with this new vaccine there is a real possibility that this association does not exist.
Meningocuccus classes B–C
After the introduction of MCC in clinical practice in 1999, concerns emerged about the possibility that they could be associated with recurrence of NS (Table 3). In 2003, Abeyagunawardena et al. [59] reported an increased incidence of NS relapse in a cohort of 106 NS children during 12 months after vaccination compared to the pre-vaccination phase (Inc. 90% vs. 59%). Taylor et al. [60] followed 53 children with NS for 12 months after MCC vaccination and did not confirm the previous report (post vs. pre vaccine relapse Inc. 0.95 vs. 1.05) (Table 3). The successive development of the new multi-component meningococcal group B vaccine (4CMenB) has reduced the clinical use of MCC to areas where Neisseria meningitides Group C is endemic, limiting the interest on NS recurrence following this vaccine.
Also in the case of 4CMenB, there was variability of results concerning recurrence of NS (Table 3). De Serres et al. [61] compared the incidence of first hospitalization for NS in the province of Quebec and focused, in particular, on the region of Saguenay-Lac-Saint-Jean (SLSJ), an endemic area for group B meningitis, where vaccination with 4CMenB started earlier than in other regions of Canada. They found a sharp increase in the hospitalization for NS of children during the year following vaccination (13.3/100,000 inhabitants vs. 1.6/100,000 of the preceding 10 years), corresponding to 3.6 times higher rate of hospitalization for NS compared to the rest of the Quebec province and 8 times greater than during the eight years preceding the immunization campaign. Andrews et al. [62] evaluated the English hospital admissions for NS from 2005 to 2019, in a population of 2–23-month-old children stratified for age. They considered huge cohorts of children who received a first dose (2.35 million), a second dose (2.25 million) and a booster dose (1.78 million) and compared pre and post 4CMenB vaccine phases. No evidence of increased NS episodes was observed. Finally, NS was not reported to be a side effect of 4CMenB in large populations of children receiving the vaccine in the UK [63] and in Germany [64].
In conclusion, large epidemiologic studies have not confirmed the first Canadian report that was limited to a portion of Quebec.
Human papilloma virus
Vaccination for papilloma is indicated in females before the start of sexual activity around 12 years. No association of human papilloma virus (HPV) vaccines (of any kind) and NS is reported in the literature.
Pertussis
See section of Diphteria–Tetanus (Diph–Te–Per) below.
Toxoid or anatoxin
Diphtheria–tetanus–pertussis
The recent study by Ajay et al. [23] indicated sufficient seroprotection after three Diph–Te–Per doses given to 40 children with SSNS and 36 with FSGS. The comparative antibody titers were higher in SSNS than in FSGS. Incidence of recurrent episodes of NS was not reported.
Single reports of “de novo” NS have been described in association with mixture of diphtheria and tetanus vaccines (Table 3) in two adults: a man vaccinated with a mixture of diphtheria, tetanus, Haemophilus influenzae type B, and Pneumovax vaccines, 1 year after hematopoietic stem cell transplantation for acute myelogenous leukemia [65] and a second case of a 82-year-old female who developed NS (Minimal Changes was the histological diagnosis) 6 weeks after a booster dose of REVAXIS [66]. Angeletti et al. [52] prospectively followed for 24 months 9 children/young patients with NS who had received the diphtheria, tetanus, acellular pertussis vaccine combined with the inactivated poliovirus and found an incidence of recurrence not different from the control group of NS not receiving influenza vaccines.
Anti SARS-CoV-2mRNA and adenovirus vaccines
The SARS-CoV-2 pandemic has represented an extremely serious risk for public health during 2020–2021 and still has a relevant impact, in terms of the incidence of the new Omicron variants. The kidney has been one of the major targets of SARS-CoV-2, causing either “de novo” or relapses of inflammatory and autoimmune glomerulonephritis [67, 68]. Children with NS seemed protected from the first variant [69], whereas they are now more prone to be affected by Omicron even with a limited clinical impact [70]. We cannot exclude that immunosuppressed children with NS become persistent SARS-CoV-2 carriers, as studies on other conditions requiring prolonged immunomodulatory treatments have suggested [71]. Wide vaccination is a necessary step to limit SARS-CoV-2 dissemination.
New onset or recurrence of several forms of glomerulonephritis and NS in children and adults have been reported after vaccination with both mRNA and adenovirus vaccines re-opening “de facto” the broad and important question on the impact of SARS-CoV-2 vaccine in the renal arena [72, 73]. Generally speaking, it should be noted that the impressive number of vaccines distributed in the short period in the world reduces the numerical impact of side effects (in this case, recurrence of NS) since they represent an infinitesimal portion of vaccinated subjects. Considering the stringent temporal association between vaccination and NS in a few cases, we should, however, consider and discuss this possibility (Table 5).
SARS-CoV-2 mRNA
To date (July 2022), there are in the literature 66 cases of NS “de novo” or relapses that occurred in concomitance, or near to, the administration of a mRNA vaccine, where concomitance is defined as NS occurring within 1 month after vaccination [74–89]. The numerically most significant study (27 cases) was undertaken in Japan as part of a web-based survey within council members of the Japanese Society of Nephrology [89]. This study included children and adults with relapse and de novo NS with variable pathologic characteristics (12 MCD, 4 membranous nephropathy, 2 FSGS, 2 IgA nephropathy and various other cases). Of the 66 cases with de novo/relapse NS of the literature, 60 (Table 4) occurred after the Pfizer-BioNTech BNT162b2 vaccine with a numerical difference that probably reflects the larger use of this vaccine. Relapses of NS were more frequent than “de novo” episodes (41 vs. 19) and the age varied from 14 to 80 years with a median of 43 years (in the Pfizer-BioNTech BNT162b2). Lack of post-vaccine NS in children under 14 years reflects the only recent extension of vaccination under this age. Pathology pictures were available in at least 50% of cases: MCD and FSGS represented the prevalent findings but there were a few cases with membranous nephropathy, IgA and C3 glomerulonephritis. The outcome was good in the majority of cases after steroids associated with mycophenolate mofetil (MMF) (i.e., 28 had complete and 6 partial remission) or calcineurin inhibitors (CNI) in 4 patients; the chimeric anti-CD20 antibody rituximab was administered in 3 cases and the humanized anti-CD20 antibody obinutuzumab in 1 (Table 4). The outcome was not clearly reported in a significant number of patients (n = 28).Table 4 Summary of studies on anti Sars-Cov-2mRNA and adenovirus vaccines
Type of vaccine N Sex F/M Age (years) Days after vaccination Relapse/de novo Treatments Outcome Ref
Pfizer-BioNTech BNT162b2 60 24/36 43 (14–80) 12 (3–30) 41/19 Ste 50
CNI 2
MMF 8
RTX 3
OBI 1
No Th. 5
CR 25
PR 6
No R 1
NA 28
[72–82]
Moderna mRNA 1273 6 4/2 45 (16–63) 4 (1–7) 4/2 Ste 5
MMF2
CR 5 [83, 84]
Astrazeneca ChAdOx1 8 2/6 41 (22–83) 12 (2–20) 5/3 Ste 6
MMF 2
CR 5
PR 1
NA 1
[90–93]
CNI calcineurin inhibitor, CR complete remission, MMF mycophenolate mofetil, NA not available, OBI obinutuzumab, PR partial remission, RTX rituximab, Ste steroid
Among the 6 cases of NS associated with the Moderna mRNA 1273 vaccine, 4 were “de novo” NS and 2 were relapses. Complete remission was obtained with steroids alone (5) or in association with MMF (2) (Table 4) [82–84, 89].
SARS-CoV-2 adenovirus
Five relapses and 3 “de novo” NS have been reported in association with the Astrazeneca ChAdOx1 [90–93]. Patients’ characteristics and clinical details are the same as the patients group above (Table 4).
Conclusions
Vaccines for SARS-CoV-2 (all kinds) offer a concrete and safe approach to reduce the clinical impact of the pandemic in patients with NS. We strongly support their use in children and adults. Very rare episodes of “de novo” NS or recurrence may occur and generally respond to steroids, therefore, do not represent a numerical and clinical problem.
Indications for vaccinations by deputed organisms
Limited specific indications for vaccination in NS have been formulated over time by deputed medical organizations and official organisations of public health. The 2021 KDIGO Guidelines have integrated most of the issues above and recommend vaccination in NS for pneumococcal, annual influenza virus, and, more generally, accepted inactivated vaccines, while vaccines produced with live attenuated virus (measles, mumps, rubella, varicella, rotavirus) are not indicated, especially in patients receiving chronic immunosuppressive or cytotoxic agents [94]. The American Academy of Pediatrics (AAP) recommended immunizing NS children with pneumococcal PCV13 followed by PPSV23 vaccines after 8 weeks and 5 years from the time of the first dose [95]. The AAP also indicated to defer live attenuated vaccines in case of high steroids and immunosuppressor administration [95]. The Advisory Committee on Immunization Practices (ACIP) confirmed seasonal anti-flu yearly, while it was more restrictive about measles, mumps, rubella, varicella and rotavirus vaccines [96]. In almost all countries (with the limitation above reported by the AAP [95] and the UK Department of Health [97]), vaccinations of NS patients with live attenuated vaccines are not indicated. Moreover, the International Pediatric Nephrology Association [98] recently recommended to complete all vaccinations without delay in NS, including pneumococcal, meningococcal, Haemophilus influenzae, and VZV. Inactivated influenza vaccine was recommended annually. For immunocompromised patients, national vaccination guidelines were recommended for inactive and live attenuated vaccines. On the other hand, national vaccination programs were discouraged in subjects with steroid-resistant NS who usually were treated with daily immunosuppressive medication, including CNIs, MMF, and steroids.
Final considerations
We conclude that all types of vaccines (live attenuated, inactivated, vaccines containing recombinant and purified antigens, toxoid and anatoxins, and the recently developed vaccines for SARS-CoV-2) result safe in terms of both recurrence and “de novo” occurrence of NS. Immunization was effective for the majority of vaccine types, including in subjects with chronic immunosuppressive treatments. The following general considerations complete the synthesis on effectiveness: (1) patients who received vaccinations as a part of routine (not in the presence of proteinuria) have higher antibody titers than after the onset of NS; (2) the connection between specific serum immunoglobulin conversion with proteinuria is variable: HBV and varicella vaccines are an example of limited seroconversion during florid proteinuria (60–70%); for other vaccines such as anti-tetanus, diphtheria, pertussis, measles, mumps, rubella, the presence of proteinuria does not influence specific IgG levels; (3) the persistence of adequate antibody titers following different vaccination is also variable and it is strictly “vaccine type” dependent; vaccination with Pneumococcal conjugate, for example, maintains protection for 1 year, for other vaccines protection is maintained for longer periods.
Guidelines support the use of almost all vaccines in patients with NS with the exception of live attenuated especially in patients receiving chronic immunosuppressive treatments. All other vaccines can be utilized also in concomitance with immunosuppressive treatments with steroids, CNI and MMF. In patients with NS treated with monoclonal anti-CD20 antibodies, all types of vaccine should be provided at least 6 months after last infusion; during the pandemic, vaccines for SARS-CoV-2 should be provided, if possible, 3 months before the infusion of monoclonal anti-CD20 antibodies.
However, in the real-world practice, facts are distant from theory. Only a minority of parents accept to vaccinate their children affected by NS with vaccines that are permitted by guidelines and even doubt vaccinations (such as for influenza) that we know protect from complications of the pandemic and also from relapses of NS. Popular credence supported these concerns for years and we hope that evidence will change current distorted practice.
Based on the above presented data, we may conclude that (1) all types of vaccinations are safe in subjects with NS also in those patients receiving steroids, CNIs and MMF; (2) vaccinations (all kinds) are recommended by guidelines in NS, with the exception of vaccines produced with live attenuated virus (measles, mumps, rubella, varicella, rotavirus) in patients receiving chronic immunosuppressive or cytotoxic agents; (3) vaccinations for annual influenza virus reduce the number of recurrences in patients with NS; and (4) vaccines for SARS-CoV-2 (all kinds) offer a concrete and safe approach to reduce the clinical impact of the pandemic in patients with NS without any risk of recurrence of the disease.
Acknowledgements
The submission of the present Manuscript was supported by the Italian Ministry of Health—5X1000 anno 2020.
Data availability
Not applicable.
Code availability
Not applicable.
Declarations
Conflict of interest
The authors declare no conflict of interest.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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82. Salem F Rein JL Yu SM Abramson M Cravedi P Chung M Report of three cases of minimal change disease following the second dose of mRNA SARS-CoV-2 COVID-19 vaccine Kidney Int Rep 2021 6 2523 2524 10.1016/j.ekir.2021.07.017 34337193
83. Holzworth A Couchot P Cruz-Knight W Brucculeri M Minimal change disease following the Moderna mRNA-1273 SARS-CoV-2 vaccine Kidney Int 2021 100 463 464 10.1016/j.kint.2021.05.007 34048824
84. Thappy S Thalappil SR Abbarh S Al-Mashdali A Akhtar M Alkadi MM Minimal change disease following the Moderna COVID-19 vaccine: first case report BMC Nephrol 2021 22 376 10.1186/s12882-021-02583-9 34763669
85. Kobayashi S Fugo K Yamazaki K Terawaki H Minimal change disease soon after Pfizer-BioNTech COVID-19 vaccination Clin Kidney J 2021 14 2606 2607 10.1093/ckj/sfab156 34938534
86. Mancianti N Guarnieri A Tripodi S Salvo DP Garosi G Minimal change disease following vaccination for SARS-CoV-2 J Nephrol 2021 34 1039 1040 10.1007/s40620-021-01091-1 34143368
87. Nakazawa E Uchimura T Hirai Y Togashi H Oyama Y Inaba A Shiga K Ito S New-onset pediatric nephrotic syndrome following Pfizer-BioNTech SARS-CoV-2 vaccination: a case report and literature review CEN Case Rep 2022 11 242 246 10.1007/s13730-021-00656-0 34782983
88. Hummel A Oniszczuk J Kervella D Charbit M Guerrot D Testa A Philipponnet C Chauvet C Guincestre T Brochard K Benezech A Figueres L Belenfant X Guarnieri A Demoulin N Benetti E Miglinas M Dessaix K Morelle J Angeletti A Sellier-Leclerc AL Ranchin B Goussard G Hudier L Bacchetta J Servais A Audard V Idiopathic nephrotic syndrome relapse following SARS-CoV-2 vaccination: a series of 25 cases Clin Kidney J 2022 15 1574 1582 10.1093/ckj/sfac134 35979142
89. Nakagawa N Maruyama S Kashihara N Narita I Isaka Y New-onset and relapse of nephrotic syndrome following COVID-19 vaccination: a questionnaire survey in Japan Clin Exp Nephrol 2022 26 909 916 10.1007/s10157-022-02231-y 35569069
90. Leclerc S Royal V Lamarche C Laurin LP Minimal change disease with severe acute kidney injury following the Oxford-AstraZeneca COVID-19 Vaccine: a case report Am J Kidney Dis 2021 78 607 610 10.1053/j.ajkd.2021.06.008 34242687
91. Morlidge C El-Kateb S Jeevaratnam P Thompson B Relapse of minimal change disease following the AstraZeneca COVID-19 vaccine Kidney Int 2021 100 459 10.1016/j.kint.2021.06.005
92. Unver S Haholu A Yildirim S Nephrotic syndrome and acute kidney injury following CoronaVac anti-SARS-CoV-2 vaccine Clin Kidney J 2021 14 2608 2611 10.1093/ckj/sfab155 34938535
93. Biradar VG Alqahtani MA Nagaraj HC Ahmed EA Tripathi V Botto-Tobar M Atiglah HK Adult-onset nephrotic syndrome following coronavirus disease vaccination Clin Kidney J 2022 15 168 170 10.1093/ckj/sfab153 35035948
94. Radhakrishnan J Cattran DC The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines—application to the individual patient Kidney Int 2012 82 840 856 10.1038/ki.2012.280 22895519
95. Gipson DS Massengill SF Yao L Nagaraj S Smoyer WE Mahan JD Wigfall D Miles P Powell L Lin JJ Trachtman H Greenbaum LA Management of childhood onset nephrotic syndrome Pediatrics 2009 124 747 757 10.1542/peds.2008-1559 19651590
96. Nuorti JP Whitney CG Centers for Disease Control and Prevention (CDC) Prevention of pneumococcal disease among infants and children - use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine - recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Recomm Rep 2010 59 11 1 18
97. McCaffrey J Lennon R Webb NJ The non-immunosuppressive management of childhood nephrotic syndrome Pediatr Nephrol 2016 31 1383 1402 10.1007/s00467-015-3241-0 26556028
98. Trautmann A Vivarelli M Samuel S Gipson D Sinha A Schaefer F Hui NK Boyer O Saleem MA Feltran L Müller-Deile J Becker JU Cano F Xu H Lim YN Smoyer W Anochie I Nakanishi K Hodson E Haffner D International Pediatric Nephrology Association IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome Pediatr Nephrol 2020 35 1529 1561 10.1007/s00467-020-04519-1 32382828
| 36512075 | PMC9745735 | NO-CC CODE | 2022-12-15 00:02:41 | no | Pediatr Nephrol. 2022 Dec 13;:1-14 | utf-8 | Pediatr Nephrol | 2,022 | 10.1007/s00467-022-05835-4 | oa_other |
==== Front
ACS Sens
ACS Sens
se
ascefj
ACS Sensors
2379-3694
American Chemical Society
36472865
10.1021/acssensors.2c01990
Article
Rapid and Unamplified Detection of SARS-CoV-2 RNA via CRISPR-Cas13a-Modified Solution-Gated Graphene Transistors
https://orcid.org/0000-0003-3299-6941
Yu Haiyang †‡#
Zhang Huibin ‡#
https://orcid.org/0000-0002-5226-0272
Li Jinhua *‡
Zhao Zheng *†§
Deng Minhua ‡
Ren Zhanpeng ‡
Li Ziqin ‡
Xue Chenglong ‡
https://orcid.org/0000-0001-6259-3209
Li Mitch Guijun ∥
Chen Zhaowei *⊥
† State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan430070, China
‡ Collaborative Innovation Center for Advanced Organic Chemical Materials Co-constructed by the Province and Ministry, Key Laboratory for the Green Preparation and Application of Functional Materials, Ministry of Education, Hubei Key Laboratory of Polymer Materials, School of Materials Science and Engineering, Hubei University, Wuhan430062, China
§ Sanya Science and Education Innovation Park of Wuhan University of Technology, Sanya572000, China
∥ Division of Integrative Systems and Design, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR999077, China
⊥ Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan430060, China
* Email: [email protected].
* Email: [email protected].
* Email: [email protected].
06 12 2022
acssensors.2c0199012 09 2022
22 11 2022
© 2022 American Chemical Society
2022
American Chemical Society
This article is made available via the PMC Open Access Subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
The disease caused by severe acute respiratory syndrome coronavirus, SARS-CoV-2, is termed COVID-19. Even though COVID-19 has been out for more than two years, it is still causing a global pandemic. Due to the limitations of sample collection, transportation, and kit performance, the traditional reverse transcription-quantitative polymerase chain reaction (RT-qPCR) method has a long detection period and high testing costs. An increased risk of infection is inevitable, since many patients may not be diagnosed in time. The CRISPR-Cas13a system can be designed for RNA identification and knockdown, as a promising platform for nucleic acid detection. Here, we designed a solution-gated graphene transistor (SGGT) biosensor based on the CRISPR-Cas13a system. Using the gene-targeting capacity of CRISPR-Cas13a and gate functionalization via multilayer modification, SARS-CoV-2 nucleic acid sequences can be quickly and precisely identified without the need for amplification or fluorescence tagging. The limit of detection (LOD) in both buffer and serum reached the aM level, and the reaction time was about 10 min. The results of the detection of COVID-19 clinical samples from throat swabs agree with RT-PCR. In addition, the interchangeable gates significantly minimize the cost and time of device fabrication. In a nutshell, our biosensor technology is broadly applicable and will be suitable for point-of-care (POC) testing.
biosensors
transistors
CRISPR
Cas13a
SARS-CoV-2
COVID-19
nucleic acid testing
National Natural Science Foundation of China 10.13039/501100001809 52073220 Key Laboratory of Optoelectronic Chemical Materials and Devices of Ministry of Education, Jiang Han University NA JDGD-202205 Overseas Expertise Introduction Center for Discipline Innovation NA D18025 Sanya Science and Education Innovation Park, Wuhan University of Technology NA 2021KF0017 Science and Technology Department of Hubei Province 10.13039/501100018806 2020BIB020 National Natural Science Foundation of China 10.13039/501100001809 82100704 document-id-old-9se2c01990
document-id-new-14se2c01990
ccc-price
This article is made available via the ACS COVID-19 subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
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pmcA type of positive-stranded RNA virus called SARS-CoV-2 has spread over the world, creating epidemics in almost every nation.1 Since the beginning of the epidemic, it has been challenging to contain, and the current outbreak of Omicron has only made this difficulty worse.2 The RT-qPCR is the gold standard for detecting SARS-CoV-2 and is usually used to detect the pathogenic virus RNA in respiratory secretions.3 However, the key drawback of current nucleic acid diagnostic methods based on RT-qPCR is that they are time-consuming and often require additional pretreatment, complex experimental procedures, and trained operators.4 In addition, many COVID-19 patients may go undetected due to restrictions on sample collection and transportation, as well as limitations on kit performance, posing a risk of transmission of SARS-CoV-2 to a wider community.5 Several point-of-care (POC) RNA detection technologies that do not require special instruments are also used for the nucleic acid diagnosis of COVID-19,6,7 including the loop-mediated isothermal amplification (LAMP) method8,9 and the final product of rolling circle amplification (RCA).10,11 These technologies have several benefits over RT-qPCR for SARS-CoV-2 detection, including a quick reaction time, a short turnaround time, a relatively simple readout, ease of operation, and a low development cost.12 But they could suffer from nonspecific amplification under isothermal conditions, resulting in false-positive results.6,13
For nucleic acid biosensors based on the complementary base pairing rule, the specificity of hybridization is one of the main factors affecting the detection results.14 For some oligonucleotide probes that are simply immobilized on the sensing surface, thermodynamic equilibrium conditions cannot be obtained without sufficient incubation time. As a result, the hybridization may be kinetically or sterically inaccessible.15 Furthermore, differences in probe density and stereo-hindrance effect, as well as the types and compositions of probes, deposition technologies, labeling, and hybridization protocols, can affect the binding ability of the probe to the target sequence, resulting in obvious differences between detection results analyzed by different platforms.16 Therefore, nucleic acid probes frequently appear to be partially complementary to the target sequence or even to nontarget sequences, making it difficult to discern single base-pair variations.17
A promising alternative to established genomic diagnostic tools that fit the specifications for POC testing is clustered regularly interspaced short palindromic repeats (CRISPR)-associated nuclease (Cas)-based biosensing.18 The combination of the Cas13a effector protein and CRISPR RNA (crRNA) can be engineered for specific recognition of target RNA.19 The hybridization of crRNA to target RNA allosterically activates significant conformational changes, bringing together two HEPN domains to form a composite catalytic site. Cas13a can cleave target RNA beyond the guide complementary region, as well as untargeted collateral of single-stranded RNA (ssRNA).20−22 The Cas13-based nucleic acid detection platform specific high-sensitivity enzymatic reporter unlocking (SHERLOCK) has the potential to address the key challenges associated with viral diagnostics,23 which can distinguish single-nucleotide mismatches in the target sequence using the specificity of Cas13, and this method is fast and inexpensive.24 Currently, CRISPR-Cas13a-based nucleic acid detection methods have been widely studied and applied13,25−27 and demonstrate high specificity and sensitivity over nucleic acid probes, which provide a rapid and in-field assay for SARS-CoV-2 detection. However, the potential limitations of SHERLOCK are the multistep nucleic acid amplification process and the additional fluorescent labeling. These may affect precise target quantification24 and increase time and reagents.28
Here, we report the design and construction of a CRISPR-Cas13a-modified solution-gated graphene transistor (SGGT) biosensor with a functionalized gold (Au) gate. A self-assembled monolayer (SAM) and a layer of flexible carboxymethyl-modified dextran polymer immobilized on the gate surface were constructed as a substrate for the immobilization of the Cas13a-crRNA composite structure. This structure acts as a barrier, preventing proteins and other things from contacting the gold surface.29 CRISPR-Cas13a specifically recognizes SARS-CoV-2 nucleic acid sequences by scanning the whole genomic sample. This strategy enables precise control of the position and orientation of the molecules to form a uniform and consistent biosensing layer, which reduces the interaction between Cas13a. Because of signal amplification, SGGTs combined with the gene-targeting capability of CRISPR-Cas13a can detect SARS-CoV-2 RNA at low operating voltage. Ultrahighly sensitive nucleic acid detection of SGGTs without nucleic acid amplification and additional fluorescent labeling can reach the limit of detection (LOD) of aM level, and the reaction time is about 10 min. These are the advantages of the biosensor compared to other nucleic acid detections reported recently (Table S1). In addition, we validated the ability of the biosensor to detect serum samples and clinical throat swab samples, and the detachable gate design reduces the cost and time to fabricate the device.
Results and Discussion
Characterization of Gate Functionalization
Figure 1 shows the design and sensing principle of CRISPR-Cas13a-modified SGGTs. The functionalization of the gate electrode includes a linker layer dextran polymer layer and the CRISPR-Cas13a ribonucleoprotein (RNP) complex (Cas13a RNPs), as shown in Figure 1a. The 11-sulfanylundecanol SAM is used as a linker layer to modify the Au surface at first. Thiol has a strong affinity with the Au surface. The Au–sulfur SAMs formed on Au surfaces from SH-terminated precursors can be related to chemisorbed (or covalent) and physisorbed.30 Then, a dextran polymer layer is covalently bound to the SAM using epichlorohydrin as a cross-linking agent, providing a surface suitable for rapid and simple in situ covalent binding of proteins.31 As shown in Figure 1b, Cas13a RNPs are covalently bound to the dextran polymer as the recognition layer of the target RNA. The Cas13a RNP can interact with its target sequence by scanning the whole genomic sample. The unreacted protein molecules are subsequently blocked by amino-PEG5-alcohol and ethanolamine hydrochloride, minimizing nonspecific binding. The hybridization of the negatively charged target RNA and immobilized RNPs on the surface of the gate electrode changes the potential of the EDL between the gate and the electrolyte, thus enabling the conversion of biological to electrical signals, as shown in Figure 1c.
Figure 1 Design and sensing principle of CRISPR-Cas13a-modified SGGTs. (a) Schematic diagram of the sensing layer structure. (b) Schematic diagram of the sensing principle (PDB, 5XWP). (c) The characterization process of converting biological signals into electrical signals. Created with BioRender.com.
To demonstrate that CRISPR-Cas13a-modified SGGT sensors are successfully constructed, the characterization of the functional layer of the gate modification is performed. The scanning electron microscopy (SEM) images in Figure 2a clearly show the morphologies of different modified layers on the Au gate. Flat and uniformly dense distribution of Au particles can be observed on the surface of the bare Au electrode. When the SAM is modified on the Au surface, the surface of the gate electrode becomes denser and smooth. The Au nanoparticles of the gate surface are still observed. After the modification of the dextran polymer layer, the original self-assembled film surface is almost invisible, implying that the dextran polymer could cover the surface of the gate electrode well. When the RNPs are modified on the surface of the dextran polymer layer, its surface morphology exhibits a large change, showing some tiny particles. The surface morphologies and roughness of the different modification layers are also characterized by an atomic force microscope (AFM), as shown in Figure S1. And the roughness of the gate surface increases from 2.83 to 28.4 nm. It implies that the RNPs have been successfully modified on the surface of the dextran polymer film. Figure 1b shows the X-ray photoelectron spectroscopy (XPS) spectra of the different modification layers. High-resolution C 1s XPS spectra of the dextran polymer and Cas13a RNPs demonstrated the different immobilization steps by revealing C–O–C and C=O bonds, and a peak at about 284.8 eV was attributed to the C–C bond.32 As Cas13a RNPs were introduced, two new peaks appeared at high-resolution N 1s and P 2p XPS spectra. They were attributed to the C–NH2 and −PO4–– bonds from nucleobase, amino acid, and backbone, respectively.33,34 The Au electrode with the SAM layer displays the characteristic peak of the thiol–gold (S–Au) in its high-resolution S 2p XPS spectrum.35 The collateral activity of CRISPR-Cas13a can be triggered to cleave the biotin-fluorescein RNA reporter to form a fluorescence signal when the Cas13a RNP targets the complementary RNA. The activity of the Cas13a RNP as a probe can be likewise assessed by fluorescence intensity (Table S2). We further demonstrate that the CRISPR-Cas13a-based SARS-CoV-2 N gene assay is specific for SARS-CoV-2 compared to no template control, as shown in Figure 2c.
Figure 2 Characterization of functionalized gate electrodes. (a) SEM images of bare Au gate and different modifying layers. (b) High-resolution XPS spectra of the gold electrode after modifications of the link layer, dextran polymer, and Cas13a RNPs. (c) Fluorescence signal generation of the CRISPR-Cas13a reaction in synthetic RNA fragments. (d) The Dirac point position of SGGT in signal output (***P < 0.0001, two-tailed t-test, n > 3) before and after the gate modification.
To determine the effect of gate functionalization on the electrical signal, the transfer characteristics of the CRISPR-Cas13a-modified SGGT biosensor were measured before and after the gate electrode modification. As shown in Figures 2d and S2, several groups of samples with/without the gate modification were tested, and their positions at the Dirac point were recorded. The average values of the Dirac point for the unmodified and modified groups are 0.458 and 0.276 V, respectively. These results indicate that the transfer characteristic curve shifts to the left by 0.182 V, which has changed significantly (P < 0.0001). This is probably because the positive charge induced by Cas13a on the gate increases the gate surface potential,21 which is equivalent to applying an additional positive voltage to the gate. Therefore, a smaller gate voltage is just required to achieve the previous channel current (ID) magnitude. It can be found that the relation of VDirac and the multiple sets of functionalized gates are very close, indicating that the probe density of different Au gates is similar.36 In addition, in the gate functionalization process, the three immobilization steps (SAMs, dextran polymer, and Cas13a RNPs) were monitored by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS; Supporting Discussion 1).
After the final gate functionalization, the stability tests of the device (Supporting Discussion 2) are also performed. The stability of the device in the testing process is excellent and can ensure long-time continuous testing requirements. Therefore, stable and consistent gate-sensing surfaces are formed through multilayer modification, and the functionalization of the gate is successfully realized.
Sensitivity and Specificity
The N gene fragment was synthesized and compared to nonspecific sequences to assess the sensing specificity and sensitivity of CRISPR-Cas13a-modified SGGTs, as shown in Figure S6. The detection procedure consists of the three steps listed below: (i) 10 μL of samples with different concentrations were incubated on the functionalized gate surface for 10 min, (ii) the gate surface was washed with 2 mM MgCl2 to remove the nonspecific adsorption, and (iii) the transfer characteristic curve was measured using two Keithley measurement units (Keithley 2400) with a constant drain voltage (VDS) of 0.1 V after the gate was immersed in the electrolyte (2 mM MgCl2). Before the detection procedure, the upper end of the gate modification layer was encapsulated with silicone gel to remove the effect of the liquid level change on the signal. Different transfer curves (ID versus VG) were obtained for a range of different concentrations of target RNA after incubation on the sensing surface, as shown in Figure 3a. The transfer curve shifted toward a more positive gate voltage as the concentration of target RNA increased, implying that Cas13a RNPs bound more target RNA molecules. This is because electronegative RNA bound on the sensing surface can increase the electronegativity of the gate, which corresponds to a negative voltage applied to the gate.37 Meanwhile, the N gene fragment of HCoV-229E was used as a control group, and the same three detection steps as above were performed. As shown in Figure 3b, as the concentration of nontarget RNA increases, the characteristic transfer curve shifts slightly toward the positive voltage, which could be due to nonspecific adsorption and noise interference. As a blank control, the above steps were repeated for the unmodified gate incubated with different concentrations of target RNA. The results revealed that transfer curves barely moved, as shown in Figure S7. The Dirac point offset (ΔVDirac) of the curve is analyzed as the degree of response to show the difference between the two groups more visually, given by the following equation1
where VDirac is the gate voltage when the Fermi level in the graphene channel is modulated to the charge neutrality point (Dirac point).38VDirac0 is the initial position of the Dirac point measured in the buffer. Figure 3c shows the ΔVDirac values when the gate is incubated separately with the target and nontarget sequences. It is clear that ΔVDirac increases significantly with increasing the concentration of the target sequence, while the ΔVDirac of the nontarget sequence remains almost unchanged. To evaluate the effect of noise on the detection signal and the LOD of the device, the noise value of the device was calculated and analyzed. The main method to obtain noise data is to measure the incubated blank samples (10 μL DEPC-treated water) on the functionalized gate surface in the same steps and calculate ΔVDirac values (see Supporting Discussion 3). According to ΔVDirac corresponding to the target RNA and its calibration curve, the LOD of CRISPR-Cas13a-modified SGGTs for the detection of the SARS-CoV-2 N gene synthetic fragment is 1.3 × 10–17 M. The ΔVDirac and logarithmic value of target RNA concentrations could be well fitted by a linear curve, as shown in Figure S8a.
Figure 3 Performance of CRISPR-Cas13a-modified SGGT biosensors for detecting SARS-CoV-2. (a) Transfer curves upon incubation with varying concentrations of the SARS-CoV-2 N gene. (b) Transfer curves upon incubation with nonspecific sequences (HCoV-229E N gene). (c) ΔVDirac of the device at the different concentrations of SARS-CoV-2 and HCoV-229E. The error bars represent the standard error of the mean calculated from at least three gate electrodes. (d) Schematic diagram of potential drops in the two double layers before/after the Cas13a RNPs target the N gene.
Figure 3d shows the schematic diagram of potential drops in the two double layers before/after Cas13a RNPs screen the N gene. When the target RNA bind Cas13a RNPs on the sensing surface, the electrical potential on the gate surface decreases because the target molecules have negativity. It is equivalent to applying an offset voltage (Voffset) in the gate electrode. The Voffset can be expressed by the following equation39,402
where the amount of charge change (Δq) is induced by the hybridization of target RNAs, and C is the total capacitance of the SGGT. According to eq 2, Voffset is determined by the total charges of the target RNA specifically recognized with Cas13a RNPs. Due to field-effect doping, the channel conductance of the SGGT can be regulated by the gate voltage, and the channel current ID is given by38,413
4
where W and L are the width and length of the channel, respectively; μ is the carrier (electron or hole) mobility in graphene. VGeff is the effective gate voltage, VG is the applied gate voltage, and VD is the applied drain voltage. When the target RNA bind Cas13a RNPs, a higher VG needs to be applied to keep VGeff constant due to the negative voltage of Voffset. This change is specifically reflected by the shift of the characteristic transfer curve of SGGT toward the positive voltage direction. On the other hand, the channel current can also be measured to quantify the target molecules. When VG and VD are fixed, the channel current (ID) will change due to the shift of the Dirac point. Figure S9b shows the curve of ID versus time. It can be seen that ID increases accordingly as the concentration of target RNA increases, which is consistent with the results in Figure 3a. Meanwhile, the equivalent molar concentrations of target RNA were added to the gate-unmodified device for comparison. The current response of the device without gate modification of CRISPR-Cas13a was far smaller than that of the gate-modified group, as shown in Figure S9d. Therefore, the CRISPR-Cas13a-modified SGGT biosensor was successfully realized with high sensitivity and high specificity for SARS-CoV-2 recognition.
Detection of SARS-CoV-2 in Serum
To allow unskilled operators to perform to meet the detection needs of the POC,18 the testing steps should be minimized. Meanwhile, the on-site and just-in-time detection is often disturbed by the testing environment. Therefore, the anti-interference capability and specificity of biosensors in complex environments are also important evaluation dimensions. Notably, CRISPR-Cas13a-based nucleic acid detection in the POC test is susceptible to interference from RNase contamination due to the lack of necessary RNase-specific cleaning equipment in some application scenarios. RNases can cause RNA degradation, resulting in false signal output.13 Here, different concentrations of SRAS-CoV-2 N gene synthetic fragments were added to undiluted serum to assess the sensing ability of the device in conditions containing complex components and RNase contamination. Figure 4a shows the characteristic transfer curves of devices at the different concentrations of the target RNA in the serum sample. It can be observed that the characteristic transfer curves of the device still shift regularly toward the positive voltage as the concentration increases. For comparison, the synthetic fragment of the HCoV-229E N gene was added to undiluted serum to prepare equivalent molar concentrations of control samples. As shown in Figure 4b, the transfer curves of the device show far smaller shifts. It indicates that the probe molecules have excellent specificity to the SARS-CoV-2 N gene in serum samples, as shown in Figure 4c. The relation of ΔVDirac and the concentration of RNA in serum is fitted by a linear regression equation (Figure S8b). It reveals that ΔVDirac still shows a high positive correlation with target RNA concentration. In addition, noise data were obtained and analyzed by incubating blank samples (10 μL undiluted serum) on the functionalized gate surface. The LOD is calculated to be 4.0 × 10–16 M (see Supporting Discussion 3). To further analyze the effect of the serum environment on sensing sensitivity, the degree of response of target RNAs under buffer and serum conditions was compared separately. Figure 4d shows that even at concentrations an order of magnitude higher, the degree of response (ΔVDirac) of sensors in serum samples is still significantly lower than that of buffer samples. This may be due to nonspecific adsorption and RNA degradation. However, there is still a significant response output compared to the control and noise signals, which can clearly distinguish nontarget and target RNAs within the detection limits. Therefore, the anti-interference capability of the CRISPR-Cas13a-modified SGGT biosensor was assessed by simulating a complex detection environment. The result shows that the biosensor is still able to recognize target RNA in serum, which has positive implications for the implementation of POC nucleic acid detection in complex and variable detection environments.
Figure 4 Detection of the SARS-CoV-2 N gene using CRISPR-Cas13a-modified SGGTs in serum. (a) Transfer curves of the device upon incubation with a series of concentrations of target RNA in 100% serum samples. (b) Transfer curves of the device upon incubation with varying concentrations of nonspecific sequences in 100% serum samples as a negative control. (c) Response of CRISPR-Cas13a-modified SGGTs to SARS-CoV-2 N and HCoV-229E N in serum. (d) Direct comparison of detection results in 2 mM MgCl2 and 100% serum samples by the same method.
Detection and Analysis of SARS-CoV-2 in Clinical Samples
To further validate the actual detection capability of CRISPR-Cas13a-modified SGGT biosensors in clinical samples, heat-inactivated throat swab RNA extracts from five COVID-19 patients (positive samples) and five healthy individuals (negative samples) were used for the evaluation of sensing performance. Each sample was diluted twice with DEPC-treated water (containing 2 mM MgCl2) before detection. Figure 5a shows the characteristic transfer curves of the devices after successively incubating the negative and positive samples on the sensing surface for 10 min. The detection procedure is the same as for the buffer and serum samples. It was found that the curve shifted a little in the direction of positive voltage (ΔVDirac = 20 mV) after incubation of the negative sample, while the transfer curve shifted significantly in the positive direction (ΔVDirac = 100 mV) after incubation of the positive sample. We repeated the same detection steps after sequential incubation of positive and negative samples. The results show that the biosensor has a large response to the positive sample (ΔVDirac = 64 mV), while the biosensor is almost unaffected by negative samples (ΔVDirac = 17 mV), as shown in Figure 5b. It was demonstrated that only positive samples can cause a large shift in the curve. In Figure 5c, the ΔVDirac values of all samples are recorded and analyzed. It is found that the ΔVDirac of all positive samples are significantly higher than those of the negative samples, and they can be easily distinguished. The responses (ΔVDirac) of the devices to the positive and negative samples (P < 0.0001) are statistically analyzed, as shown in Figure 5d. It is obvious that the biosensor can distinguish well between COVID-19 patients and healthy people. The results are reliable and agree with RT-PCR. Therefore, this study provides a new strategy for SGGTs in the field of nucleic acid detection, such as early screening of SARS-CoV-2. It is of positive significance for building a new POC detection platform that is more intelligent and portable.
Figure 5 CRISPR-Cas13a-modified SGGT biosensors achieve the detection of SARS-CoV-2 N by scanning the whole genomic extracted from clinical throat swab samples. (a) Transfer characteristic curves of the device by adding negative samples first and then positive samples. (b) Transfer the characteristic curve of the device by adding positive samples first and then negative samples. (c) Electrical signal evaluation of SARS-CoV-2 from five COVID-19 patients and five healthy individuals. (d) The Dirac point shifts are significantly different for positive samples compared to negative samples (P < 0.0001, two-tailed t-test).
Conclusions
By combining the respective advantages of SGGTs and CRISPR-Cas13a systems, a SARS-CoV-2 direct detection platform without additional markers and nucleic acid amplification was realized. The sensitivity and specificity of the biosensor were first evaluated in the buffer. The biosensor was able to distinguish well between target and nontarget molecules within the LOD of 1.3 × 10–17 M. ΔVDirac and target RNA concentration exhibited a good linear correlation in the range of 10–17–10–11 M. The anti-interference capability of the biosensor was also evaluated by simulating a complex environment. The result showed that the biosensor could even reach the LOD of 4.0 × 10–16 M in serum samples. The degree of response remained highly positively correlated with target RNA concentration. Subsequently, 10 clinical samples from 5 COVID-19 patients and 5 healthy individuals were used to evaluate the actual detection capability of the biosensor. The results showed that the positive samples corresponded to a significantly higher degree of response than the negative samples. The above results show the great potential of CRISPR-Cas13a-based SGGTs in nucleic acid detection.
The COVID-19 pandemic on a global scale has revealed that early nucleic acid screening is crucial for the prevention and control of the outbreak. Many commercial RT-qPCR kits have high sensitivity and play an important role in virus detection.42 These methods are usually based on targeting the genes specifying the spike (S), envelope (E), nucleocapsid (N), and open reading frame (Orf1ab) genes of SARS-CoV-2.13,43 However, besides the influence from the preanalytical steps and supply chain,13 it is also difficult to accurately quantify the analysis when evaluating samples with very low viral loads.44 The SGGT has been widely developed and applied as an emerging sensing platform that is expected to break the bottleneck of detection technology. This is due to the SGGT’s high solution stability, biocompatibility, and signal amplification capabilities. In particular, the solution-gated structure of the transistor can alleviate the limitations associated with charge shielding effects, enabling the detection beyond Debye’s length.45,46
Despite the discovery of the CRISPR-Cas13a system and the development of related technologies that have inspired numerous advances in nucleic acid detection, there are still potential application pitfalls. The protospacer flanking site (PFS) is required for CRISPR-Cas13-mediated nucleic acid tests, which limits the breadth of application.47 Off-target issues in CRISPR-Cas systems are equally worrisome. The catalytic site of Cas13a for RNA-guided target cleavage is located on the external surface,21 which allows the potential for the promiscuous cleavage of RNAs.48 In fact, for CRISPR-Cas13a-modified SGGTs, the gene-targeting ability of CRISPR-Cas13a is only required, and RNase activity is not necessary. The catalytically deactivated Cas13a can be used to target the entire gene sequence without cleavage activity, which will further improve the response of the sensor.28 After that, we will develop multichannel transistor arrays for simultaneous multigene sequence detection by designing different crRNAs. More research is needed in the future to ensure a standardized process for device fabrication and gate functionalization, improving the recognition of single-nucleotide mismatches and reducing errors between devices.
Method
Solution-Gated Graphene FET Sensor Fabrication
SGGTs were fabricated on glass substrates based on established protocols using the thermal evaporation method and wetting transfer technology. The soda-lime glass substrates were ultrasonically cleaned with acetone, isopropyl alcohol, ethanol, and deionized water successively. Cr/Au source, drain, and gate electrodes were deposited on 12.5 mm × 12.5 mm glass substrates using a thermal evaporator. The devices were then plasma-treated to eliminate the organic residues and improve their surface hydrophilicity. The poly(methylmethacrylate) (PMMA) solution was spin-coated on the surface of the CVD-grown graphene/Cu foil (Sixcarbon tech. Shenzhen). Then, the Cu substrate of graphene was etched in FeCl3 solution to form PMMA/graphene films. The film was then transferred to the channel between the source and drain electrodes and was heated at the temperature of 100 °C for 3 h. PMMA was removed by immersing the PMMA/graphene films in the acetone. The Raman spectrum shows the typical peaks of the monolayer graphene spectrum (Figure S10).49 To accommodate the electrolyte (200 μL of 2 mM MgCl2 in DEPC-treated water), a poly(dimethylsiloxane) (PDMS) well was constructed on the device. The device was cleaned with DEPC-treated water.
SAM/Dextran Immobilization on the Gate Surface
Gate electrodes were ultrasonically cleaned using acetone, ethanol, and deionized water and dried under a N2 stream. The SAM/dextran was immobilized on the gate surface as described by others.29 The bare Au surface of the gate electrode was treated with 5 mM 11-sulfanylundecanol in a solution of ethanol:water (4/1) to form the hydrophilic SAMs. Then, Au surfaces were immersed in a 0.6 M epichlorohydrin solution with a 1:1 mixture of 0.4 M NaOH and diglyme for 4 h at 25 °C. The electrodes were rinsed with water, ethanol, and water again and dried under a N2 stream. The electrodes were then incubated for 20 h at 25 °C in the dextran T500 (Solarbio) solution (0.3 g mL–1) with 0.1 M NaOH and then washed in deionized water. Subsequently, the carboxymethylated matrix was obtained by reaction with 1 M bromoacetic acid (in 2 M NaOH solution) for 16 h at 25 °C. The surface of the gate electrode was then rinsed with deionized water and allowed to dry completely.
Cas13a-crRNA (Cas13a RNPs) Functionalization as the Sensing Surface
The gate electrode with the SAM/dextran modification was then activated using a 1:1 volume ratio of 200 mM N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) and 50 mM N-hydroxysuccinimide (NHS, Aladdin) in 50 mM buffer of 2-(N-morpholino)ethanesulfonic acid (MES) for 3 h at room temperature. After the activation, the surface of the gate electrode was incubated in 1× buffer (10 mM Tris-HCl (pH 8.6), 1 mM DTT, 40 mM KCl, 1.5 mM MgCl2) with 0.1 μM of Leptotrichia wadei Cas13a (LwaCas13a, Guangzhou Bio-Lifesci) for 1 h at 37 °C. The LawCas13a in storage buffer (20 mM Tris-HCl (pH 7.4), 0.1 mM EDTA, 1 mM DTT, 200 mM NaCl, 50 % (v/v) glycerol) was stored at −20 °C for use. Unreacted intermediates formed by the reaction of NHS and carboxyl groups were then blocked using amino-PEG5-alcohol (1 mM, 10 min at 37 °C, Jiangsu Aikon) and ethanolamine hydrochloride (1 M, 10 min at 37 °C, Aladdin) and then washed with 2 mM MgCl2 solution in DEPC-treated water (Sangon Biotech). Finally, 10 μM crRNA (in 2 mM MgCl2; synthesized by Guangzhou Bio-Lifesci) that could recognize the target sequence was introduced onto the gate electrode surface and incubated for 30 min at 37 °C and overnight at 4 °C to form Cas13a RNPs. The sensing surface was then washed with 2 mM MgCl2 to remove any unbound crRNA before building a complete sensing system. This final step resulted in full Cas13a RNPs formation on the gate electrode surface.
Electrochemical Characterization
The electrochemical characteristics of the gold electrode were investigated before and after the formation of SAM, dextran polymer, and Cas13a RNPs by EIS and CV performed in a three-electrode setup using an electrochemical workstation. A platinum wire and a Ag/AgCl electrode were used as the counter electrode and reference electrode, respectively, while the gold electrode was connected as the working electrode. All measurements were carried out in PBS (pH 7.4) solution containing 5 mM Fe(CN)63–/Fe(CN)64–. For cyclic voltammetry measurements, the potential window was between −0.5 and 0.8 V, and the scan rate was 50 mV s–1. Electrochemical impedance spectra were recorded with an AC amplitude of 5 mV over a frequency range of 0.1–100 kHz. The data were analyzed using Nova software with the appropriate equivalent circuit modeling.
Device Characterization
The electrical characteristics of CRISPR-Cas13a-modified SGGTs were measured using two Keithley measurement units (Keithley 2400) operating by LabVIEW software under a constant drain voltage (VDS) of 0.1 V. The characteristics of SGGTs were obtained by measuring transfer characteristics (ID as a function of VG) and current-time response (ID as a function of time).
Evaluation of CRISPR-Cas13a-Modified SGGTs for the Detection of the Synthetic N Gene Fragment
The gate voltage of the functionalized SGGT was swept within a certain voltage range in 2 mM MgCl2 solution to obtain the stable initial baseline. Next, the different concentrations of target RNA (10 μL in 2 mM MgCl2, synthesized by GENSCRIPT) were incubated for 10 min. The transistor characteristics were measured by applying VG in the range of −0.3–0.7 V with a VDS of 0.1 V. Similarly, the different concentrations of target RNA solutions were added to 100% fetal bovine serum (Shanghai Macklin Biochemical) and were measured by applying the gate voltage between 0 and 1 V with a VDS of 0.1 V.
Clinical Sample Preparation and Testing
The clinical samples (human throat swab specimens) used in this study were collected from Zhongnan Hospital of Wuhan University as part of registered protocols approved by the hospital ethics committee. The total RNA from clinical throat swabs was extracted with a respiratory sample RNA isolation kit (Zhongzhi, Wuhan, China) and was applied for subsequent assays using RT-PCR. The total RNA obtained was diluted two times with DEPC-treated water (containing 2 mM MgCl2) for the measurement of the characteristic transfer curves of CRISPR-Cas13a-modified SGGTs by applying VG between 0 and 1 V with a VDS of 0.1 V.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acssensors.2c01990.Additional experimental details; materials; and methods, including AFM; CV; EIS of the gate surface; Cas13a-crRNA activity analysis; LOD; stability of device; gene sequence; channel current responses; and Raman spectrum of graphene (PDF)
Supplementary Material
se2c01990_si_001.pdf
Author Contributions
# Contributed equally to this work. H.Y.: conceptualization, methodology, investigation, formal analysis, and writing—original draft. H.Z.: methodology, formal analysis, resources, validation, visualization, and data curation. J.L.: resources, formal analysis, supervision, and writing—review & editing. Z.Z.: resources, formal analysis, supervision, and writing—review & editing. M.D.: visualization and data curation. Z.R., Z.L., and C.X.: investigation and resources. M.G.L.: writing—review & editing and resources. Z.C.: resources and supervision.
The authors declare no competing financial interest.
Acknowledgments
This study was financially supported by the Hubei Provincial Department of Science and Technology (2020BIB020), the National Natural Science Foundation of China (52073220 and 82100704), Sanya Science and Education Innovation Park of Wuhan University of Technology (2021KF0017), the Opening Project of Key Laboratory of Optoelectronic Chemical Materials and Devices of Ministry of Education, Jiang Han University (JDGD-202205), and Overseas Expertise Introduction Center for Discipline Innovation (D18025). The authors also thank Sixcarbon Tech. (Shenzhen) for graphene supplies. Some graphic elements of Figure 1 are created with BioRender.com.
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| 36472865 | PMC9745736 | NO-CC CODE | 2022-12-15 00:02:41 | no | ACS Sens. 2022 Dec 6;:acssensors.2c01990 | utf-8 | ACS Sens | 2,022 | 10.1021/acssensors.2c01990 | oa_other |
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Biometals
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Article
Nanoparticular and other carriers to deliver lactoferrin for antimicrobial, antibiofilm and bone-regenerating effects: a review
Ong Ray
http://orcid.org/0000-0001-5565-1714
Cornish Jillian
http://orcid.org/0000-0001-7833-5546
Wen Jingyuan [email protected]
grid.9654.e 0000 0004 0372 3343 Faculty of Medical and Health Sciences, School of Medicine, The University of Auckland, Auckland, 1142 New Zealand
13 12 2022
119
30 7 2022
27 9 2022
© The Author(s), under exclusive licence to Springer Nature B.V. 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Bone and joint infections are a rare but serious problem worldwide. Lactoferrin’s antimicrobial and antibiofilm activity coupled with its bone-regenerating effects may make it suitable for improving bone and joint infection treatment. However, free lactoferrin (LF) has highly variable oral bioavailability in humans due to potential for degradation in the stomach and small intestine. It also has a short half-life in blood plasma. Therefore, encapsulating LF in nanocarriers may slow degradation in the gastrointestinal tract and enhance LF absorption, stability, permeability and oral bioavailability. This review will summarize the literature on the encapsulation of LF into liposomes, solid lipid nanoparticles, nanostructured lipid carriers, polymeric micro and nanoparticles and hydroxyapatite nanocrystals. The fabrication, characterization, advantages, disadvantages and applications of each system will be discussed and compared.
Keywords
Lactoferrin
Bone
Nanoparticles
Microparticles
Hydroxyapatite
==== Body
pmcIntroduction
Bone and joint infections are difficult to treat, require high healthcare costs and are highly debilitating conditions (Pereira Rosa et al. 2015). Reports of osteomyelitis are as high as 1 in 675 hospital admissions in the United States annually (Momodu and Savaliya 2022). Around 6–12 weeks of antibiotics are needed to treat osteomyelitis (Baldwin et al. 2018), including spending about 2 weeks in hospital to receive intravenous antibiotics (Webb et al. 2022). Osteomyelitis can lead to severe complications including sinus tract formation, contiguous soft tissue infection, abscess, septic arthritis, systemic infection, bony deformity and fracture (Lalani and Schmitt 2022).
Lactoferrin (LF) is a single-chain globular glycoprotein of the transferrin family with ~ 700 amino acids with a molecular weight of ~ 80 kDa (González-Chávez et al. 2009). Its molecular weight varies with the amount of glycosylation (Avery et al. 2021). It has an isoelectric point (pI) around 8–9 (Roohinejad et al. 2018). This means that LF is positively charged at the physiological pH of 7.4 and at a pH below its isoelectric point (Abad et al. 2021). The melting temperature is 60–85 °C (Roohinejad et al. 2018). The protein is folded into two globular lobes called the N and C lobes, which each bind one Fe3+ ion (Ammons and Copié 2013). Each iron binding requires synergistic binding of one bicarbonate (Prieels et al. 1978) or carbonate anion (Adlerova et al. 2008). LF is present in mammalian secretions and has a high homology between mammalian species (Icriverzi et al. 2019).
Several mechanisms for LF’s direct antimicrobial and antibiofilm activity have been found. LF chelates iron, an essential nutrient for many bacteria including S. aureus (Hammer and Skaar 2011). S. aureus is a common causative pathogen of osteomyelitis and prosthetic joint infection (Brady et al. 2007; Berbari et al. 2021; Krogstad 2021). Iron chelation also helps prevent biofilm formation (Vogel 2012). Furthermore, the N lobe of LF can interact with bacterial membranes resulting in membrane permeabilization (van Veen et al. 2002), opsonization (Jenssen and Hancock 2009) and release of bacterial lipopolysaccharide from the cell wall leading to lysis of bacteria (Wang et al. 2017).
In vitro and in vivo studies have shown that bovine and human LF have bacteriostatic effects against gram positive and gram negative bacteria (Bhimani et al. 1999; González-Chávez et al. 2009; Wang et al. 2017; Avery et al. 2021). Clinical trials have shown mixed reports that bovine LF-fortified formula given to neonates and infants reduces the incidence of diarrhoeal illness and respiratory disease (King et al. 2007; Chen et al. 2016). To explain these findings, it is proposed that orally delivered bovine LF (bLF) alters the gut microbiota and gut mucosal immune system, modulating the immunity of other mucous membranes such as the respiratory tract (Chen et al. 2016; Kowalczyk et al. 2022).
Bone-regenerating properties of LF have also been documented. Subcutaneous injections of bLF into rat calvariae increases bone growth compared to control (Cornish et al. 2004; Görmez et al. 2015; Gul Koca et al. 2022). In vitro, bLF produces a dose-related increase in the proliferation of rat osteoblast-like cells (Cornish et al. 2004). Many mechanisms for this osteoblast mitogenesis have been described: bLF increases COX2 and NFATc1 activity (Cornish and Naot 2010; Naot et al. 2011); bLF also binds to LRP1, a protein found on the osteoblast cell membrane, activating p42/44 MAPK signalling (Naot et al. 2004); other mechanisms include activation of PI3 kinase, Akt and upregulation of IGF-R1 (Cornish and Naot 2010; Icriverzi et al. 2019).
In considering its antimicrobial and bone-regenerating effects, LF could be delivered intravenously or intraosseously, however, the most convenient mode is oral delivery. Analysis of the literature shows that the bioavailability of orally delivered LF depends on multiple factors. Longer gastric emptying times as well as low pH of 1.5–2—the optimum for pepsin digestion—leads to greater gastric digestion of LF (Wang et al. 2017). Under fasting conditions, the intragastric pH of adults is ~ 5–6 and it takes up to 100 min to generate enough gastric acid to reach the optimum pH (Wang et al. 2017). These findings correlate well with one clinical trial, in which bovine LF (bLF) administered before meals, in contrast to during meals, was found to survive gastric degradation and improve the blood profile of pregnant women with hereditary thrombophilia and anaemia of inflammation (Rosa et al. 2020). Meanwhile, gastric pH higher than 4 and gastric emptying rate of 30 min have shown to be partially ineffective at digesting bLF (Troost et al. 2001).
Intact bLF that survives gastric degradation can then be degraded by the intestinal enzymes trypsin and chymotrypsin, based on in vitro studies (Yao et al. 2013, 2014a). However, bLF can also be absorbed in intact form by intestinal epithelial cells by binding to surface receptors and undergoing transcytosis; then, according to findings from rat studies, bLF enters the lymphatic system, travels through the thoracic duct lymph and enters the systemic circulation (Takeuchi et al. 2004; Nojima et al. 2008; Kilic et al. 2017). Here, free LF has a short half life of 12–60 min in blood plasma (van Snick et al. 1974; Beauchamp et al. 1983; Nojima et al. 2009; Shiga et al. 2015), due to rapid removal by the reticuloendothelial system, the liver and spleen (van Snick et al. 1974; Beauchamp et al. 1983; Onishi 2011).
Given its short half-life, it is not surprising that oral formulations of LF tend to produce low levels of LF in human serum, regardless of the formulation (Dix and Wright 2018). Prof. Harada could detect bLF in human blood after oral delivery of 900 mg of enteric-coated bLF to a 60 kg adult (Shimizu 2004). The concentration of bLF was only ~ 150 ng/ml 4 h after administration (Shimizu 2004). It should also be noted that the endogenous LF concentration in blood of healthy humans is 0.02 to 2 μg/ml rising to 200 μg/ml during inflammation and infection (Sienkiewicz et al. 2021). Why then, do some oral formulations of lactoferrin seem to produce therapeutic effects? Two models have been proposed. The first is that LF and its degradation products could exert distal effects even if it remains in the wall of the gut (Kowalczyk et al. 2022). This could occur by interaction of LF with gut associated lymphoid tissue (Kilic et al. 2017). The second is that LF is absorbed, as previously described, and accumulates in target organs exerting direct effects (Shimizu 2004). Little information exists on the oral bioavailability of bLF and the relationship between bLF’s effects and its concentration in the blood (Nojima et al. 2009). Future studies could address this issue by using fluorescent-labelled LF and calculating the concentration of absorbed LF based on fluorescence intensity (Kilic et al. 2017).
LF has immunomodulatory effects. An immune response normally begins with the deposition of pathogens in host tissue. In osteomyelitis, bacteria can colonize the bone marrow, soft tissue surrounding bone or the osteocyte-lacuno canalicular network (Masters et al. 2019). Microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) allow bacteria to adhere to host polysaccharides like fibronectin, fibrinogen and collagen (Schmitt 2017). LF can prevent adherence of bacteria to epithelial cells (Ammons and Copié 2013). Neutrophils can recognize bacterial lipopolysaccharide (LPS). LF can bind LPS, reducing the activation of pro-inflammatory pathways (Fischer et al. 2006; Siqueiros-Cendón et al. 2014). Bacterial LPS can also stimulate osteoclastogenesis (Yamano et al. 2010; Janani et al. 2021). The extent of immune stimulation during sepsis, which can be a sequela or precursor to osteomyelitis, is also reduced by LF due to LF attenuating the LPS/CD14/TLR-4 pathway (Vogel 2012; Siqueiros-Cendón et al. 2014).
LF may have a role in osteoimmunology. Importantly, receptor activator of NF-κB ligand (RANKL) is expressed on osteoblasts and activated T cells, while RANK is expressed on osteoclasts and dendritic cells (Fan et al. 2018). RANKL-RANK binding results in bone resorption by osteoclasts. bLF orally administered to an osteoporosis mouse model decreased serum RANKL and increased serum OPG—these effects favour bone preservation (Fan et al. 2018). bLF was found to increase serum IFN-γ, IL-5 and IL-10. IFN-γ is known to inhibit RANKL/RANK signalling; IL-5 and IL-10 are known to increase OPG expression (Fan et al. 2018). RANKL and tumour necrosis factor (TNF) play an important role in bone destruction in rheumatoid arthritis (RA) (Firestein and Guma 2022). Oral liposomal bLF reduces osteoclastic bone destruction in a RA mouse model (Yanagisawa et al. 2022). This effect could be due to bLF-induced increase in Treg cells relative to Th17 cells and bLF-induced suppression of TNF-α production (Antoshin et al. 2021; Yanagisawa et al. 2022).
LF may have a role in coronavirus disease 2019 (COVID-19) treatment. LF’s antiviral activities are well known. It can bind to intelectin-1 receptor on host cells triggering the intracellular production of interferon which inhibits viral replication (Sienkiewicz et al. 2021). LF also down-regulates IL-6 which helps prevent intracellular iron overload, a situation which favours viral replication (Campione et al. 2021a). In particular for the SARS-CoV-2 virus that causes COVID-19, moieties of LF can attach to heparan sulfate proteoglycans, limiting the binding of the virus to ACE2, a protein expressed on the surface of multiple human epithelial cells that facilitates viral fusion with host epithelial cells (Sienkiewicz et al. 2021). In vivo studies have demonstrated that oral or intranasal liposomal bLF enables faster SARS-CoV-2 RNA negativization for patients with asymptomatic or mild-to-moderate infection compared to standard of care-treated or untreated patients (Rosa et al. 2021; Campione et al. 2021b). Negativization refers to the negative conversion of naso-oropharyngeal swab results for COVID-19 patients.
Considering its antimicrobial role in infections such as osteomyelitis, endogenous LF is secreted in high concentrations at the infection site. It binds to neutrophil extracellular traps (NETs) that help contain bacterial pathogens. These NETs help expose bacteria to high local concentrations of LF and other antimicrobial peptides (Vogel 2012). If exogenous LF is to be used as part of local therapy for osteomyelitis and other infections, it would need to be delivered to bacteria at high concentrations for a prolonged period in order to effectively eliminate the pathogen. High concentrations of LF would also help regenerate injured bone tissue. Therefore, a review of drug delivery carriers of LF would be useful to introduce effective formulation approaches that can enhance LF stability for parenteral use. The review will also discuss oral formulations of LF, to explore its possible role as an adjuvant for systemic infection (Vincent et al. 2015; Sherman et al. 2016). Oral formulations of LF may be able to enhance oral bioavailability and increase the permeability of LF through mucosal tissue and uptake by target cells. Therefore, we will discuss the applications of liposomes, solid lipid nanoparticles, nanostructured lipid carriers, polymeric micro and nanoparticles and hydroxyapatite nanocrystals and microspheres as potential methods of delivering LF orally and/or parenterally.
Liposomes
Liposomes are vesicles made of bilayer(s) of phospholipid enclosing an aqueous environment. They can be fabricated by four methods—thin film hydration, microfluidization also known as high pressure homogenization, reverse phase evaporation and ether injection (Guan et al. 2012). Liposomal LF (L-LF) has been administered intra-articularly, topically or orally (Table 1, Fig. 1).Table 1 Details of studies of LF-loaded micro/nano carriers
Carrier type Study authors Mode of delivery Species of LF used Components of vehicle Entrapment efficiency and particle size Half life of delivery vehicle Advantages of the carriers Limitations of the carriers
Liposomes Trif et al. 2016; Icriverzi et al. 2019 Intra-articular Human Negatively or positively charged liposomes Not stated Not stated Fast action Requires specialist training
Invasive/painful
Risk of contamination
Costly
Liposomes López-Machado et al. 2021b Topical—eye Bovine Hyaluronic acid-coated liposomes made from fat-free soybean phospholipids with 70% phosphatidylcholine (lipoid S75), cholesterol and polysorbate 80 ~ 50%; ~ 90.5 nm > 3 min Prolonged/sustained release Time taken to diffuse into cells, poor penetration
Liposomes Ishikado et al. 2005; Yamano et al. 2010 Oral Bovine Egg yolk phosphatidylcholine
Phytosterol
42%; 580 nm Not stated Safe, convenient and no pain for administration, Able to self-administer Slow action,
Gut enzymes may degrade
Liposomes Kawazoe et al. 2013 Oral Bovine Soy phosphatidylcholine EE not available; 70 nm Not stated Safe, convenient and no pain for administration, Able to self-administer Slow action,
Gut enzymes may degrade
Liposomes Vergara and Shene 2019; Vergara et al. 2020 Oral Bovine Rapeseed phospholipid
Stigmasterol
Hydrogenated phosphatidylcholine
LF
~ 90%; ~ 200 nm Not stated Safe, convenient and no pain for administration, Able to self-administer Slow action,
Gut enzymes may degrade
Liposomes Yao et al. 2014b; Yao 2015 Oral Bovine Pectin or chitosan 58.14%; 301.7 nm ~ 5 h Safe, convenient and no pain for administration, Able to self-administer Slow action,
Gut enzymes may degrade
Liposomes Campione et al. 2021b Oral or
Intra-nasal
Bovine Not stated Not stated; not stated Not stated Oral delivery:
Safe, convenient and no pain for administration, Able to self-administer
Oral delivery:
Slow action,
Gut enzymes may degrade
Intra-nasal delivery:
Easy to administer
Rapid onset of action
Avoids first-pass metabolism
Intra-nasal delivery:
Only small volumes of drug can be administered
Liposomes Rosa et al. 2021 Oral Bovine Not stated Not stated; not stated Not stated Safe, convenient and no pain for administration, Able to self-administer Slow action,
Gut enzymes may degrade
Solid lipid nanoparticles Yao et al. 2015 Oral Bovine Pectin or chitosan ~ 92.02%; 283.1 nm ~ 5 h Safe, convenient and no pain for administration, Able to self-administer Slow action,
Gut enzymes may degrade
Nanostructured lipid carriers Varela-Fernández et al. 2022 Topical – eye Not stated Glycerol monostearate
Soy lecithin
Cholesterol
Compritol 888 ATO
Capryol® 90
Miglyol® 812 N
Poloxamer 407
Poloxamer 188
D-α-Tocopherol Polyethylene Glycol 1000 Succinate
~ 75%; ~ 119.45 nm ~ 75 min Prolonged/sustained release Time taken to diffuse into cells, poor penetration
Polymeric nanoparticles Duarte et al. 2022 In vitro Bovine Gellan gum Not applicable; 92.03 nm Not stated Not applicable due to in vitro delivery Not applicable due to in vitro delivery
Polymeric nanoparticles López-Machado et al. 2021a Topical – eye Bovine PLGA Resomer® 50:50 503H
Ethyl acetate
Kolliphor ® P188
32–56%; 130–146 nm Not stated Prolonged/sustained release Time taken to diffuse into cells, poor penetration
Polymeric nano-to-micro particles Yang et al. 2020 Oral or parenteral Bovine Oat β-glucan Not applicable; Increase with rise in oat β-glucan concentration from nano to microscale Not stated Oral delivery:
Safe, convenient and no pain for administration, Able to self-administer
Parenteral delivery:
Fast action
Oral delivery:
Slow action,
Gut enzymes may degrade
Parenteral delivery:
Painful, costly, risk of contamination
Polymeric microparticles Kumar 2010; Kumar et al. 2013 Oral Bovine Barley β-glucan 63.2–91.5%; 5–50 μm Not stated Safe, convenient and no pain for administration, Able to self-administer Slow action,
Gut enzymes may degrade
Polymeric microspheres Kim et al. 2014 In vitro Not stated Poly-D,L-lactide-co-glycolide (PLGA)
Poly vinyl alcohol (PVA)
Dichloromethane
Gelatin
Dopamine
Heparin
9.31–54.4%; 400 μm Months (Scholz 2009) Not applicable due to in vitro delivery Not applicable due to in vitro delivery
Polymeric microspheres Görmez et al. 2015 Intraosseous Bovine Gelatin Not stated; not stated Not stated Fast action Requires specialist training
Invasive
Costly
Risk of contamination
Hydroxyapatite nanocrystals Nocerino et al. 2014 In vitro Bovine Hydroxyapatite Not stated; 110 nm Not stated Not applicable due to in vitro delivery Not applicable due to in vitro delivery
Hydroxyapatite nanorods Shi et al. 2017 In vitro Not stated Hydroxyapatite Not applicable; 150 nm Not stated Not applicable due to in vitro delivery Not applicable due to in vitro delivery
Hydroxyapatite microspheres Shi et al. 2017 In vitro Not stated Hydroxyapatite Not applicable; 2–10 μm Not stated Not applicable due to in vitro delivery Not applicable due to in vitro delivery
Hydroxyapatite nanocrystals Montesi et al. 2015a, b In vitro Bovine Hydroxyapatite 6.6–15.1%; 115 nm Not stated Not applicable due to in vitro delivery Not applicable due to in vitro delivery
Hydroxyapatite nanoparticles Kim et al. 2016 In vitro Not stated Hydroxyapatite
Dopamine
Heparin
1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide
88.7%-90.03%; 107.5–119.1 nm Not stated Not applicable due to in vitro delivery Not applicable due to in vitro delivery
Information on the degree of iron saturation of LF was missing from most studies, except studies by Yao et al. (2013, 2014a, b, Yao 2015), where native bLF with iron saturation of ~ 15% was used
Fig. 1 Liposome in cross-section (Buya et al. 2021). Created with BioRender.com
Liposomes can be characterized by: particle size; particle size distribution which is also known as polydispersity index (PDI); zeta potential; entrapment efficiency (EE); in vitro drug release; morphology by scanning electron microscopy (SEM); fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC).
Particle size and PDI can be measured by laser light scattering (Liu 2019). Zeta potential indicates the amount of surface charge of the liposome. The greater the surface charge, the greater the electrostatic repulsion between two liposomes. Small particle size and high zeta potential—particularly above 30 mV in modulus (Chen et al. 2019; Anali Bazán Henostroza et al. 2022)—increase the stability of liposomes. A positive zeta potential can be achieved by adding cationic compounds to liposomes, such as dioleoylphosphatidylethanolamine (DOPE) (Ding et al. 2009) and 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) (Tonguc-Altin et al. 2015). A negative zeta potential can be achieved by adding 1,2-dioleoyl-sn-glycero-3-phospho-l-serine (DOPS) (Smith et al. 2017). Entrapment efficiency (EE) refers to the proportion of the drug trapped within the liposome. Several studies show that the EE for liposomal LF can range from 42 to 90% (Table 1).
In vitro drug release can be measured by dialysis tubing or Franz diffusion cell analysis. Both methods involve the release of the drug from the liposome followed by the permeation of free drug through a dialysis membrane. Samples are taken at specified time intervals and the amount of released drug is often measured (Chen et al., 2019) by high performance liquid chromatography (HPLC). FTIR and DSC can detect whether LF is loaded within the aqueous compartment or within the bilayer of the liposome.
Liposomes have many advantages as drug delivery vehicles. They are able to contain hydrophilic and hydrophobic drugs (Icriverzi et al. 2019); as their components are found endogenously (Anabousi et al. 2006), they are biocompatible (Icriverzi et al. 2019), biodegradable (dos Santos Ramos et al. 2020) and have low toxicity (Icriverzi et al. 2019; dos Santos Ramos et al. 2020); they have low immunogenicity (Icriverzi et al. 2019), their surface can be modified to target delivery of the drug (Icriverzi et al., 2019). They are able to prolong the release of drugs (Al‐amin et al. 2020).
Liposomes have several challenges to their widespread use. The main issue is poor stability compared to other drug carriers (Roohinejad et al. 2018; Thorn et al. 2021). Traditional liposomes greater than 100 nm are rapidly cleared from blood circulation by circulating macrophages or dendritic cells as part of the reticuloendothelial system (Buya et al. 2021; Anali Bazán Henostroza et al. 2022). Hydrophilic polymers such as polyethylene glycol, pectin or chitosan can protectively coat the surface of liposomes, increasing their residence time in the blood circulation (Anabousi et al. 2006; Icriverzi et al. 2019; Buya et al. 2021). It has also been shown that liposomes prepared from milk derived phospholipids or rapeseed oil can slow the digestion of LF in simulated gastric and intestinal conditions (Liu et al. 2013; Vergara et al. 2020).
Liposomes are difficult and costly to make on an industrial scale (Al‐amin et al. 2020). Microfluidization may achieve scalability with low batch-to-batch differences, however, this high energy process may damage proteins (Al‐amin et al. 2020). Supercritical carbon dioxide technique is a recently developed technique used to prepare liposomes and niosomes (Hallan et al. 2022). It is an inexpensive, inert, harmless, fire-resistant and environmentally friendly approach that avoids the use of organic solvent. The method involves atomized water droplets used to coat phospholipid vesicles under high diffusion of carbon dioxide. Several studies have demonstrated encapsulation efficiencies above 66% for various drugs using this method (Hallan et al. 2022).
Locally delivered L-LF can greatly prolong LF residence time at the administration site. Human LF (hLF) entrapped in positively charged liposomes delivered intra-articularly to mice with collagen-induced arthritis was retained longer in the injected joint compared to free protein or neutral or anionic liposome formulations (Trif et al. 2001; Icriverzi et al. 2019). However, negatively charged liposomes containing hLF had enhanced accumulation in human synovial fibroblasts from rheumatoid arthritis patients (Trif et al. 2001). Additionally coating liposomes with hyaluronic acid has increased the residence time of LF on the corneal surface (Table 1) (López-Machado et al. 2021b).
Liposomes, especially when coated with hydrophilic polymers such as chitosan, can increase the oral bioavailability of LF by protecting it from gastrointestinal degradation and delaying its removal from the systemic circulation by the reticuloendothelial system (Yao et al. 2015; Gorantla et al. 2021; Mohammadi et al. 2023). Two studies have found that orally administered L-LF inhibits bacterial LPS-induced bone resorption of alveolar bone in a rat periodontitis model (Table 1) (Yamano et al. 2010; Kawazoe et al. 2013). Yamano et al. (2010) administered L-bLF to rats for 7 days, then stimulated periodontitis by administering LPS. Therefore, it was concluded that L-LF can reduce alveolar bone destruction in periodontitis patients. This effect is probably due partly to the gastrointestinal ingestion and absorption of L-LF because of the pre-administration of bLF before stimulating periodontitis.
Vergara Shene (2019); Vergara et al. (2020) used combinations of rapeseed phospholipid, stigmasterol and hydrogenated phosphatidylcholine to make L-bLF with an entrapment efficiency of ~ 90%. A high entrapment efficiency is beneficial as it means relatively less amount of excipient can encapsulate a large amount of drug, increasing the cost-effectiveness and safety of the formulation. The liposomes of Vergara Shene (2019); Vergara et al. (2020) also had improved stability, delaying hydrolysis in gastric and intestinal environments. Further study needs to be done to investigate the therapeutic effects of this oral formulation of bLF. Another study by Yao et al. (2014b) reported that liposomes and solid lipid nanoparticles modified with chitosan or pectin increased the oral bioavailability of bLf 1.95–2.69 times in vivo compared to free bLF.
Solid lipid nanoparticles (SLNs)
SLNs are made of a core of biodegradable lipids that are solid at room and body temperature (Buya et al. 2021) surrounded by a layer of surfactant. The term “lipids” is used broadly here, and includes long chain triglycerides, partial triglycerides, fatty acids, phospholipids, waxes, cetyl palmitate and alkanoic acids (Pignatello et al. 2018; Buya et al. 2021). These are highly biocompatible. The surfactants used may have a concentration ranging between 1 and 5% (w/v) and can include polysorbate 80, poloxamer 188 and/or lecithin (Buya et al. 2021). Bioactive compounds, both hydrophilic and lipophilic (Moutinho et al. 2012), are encapsulated into the solid lipid matrix and released in a controlled manner (Buya et al. 2021). SLNs are generally spherical, with particle sizes of 10–1000 nm (Buya et al. 2021) (Fig. 2).Fig. 2 Solid lipid nanoparticle (Roohinejad et al. 2018; Buya et al. 2021). Created with BioRender.com
Only one group investigated the encapsulation of LF into solid lipid nanoparticles and compared this with liposomal-LF. SLN-LF showed higher heat resistance and greater electrolyte tolerance than L-LF (Yao et al. 2015). Furthermore, SLN-LF was physically more stable, demonstrated by pH and thermal treatment, ionic strength and storage at room and body temperature. This suggests that SLN-LF is, in general, more resistant to degradation in the gastrointestinal tract than L-LF. The rank order of oral bioavailability was chitosan-modified SLNs > pectin-modified liposomes > pectin-modified SLNs > chitosan-modified liposomes, with chitosan-modified SLNs showing 2.69-fold increase in oral bioavailability compared with free bLF (Yao et al. 2014b).
SLNs have the potential to be implanted into bone defects via embedding in hydrogels. One study investigated resveratrol loaded SLNs (Res-SLNs) embedded in a gelatin methacrylate (GelMA) hydrogel scaffold (Wei et al. 2021). Resveratrol is known to promote osteogenic differentiation and bone formation. Res-SLNs-GelMA was implanted into rat calvarial critical-size defects. Micro-CT results showed that the Res-SLNs-GelMA group showed the highest bone regeneration rate compared to GelMA only or SLNs-GelMA without Res. The study also found that SLNs significantly prolonged the release of Res from GelMA: 14% of the total drug was released at 0.5 days and 75% was released at 28 days. One limitation of this study is that the micro-CT results of Res-GelMA without SLNs weren’t obtained. This would shed more light on the synergistic effect of SLNs and GelMA hydrogel on bone regeneration.
SLNs can be characterized similarly to liposomes, namely particle size, zeta potential and entrapment efficiency (Wei et al. 2021). Their surface morphology can be determined by transmission electron microscopy (Wei et al. 2021). SLNs can be freeze-dried and their crystalline structure determined using an X-ray diffractometer (Wei et al. 2021), in order to ascertain whether LF has been successfully incorporated into the SLN.
Similar to liposomes, SLNs demonstrate sustained drug delivery, low toxicity, increased bioavailability compared to free drug and biodegradability (Naseri et al. 2015; Sayed 2017). However, unlike liposomes, SLNs and nanostructured lipid carriers (NLCs) have improved shelf-life stability (Thorn et al. 2021). SLNs can protect the drug from degradation (from light or oxygen) (Patel and San Martin-Gonzalez 2012; Pignatello et al. 2018; Thorn et al. 2021). Storage stability can be further increased by lyophilization and spray-drying (Hallan et al. 2022). Interestingly, SLNs can be designed to have prolonged circulation in the blood and may be able to accumulate in the bone marrow. This study (Göppert and Müller 2003) showed that poloxamer-188-stabilized SLNs (P188-SLNs) had prolonged circulation time, possibly due to the adsorption of albumin, a dysopsonic protein, on the P188-SLNs. The P188-SLNs also adsorbed apolipoprotein C-II and C-III in sufficient amounts that the researchers postulated that P188-SLNs could accumulate in the bone marrow, similar to poloxamer 407 polystyrene particles (Göppert and Müller 2003). Compared to liposomes and polymeric nanocarriers, SLNs are also easier and cheaper to mass-produce (Naseri et al. 2015; Sayed 2017; Hallan et al. 2022) and sterilize (Pignatello et al. 2018).
The main disadvantage of SLNs is that loading highly polar compounds often results in very low encapsulation (Furneri et al. 2017). However, there are ways to circumvent this, including: loading a non-polar basic form of the drug, coating the drug with a surfactant capsule before loading into SLN, utilizing lipophilic prodrugs or using hydrophobic ion-pairing (Thorn et al. 2021).
Nanostructured lipid carriers (NLCs)
NLCs are similar to SLNs but have a less structured lipid matrix composed of a mix of solid and liquid lipids (Buya et al. 2021). This allows NLCs to increase the encapsulation of active drug compared to SLNs, demonstrate higher loading capacity, reduce expulsion of drug during storage and prolong stability of the drug (Ali 2015; Roohinejad et al. 2018; Buya et al. 2021). NLCs have a greater capacity to store hydrophilic and lipophilic drugs compared to SLNs (Buya et al. 2021) and are more able to penetrate cell membranes (Buya et al. 2021). NLCs are also biodegradable, exhibit low toxicity and are easy and cost-effective to mass-manufacture (Roohinejad et al. 2018) (Fig. 3).Fig. 3 Nanostructured lipid carrier (NLC). The cores of NLCs are composed of liquid and solid lipids resulting in the formation of imperfect crystals. This allows more space to incorporate bioactive compounds (Roohinejad et al. 2018; Buya et al. 2021). Created with BioRender.com
The main methods for fabricating NLCs are hot homogenization, cold homogenization and solvent emulsification-evaporation (Roohinejad et al. 2018). Solvent emulsification-evaporation is typically employed to encapsulate hydrophilic drugs like the protein LF (Varela-Fernández et al. 2022).
NLCs can be characterized by particle size, morphology, entrapment efficiency, zeta potential and in vitro release behavior. Moreover, the crystallinity and melting behavior of the lipid are important to determine as these affect the release rate, drug loading, and EE (Roohinejad et al. 2018). X-ray spectroscopy and DSC are used to investigate lipid status.
Only one study investigated LF-loaded NLCs (Varela-Fernández et al. 2022). The context of the research was ocular drug delivery for keratoconus treatment. Entrapment efficiency and loading capacity was ~ 75% for 1 mg/ml LF. The in vitro release study demonstrated an initial burst release of 20% of total LF in the first hour followed by a controlled release where a cumulative ~ 50% of total LF was released after 24 h. The NLC-LF were stable, non-toxic and showed mucoadhesive properties. The study demonstrated the potential of topical ophthalmic delivery of NLC-LF.
Polymeric micro- and nanoparticles
Polymeric micro- and nanoparticles form a diverse group of compounds. Only 6 studies were found for lactoferrin delivery by polymeric particles. LF and gellan gum was combined through electrostatic complexation to enhance the antimicrobial properties of LF (Duarte et al. 2022). Fabrication of LF-gellan gum complexes was done by mixing vacuum-filtered stock solutions of LF and gellan gum at pH 4—the pH at which the greatest net charge difference between the biopolymers was observed. The LF-gellan gum complexes were characterized by zeta potential, isothermal titration calorimetry, FTIR, atomic force microscopy and minimum inhibitory concentration (MIC) assays to assess antimicrobial activity against S. aureus and E. coli. Duarte et al. (2022) found that LF-gellan gum complexes reduced the MIC for S. aureus compared to free LF, however the effect was reduced in tryptic soy broth, which contained higher concentrations of divalent cations—Fe2+, Mn2+, Zn2+, Cu2+ that competed with LF for anionic sites on the microbial membranes (Duarte et al. 2022). The study also reported that complexation to gellan gum reduced the flexibility of LF, which may limit its interaction with bacterial membranes. This may help explain why the MIC for E. coli was unaffected by LF-gellan gum. The findings from Duarte et al. (2022) suggest that LF-gellan gum complexes could be effective against S. aureus infections in vitro, however, further studies need to be done to investigate its effects in vivo.
López-Machado et al. (2021a, b) fabricated bLF-loaded polymeric nanoparticles (bLF-NPs) composed of poloxamer 188 (P188) and poly (lactic-co-glycolic acid) (PLGA). The bLF-NPs were fabricated by double emulsion and characterized by particle size, particle size distribution, zeta potential and EE. The optimum formulation achieved an EE of 56%. The bLF-NPs exhibited prolonged release of bLF with a cumulative 83.6% of bLF released after 48 h. P188 and PLGA were chosen as they could demonstrate improved permeability across corneal tissue, enhancing the anti-inflammatory effect of bLF. These polymers were also biocompatible and biodegradable and relatively large amounts of bLF could be loaded into these nanoparticles: concentrations of bLF of 8–11 mg/ml reached 50–60% encapsulation for P188 and at 19 mg/ml bLF, the maximum loading capacity was reached for PLGA particles. Moreover, the bLF-NPs could be sterilized with γ-irradiation with little effect on their physicochemical properties. The effect of these nanoparticles on bone tissue, bacteria or biofilms was not studied. However, these nanoparticles decreased the expression of inflammatory cytokines in the tear film to levels similar to free bLF, indicating that bLF encapsulated in these NPs retained its effect.
Two studies investigated the combination of bLF with beta-glucan (bG) (Kumar 2010; Kumar et al. 2013; Yang et al. 2020). Yang et al. mixed bLF and oat bG solutions at different proportions at 25 °C and at pH 5. Mixing of the two solutions was also carried out at 90 °C. The bLF-oat bG complexes were characterized by isothermal titration calorimetry (ITC), particle size, zeta potential, SEM, fluorescence spectroscopy, far-UV circular dichroism measurements, raman spectra collection and flow behaviour measurements. ITC showed that bLF and oat bG can bind to each other and suggests that the interaction is at least partly electrostatic. bLF is positively charged at pH 5, and oat bG is neutral or slightly negatively charged due to the presence of phosphate residues. Importantly, fluorescence spectroscopy showed that oat bG can change the structure of bLF. Turbidity and particle size was larger for complexes heated at 90 °C compared to 25 °C. This suggested the formation of larger biopolymer complexes at higher temperatures, involving aggregation and thermal denaturation of bLF in the presence of oat bG. Therefore, complexation of bLF with oat bG may result in the limitation of bLF’s properties, especially under elevated temperature conditions above 25 °C.
Hemant Kumar loaded bLF into barley bG microparticles (bLF-barley bG) using a cryo-milling technique to investigate its effect on osteoblasts and bone mineral density (Kumar 2010; Kumar et al. 2013). In vitro, bLF was released in a sustained manner from cryomilled barley bG. Initially, 25% burst bLF release was found and after 7 h, reached only 35%. Addition of Kollicoat increased the burst release to 57% and final bLF release after 7 h was 91%. In vivo, the study found that carriage of cryomilled bLF in barley bG increased the oral bioavailability of bLF in ovariectomized mice. However, bLF extracted from cryomilled bLF-barley bG complexes showed less activity on osteoblast proliferation compared to cryomilled free bLF. Importantly, complexation of bLF to barley bG did not increase bone mineral density to a greater extent compared to orally delivered free bLF. These results suggest that complexation of bLF to barley bG increases the oral bioavailability of bLF and preserves but does not enhance bLF’s bone-regenerating effects.
Kim et al. (2014) prepared poly(lactide-co-glycolide) (PLGA) microspheres coated with LF in order to study their effect on the osteogenic differentiation of rabbit adipose-derived stem cells (Fig. 4).Fig. 4 PM with adsorbed lactoferrin. Image used with permission from (Kim et al. 2014)
PMs were fabricated using a fluidic device with discontinuous and continuous phases (Kim et al. 2014). The discontinuous phase was a water-in-oil polymer emulsion composed of PLGA, polyvinyl alcohol (PVA) and gelatin in dichloromethane solution. The continuous phase was PVA solution. The discontinuous and continuous phases were mixed together at different flow rates through the fluidic device. The PMs were modified with negatively-charged heparin by immersion in Tris buffer. Then, LF was adsorbed on the surface of the PMs by combining Hep-PMs with LF in 2-(N-morpholino) ethanesulfonic acid (MES) buffer.
The PMs were characterized by SEM and X-ray photoelectron spectroscopy. In vitro release of LF into phosphate buffered saline was also measured. The release of LF was prolonged: ~ 47% of cumulative LF was released over 28 days. Furthermore, the study demonstrated that LF-impregnated PMs induced osteogenic differentiation of rabbit adipose-derived stem cells (rADSCs) by increasing ALP activity, calcium deposition, osteocalcin and osteopontin expressions compared with rADSCs grown in PMs without LF. In vivo studies will be needed to further determine the effects of LF-impregnated PMs.
Porous microspheres (PMs) offer two benefits for bone regeneration: they can be used as injectable scaffolds to repair irregularly-shaped bone defects during minimally invasive surgery; they can also contain and release many different drugs or proteins. PLGA has been used in orthopaedic implants and may be suitable for bone regeneration as it takes months to degrade in the body, approximating the rate of bone healing (Scholz 2009).
Görmez et al. (2015) prepared bLF-loaded gelatin microspheres (bLF-GM). The bLF-GM were fabricated by adding bLF in phosphate buffer to gelatin solution. Glutaraldehyde solution was added to harden the microspheres. bLF-GM was characterized by in vitro release of bLF: approximately 3 mg of bLF was released over 24 days (Görmez et al. 2015). Increasing the cross-linking density of the microspheres extended the duration of release. Görmez et al. (2015) found that 3 mg bLF-GM in combination with inorganic bovine bone promoted bone regeneration in bone defects surgically created around tooth implants in pigs. Compared to inorganic bovine bone alone, adding bLF-GM increased the percentage of hard tissue and newly formed bone and decreased the percentage of residual graft tissue.
Hydroxyapatite nanocrystals and micro-particles
Hydroxyapatite (HA) nanocrystals are a major inorganic constituent of bone tissue and are widely used as a bone graft material due to high biocompatibility and osteoconductivity (Murugan et al. 2010; Montesi et al. 2015a; Shi et al. 2017; Bastos et al. 2019). Synthetic biomimetic HA nanocrystals can be made to have a length of 100 nm, the width of 20–30 nm and a thickness of 3–6 nm, resembling the natural HA nanocrystals found in bone (Nocerino et al. 2014).
Nocerino et al. (2014) found that bLF-coated HA nanocrystals possessed concentration-dependent bacterial growth-inhibiting properties, including against S. aureus. bLF-HA was synthesized by precipitation of HA nanocrystals using (CH3COO)2Ca and H3PO4. bLF was then dissolved in HEPES buffer at pH 7.4 and was found to be strongly attracted to HA forming a monolayer protein coat around the nanocrystals. bLF-HA was characterized by FTIR and fourier transform Raman spectroscopy, which determined that the conformation of adsorbed bLF was only slightly altered compared to unadsorbed bLF. A downside to the bLF-HA particles was the slight cytotoxicity to THP-1 cells at concentrations used to inhibit the growth of bacteria (Nocerino et al. 2014).
HA can also be shaped in nanorod and microsphere forms, and LF can be adsorbed onto these particles (Shi et al. 2017). HA nanorods and HA microsphere powders were combined with LF in phosphate buffer solution at pH 7.4 at 37 °C for 24 h. The complex was washed twice with ultrapure water, recovered by centrifugation and freeze-dried. LF-HA nanorods and microspheres were characterized by N2 adsorption–desorption isotherms which determined that the particles were mesoporous (having pores of diameter 2–50 nm). Thermogravimetric analysis was used to determine the amount of LF protein attached to the HA. FTIR demonstrated that LF and HA interacted stably and that LF did not affect the conformation of HA. The study found that microspherical HA had higher biocompatibility compared to nanorod HA—this was attributed to the greater aggregation of the nanorods impairing nutrient and water absorption. The main study findings were that, compared to HA alone, HA-LF was more biocompatible toward MC3T3-E1 cells and HA-LF nanorods and microspheres stimulated greater cell proliferation of MC3T3-E1 (Shi et al. 2017). Importantly, microsphere HA-LF increased cell viability of MC3T3-E1 cells compared to free LF at 48 and 72 h (Shi et al. 2017).
Montesi et al. (2015a, b) fabricated HA-LF nanocrystals in a similar method as described by Nocerino et al. (2014). No LF was released from the HA surface for up to 14 days, indicating a strong affinity of LF for HA. It was found that HA and LF acted synergistically in MC3T3-E1 osteoblasts to trigger osteoblast viability, differentiation and bone matrix deposition. In contrast, osteoclast formation and activity was inhibited. These findings suggest that LF-adsorption onto HA can be used as a bone graft substitute, increasing the local concentration of LF, prolonging its residence time in the target tissue (Montesi et al. 2015a, b).
It has been reported that LF-HA particles may aggregate together and precipitate in an aqueous environment such as plasma, resulting in rapid clearance by the liver or toxicity to cells (Kim et al. 2016). Therefore, Kim et al. (2016) fabricated heparin-immobilized HA nanoparticles to deliver LF. Heparin’s negative charge was used to increase the electrostatic repulsion between HA particles and LF was conjugated to the heparin (Hep) coating the HA particles. Fabrication was a complex process involving the components HA, LF, dopamine, Hep, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDAC), N-hydroxysuccinimide (NHS), and 2-(N-morpholino) ethanesulfonic acid (MES) buffer.
LF-Hep-HA was characterized by measuring its particle size; zeta potential to determine if Hep had linked LF to HA particles; transmission electron microscopy for morphology; turbidity and precipitation studies to determine if LF-Hep-HA particles had aggregated. The study found that Hep immobilization onto HA nanoparticles prevented their aggregation and prolonged the release of LF over 4 weeks. LF-Hep-HA had low cytotoxicity and induced the osteogenic differentiation of rabbit adipose-derived stem cells. Further studies, perhaps using human adipose-derived stem cells, will be needed to determine the applicability for humans. These findings suggest the potential for LF-Hep-HA to be used as an injectable system to stimulate bone tissue regeneration (Kim et al. 2016).
Discussion
Nanoparticular drug carriers are an expanding research area as they can enhance existing treatments for diseases like infection and cancer. Nanoparticles, when targeted to specific tissues, provide a high local concentration of drug. This makes them highly suited to augmenting antimicrobial therapy. The human immune system is similarly able to create high local concentrations of antimicrobial peptides including LF around invading pathogens as part of the innate immune response (Vogel 2012). Nanoparticular carriers also prolong the release of the drug. When loaded with the right active molecule, nanocarriers can reduce the spread of antimicrobial resistance (Kalelkar et al. 2021).
The small size of nanoparticles also helps in biofilm penetration. Analysis of several studies has shown that large, highly positive or highly negatively charged lipid-based drug delivery systems penetrate biofilms poorly while a negative or near-neutral lipid nanoparticle facilitates greater biofilm penetration (Thorn et al. 2021). Lipid-based drug delivery systems include liposomes, SLNs and NLCs.
This review has introduced several nano and micro-particular carriers for LF. Liposomes are generally less stable than SLNs or NLCs, although a larger body of research exists around liposomes. Unlike SLNs and NLCs, liposomes can fuse with bacterial membranes, delivering active drug (Thorn et al. 2021; Shadvar et al. 2022). They can be made with rapeseed or milk-derived phospholipid, stigmasterol and hydrogenated phosphatidylcholine (Liu et al. 2013; Vergara and Shene 2019; Vergara et al. 2020) to improve stability and delay hydrolysis in the gastrointestinal environment. Use of these components is thought to improve stability as the fatty acid chains of the phospholipid are more saturated, hence the liposomal membrane is more rigid and less prone to leak drug (Roohinejad et al. 2018).
The cost of mass-producing liposomes is another barrier to their widespread use. Innovative techniques such as supercritical carbon dioxide need to be explored further (Hallan et al. 2022) and the effect of these processes on the structure of the drug molecule needs to be studied.
SLNs and NLCs are promising nanocarriers particularly in oral drug delivery. The use of saturated fatty acids like stearic acid improves their stability (Yao et al. 2014a). Preliminary studies involving Caco-2 cells have shown that SLN-bLF are taken up by gastrointestinal epithelium by an energy-dependent process (Yao et al. 2014a). Further research may involve oral delivery of SLN-LF to ovariectomized mice and comparing the skeletal composition with mice fed with a control diet. Ovariectomized mice are a model for post-menopausal osteoporosis. SLNs also have the potential to be implanted into bone defects via embedding in hydrogels (Wei et al. 2021).
Polymeric micro and nanoparticles represent a diverse group of compounds. Poloxamer and PLGA can preserve LF function and are able to load relatively high concentrations of bLF (López-Machado et al. 2021a). However, the biodegradation of these polymers requires careful consideration. PLGA takes months to degrade in the body. This may be an advantage if it is placed within bone tissue that is undergoing healing as it approximates the duration of the healing process (Scholz 2009). However, systemic administration of such polymers may be unsuitable due to their large size which impacts renal clearance (Wyss et al. 2020). The degradability of PLGA can be determined by several measurements (Hussein et al. 2013): (1) water uptake of the polymer—the greater the water uptake, the greater the degradability; (2) loss of mass of polymer over time; (3) change in pH of the degradation environment—the breakdown products of PLGA are acidic; (4) quantification of the acidic breakdown products of PLGA. Similar methods to determine poloxamer’s degradability can be used (Erlandsson 2002).
Despite these concerns, polymeric particles are non-toxic, biocompatible and versatile. They can be made to form porous microspheres (PMs) which prolong the release of drug. The study by Kim et al. (2014) showed that PMs containing LF could stimulate the osteogenic differentiation of rabbit adipose-derived stem cells. In vivo studies will be needed to confirm and quantify these bone-regenerating effects. It is envisioned that these PMs can be used in injectable scaffolds as part of minimally invasive surgery for bone diseases.
Certain polymers like beta glucan (bG) (Kumar 2010; Kumar et al. 2013; Yang et al. 2020) and gellan gum (Duarte et al. 2022) limit the conformational flexibility of LF. This does not necessarily lead to a reduction of efficacy of LF: complexation with gellan gum enhanced the bacteriostatic effect of LF in glucose-yeast-peptone broth (Duarte et al. 2022); complexation with barley bG increased the oral bioavailability and bone mineral density of an osteoporosis mouse model – however, the increase in bone mineral density was comparable to orally administered free bLF (Kumar 2010; Kumar et al. 2013).
Hydroxyapatite nanocrystals are biocompatible and well-established as a bone graft substitute (Murugan et al. 2010; Montesi et al. 2015a; Shi et al. 2017; Bastos et al. 2019). However, they may aggregate together (Shi et al. 2017) causing toxicity, hence may be unsuitable for systemic use.
Conclusion
In summary, different nano and microparticular drug carriers seem particularly suited to different delivery modes of LF for different therapies. Liposomes are promising oral, topical and intra-articular delivery carriers. SLNs and NLCs are promising oral delivery carriers and, if embedded within hydrogels, could be implanted into bone defects. Polymeric particles like beta glucan and gellan gum could deliver LF orally or parenterally. Other polymers like PLGA, P188 and gelatin are being investigated as a carrier for intraosseous delivery. Hydroxyapatite nanocrystals seem better suited for intraosseous delivery to affected bone tissue.
Acknowledgements
Disclosure
The authors have no relevant financial or non-financial interests to disclose.
Author contributions
JC and JW conceived the idea for the article. RO performed the literature search and data analysis. RO drafted the work. JC and JW critically revised the work.
Funding
The authors did not receive support from any organization for the submitted work.
Declarations
Competing interests
The authors declare no competing interests.
Publisher's Note
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| 36512300 | PMC9745744 | NO-CC CODE | 2022-12-15 00:02:41 | no | Biometals. 2022 Dec 13;:1-19 | utf-8 | Biometals | 2,022 | 10.1007/s10534-022-00455-9 | oa_other |
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Sci Educ (Dordr)
Sci Educ (Dordr)
Science & Education
0926-7220
1573-1901
Springer Netherlands Dordrecht
410
10.1007/s11191-022-00410-7
Article
Design-Oriented Thinking in STEM education
Exploring the Impact on Preschool Children’s Twenty-First-Century Skills
http://orcid.org/0000-0002-8571-9203
Yalçın Vakkas [email protected]
grid.448756.c 0000 0004 0399 5672 Department of Early Childhood Education, Kilis 7 Aralık University, Mehmet Sanlı Mah. Doğan Güreş Paşa Bul. No: 134, Kilis, Turkey
13 12 2022
122
17 11 2022
© The Author(s), under exclusive licence to Springer Nature B.V. 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
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Abstract
Given early childhood is a critical period for acquiring the twenty-first-century skills, the present study aimed to examine the effect of design-oriented STEM activities on the twenty-first-century skills of preschool children in line with the experimental design. A mixed factorial analysis of variance (ANOVA) of 3 (time: pre-test, post-test and persistence) × 2 (experimental group and control group) was used to test the hypothesis. The Bayesian factor analysis for mixed data was performed to identify the effects of design-oriented STEM education on differences between groups as well as within the group. The study results indicated that design-oriented STEM activities permanently increased the total scores of the children in the experimental group as regards the twenty-first-century skills. It also appeared that design-oriented STEM activities permanently enhanced all sub-dimensions of life and career skills; learning and innovation skills; and information, media and technology skills. In the end, a number of recommendations were presented in accordance with the results of the study.
Keywords
STEM education
Thinking skills
Critical thinking
Problem-solving
Technological literacy
Creativity
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pmcIntroduction
At every stage of development, children try to learn by watching their environment with inquisitiveness as well as touching and asking questions. Being the first step of programmed education, preschool period refers to the years when children’s desire and inquisitiveness to learn continues. In this respect, children’s daily lives offer very important opportunities to develop their higher-order thinking skills and gain a comprehension of the engineering design process (Lippard et al., 2017). In this context, the preschool years can be considered to be a period of critical importance for children to learn and develop basic skills. Research shows that children’s attitude towards the twenty-first-century skills begins to evolve in the preschool period, and the skills gained in this period prove to have important contributions to coping with problems and becoming a productive individual in later years of life (Tuğluk & Altın, 2018). In this sense, it is very critical to instil in children the twenty-first-century skills within the preschool period, directly in terms of raising competitive children due to the dynamic global market and indirectly in creating countries with high competitiveness. In this respect, the target for schools, trainers and education programs should be to transform pedagogical knowledge and teaching methods into more innovative strategies in the global classrooms of the twenty-first century to ensure that the twenty-first-century skills are acquired.
Factors such as changing living conditions, industrialization, urbanization, rapid population growth and technological developments result in variations in the field of education as well as in all areas of our lives. Every new change and need can reveal further problems. In order to cope with these problems, to meet the needs in new living conditions and to adapt to the constant changes, it has become very important to acquire new skills and raise children according to the needs and skills of the twenty-first century (Yalçın & Erden, 2021; Yalçın & Öztürk, 2022).
Especially with the rapid developments in technology, countries have been greatly affected to the extent that international competition has become a critical issue. These changes and developments in the world have also caused some changes in human needs, as a result of which “universal literacy” has emerged as a key issue. Communication, collaboration, critical thinking and creativity skills (4Cs) are referred to as universal literacy by the Partnership for 21st-Century Learning [P21] (2019). In addition to these skills, the twenty-first-century skills include such important skills as learning and renewal skills, information and media literacy, the ability to take responsibility, cultural and universal awareness, basic life skills, career choice and planning, entrepreneurship and leadership skills (Dede, 2010; Dupuis & Perskey, 2008; Herreid, 2007a, 2007b; Ledward & Hirata, 2011; McLoughlin & Lee, 2008).
Twenty-First-Century Skills
The National Research Council [NRC] (2011) identified the twenty-first-century skills in three dimensions given as follows: cognitive skills including judgment and decision making, systems analysis and evaluation and abstract reasoning; interpersonal skills including active listening, effective communication of verbal expressions, effective use of non-verbal communication tools, being able to organize using communicative and co-operative skills, trusting and creating, understanding and respecting differences, valuing different ideas and creating social influence on people (NRC, 2011); and finally, internal skills to enable individuals to be self-directed, self-disciplined and self-controlled as well as possessing self-development skills and the ability of time management (NRC, 2011). In a similar manner, the North Central Regional Educational Laboratory (NCREL) (2003) classified the twenty-first-century skills in four sections under the headings of globalization and digitalism, as universal literacy, creativity, communication skills and productivity (EnGauge, 2003).
According to researchers, one of the organizations that conduct the most research on the twenty-first-century skills is the Partnership for 21st-Century Skills (P21) (Dinler, Simsar & Yalçın, 2021; Göksün & Kurt, 2017; Yalçın et al., 2020). P21 deals with the twenty-first-century skills under three main headings: life and career skills; learning and innovation skills; and information, media and technology skills (Partnership for 21st-century Skills, 2018a; 2018b; 2015). Each heading contains in itself very basic skills for human life. These skills include the following:Learning and innovation skillsCreativity and innovation
Critical thinking and problem-solving
Communication
Collaboration
Information, media and technology skillsInformation literacy
Media literacy
ICT (information, communications and technology) literacy
Life and career skillsFlexibility and adaptability
Initiative and self-direction
Social and cross-cultural skills
Productivity and accountability
Leadership and responsibility
Reviewed literature demonstrates that these skills affect the competencies and features needed in the fields of work and profession in the future (Voogt & Roblin, 2012). The P21 has specified the skills that children in various education levels should possess, starting from the preschool period. The literature review on the twenty-first-century skills shows that the skills framework determined by P21 is highly accepted and referenced (Beers, 2011; Brown, 2018; Gelen, 2017; Lamb et al., 2017; Partnership for 21st-Century Skills, 2018a ,2018b; 2015). In this context, the twenty-first-century skills determined by P21 were taken into account while creating the general framework of the study.
In the previous century, getting access to knowledge and information was important, while in the twenty-first century, knowing the way information is used is much more important. In short, in the twenty-first century, there is a need for well-equipped individuals who question knowledge, with no attempt to memorize it, and change and transform existing knowledge with what has recently been learned (Çevik and ve Şentürk, 2019). Realizing this situation, some countries have made some changes in their education policies and started to conduct some studies for the purpose of training individuals with the above-mentioned qualifications (Brown et al., 2008b; Gewertz, 2008; Moyer, 2016; Rotherham & Willingham, 2009; Varis, 2007). In addition to the changes in education policies, different teaching models and approaches, such as STEM and design-oriented thinking, have appeared in order to help raise individuals with the twenty-first-century skills (Yalçın & Erden, 2021; Yalçın & Öztürk, 2022).
STEM is an acronym that stands for the words science, technology, engineering and mathematics (Gonzalez & Kuenzi, 2012; White, 2014). It specifically aims to bring together different disciplines and provide individuals with the twenty-first-century skills and multifaceted development with a holistic perspective (Yalçın, 2019). Developing these skills and introducing children to science can be achieved through well-prepared education programs starting from the preschool period (Kumtepe et al., 2009). In this respect, STEM is of great importance not only to introduce children to science, but also to enable them to develop their twenty-first-century skills, so that individuals who can adapt to the changing competitive living conditions needed by societies will be raised (Koç, 2020).
STEM approach is referred to in the literature with different names (Akgündüz et al., 2015; Bilişimgarajı, 2021) such as STEM education, STEM applications and STEM activities. Still, the main purpose is to make STEM more effective and usable. In the implementation phase of the present study, design-oriented STEM activities were included in conformity with the design thinking process. Though not being visible at first glance, design thinking is a non-linear process to be used to understand individuals, challenge assumptions, redefine problems and develop innovative solution proposals (Dam & Siang, 2018a, 2018b). Design-oriented thinking aims to solve the challenges and problems experienced by people with innovative and creative ideas.
The reviewed literature has shown that there are many studies on the twenty-first-century skills, STEM and design thinking (Akgündüz & Akpınar, 2018; Dinler, Simsar & Yalçın, 2021; Menial & Leifer, 2011; Uluyol & Eryılmaz, 2015; Yalçın & Erden, 2021; Yalçın & Öztürk, 2022; Yalçın, 2020). The given studies reported that STEM activities increased the frequency of asking questions (Haden et al., 2014) and developed self-efficacy, interest in science, spatial visualization and mental rotation skills (Lamb et al., 2015), besides developing goal-oriented design, problem-solving thinking, innovation, pattern repetition and design testing skills (Bagiati & Evangelou, 2016). In addition to these studies, Durkin (2018) stated that STEM activities proved to develop children’s collaborative learning skills, and also, Bagiati (2011) and Ata-Aktürk et al. (2017) reported that STEM education programs contributed to the development of preschool children’s scientific process skills, such as observing and asking questions. Moreover, Guo et al. (2016) concluded that STEM activities improve preschool children’s vocabulary skills, and likewise, Bagiati (2011) reported that STEM education appeared to improve children’s self-confidence.
In the literature review, however, no study was found to have investigated the impact of design-oriented STEM activities on preschool children’s twenty-first-century skills. This study is, therefore, believed to make notable contributions to the literature by filling this gap. In the study, it was aimed to examine the effect of STEM activities on the twenty-first-century skills of preschool children by comparing the skills of the children in the experimental group and control group.
Within the scope of the study, answers to the following questions were sought.Is there a statistically significant difference between the learning and innovation skills (4Cs) scores of the experimental and control group children?
Is there a statistically significant difference between the life and career skills of the experimental and control group children?
Is there a statistically significant difference between information, media and technology skills scores of the experimental and control group children?
Is there a statistically significant difference between the twenty-first-century skills total of the experimental and control group children?
Method
Research Model
A mixed method design was used in this study to examine the effect of STEM activities prepared according to the design thinking model on the twenty-first-century skills of preschool children (Creswell, 2013). By using a mixed methods research design, the weaknesses of other methods can be strengthened and more comprehensive and much clearer results can be obtained by establishing a balance between the data (Axinn & Pearce, 2006). In this study, an embedded mixed method was used. No priority was given to quantitative or qualitative data in the collection phase, reserving eventually to weight them differently during data analysis phase (Creswell and Plano Clark, 2014). Quantitative and qualitative data was collected both simultaneously and at different times to enable one data type to play a supporting role for the other data type (Creswell, 2013).
The quantitative part of the study was conducted according to an experimental design with a control group to whom a pre-test, a post-test and a persistence test were administered. In addition, the experimental and control groups were also administered the persistence test in the fifth week after the post-tests so as to determine the permanence of the design-oriented STEM education (Brown et al., 2008a).
Validity and Reliability
Multiple triangulation approach was used to increase the validity and reliability of the research (see Fig. 1) (Denzin, 1970; Kimchi et al., 1991; Mayring, 2011; Polit & Hungler, 1995; Stake, 1995). Figure 1 shows the types of multiple triangulation approaches included in this study.Fig. 1 Types of triangulation used in the study
The first triangulation used in this study is observer triangulation. During the design-oriented STEM education, both the classroom teacher and the researcher kept diaries. The classroom teacher made unattended observations during the activities and observer triangulation was made with the qualitative data obtained from both diaries and observations (Punch, 2011).
One of the triangulation methods used in the present study is data triangulation. Data triangulation, which denotes measuring the same situation with different measurement approaches, is the most widely used triangulation type in education and social sciences (Işık & Semerci, 2019). In this context, data triangulation was done by collecting research data, quantitative data, interviews and researcher diaries.
Another triangulation used in this study is method triangulation. Method triangulation is also known as a mixed method (Barbour, 1998; Greene & Coracelli, 1997; Polit & Hungler, 1995). The main purpose of choosing the mixed method is to eliminate the drawbacks or weaknesses of a method, regardless of being quantitative or qualitative.
Study Population and Sample
For the study sample, one class was chosen randomly as the experimental group from among those including 5-year-old students studying in a kindergarten, and another class formed the control group. There were 23 children in the experimental group and 22 children in the control group. Both groups consisted of children of the same age (5), from the same school and from similar socioeconomic background. Table 1 presents the demographic data of the participants.Table 1 Demographic information of the children in the experimental group and control group
Experimental group Control group
f % f %
Gender
Female 8 34,783 8 36,364
Male 15 65,217 14 63,636
Total 23 100,000 22 100,000
Age
5 23 100,000 22 100,000
The Process of Developing Design-Oriented STEM Activities
The first stage of the study includes a literature review on STEM, twenty-first-century skills and design thinking model in order to reach and consider latest studies on these issues. As a consequence, design-oriented STEM activities were prepared by examining the achievements in the context of the twenty-first-century skills mentioned in the “2013 Pre-School Education Program” (2019) of the Turkish Ministry of National Education (MEB), reviewing previous research studies and assessing many documents published and shared within the scope of the project named “Partnership for 21st Century Learning (Partnership for 21st-century Skills, 2019)” as well as by taking into consideration the relevant acquisitions presented in the following file, namely, “P21EarlyChildhoodFramework.pdf” (http://static.battelleforkids.org/documents/p21/P21EarlyChildhoodFramework.pdf, access date: 12.10.2021). Design-oriented STEM activities prepared by the researcher were sent to five academicians who are experts in early childhood education, 1 Turkish language expert and seven experts, including an assessment-evaluation expert, and asked to evaluate the activities. In line with expert opinions, one of the activities was revised because it was unsuitable for developing creativity, one of the twenty-first-century skills, and the activities were finalized.
Design-Oriented STEM Activities
The study process was prepared in accordance with the age and developmental levels of children. Table 2 presents some of the design-oriented activities according to the length of time they took. In these activities, basic science concepts such as direction, location in space, low, high and balance were mentioned.Table 2 Examples of design-oriented STEM activities used in this study
Activity name Time
Let’s save the cat in the tree! 35’
Ants want to cross 37’
Food bowls for stray animals 35’
The little sapling wants to grow 42’
The leg of the dining table is broken, how are we going to eat? 45’
Implementation Process of Design-Oriented STEM Activities
After the experimental and control groups administered the pre-tests for the twenty-first-century skills, the experimental group was taught according to STEM education, 2 days a week for 8 weeks in 16 sessions on Tuesdays and Thursdays. STEM activities with the design thinking model applied in the experimental group consist of five stages. These stages are empathy, identification, idea generation, prototyping and testing. In the first stage, children begin to determine how the design will be by making sense of the situation/event in front of them. In the next step, the focal point of the problem should be determined and defined. In the third stage, children are expected to produce a large number of ideas for the solution of the problem. In the fourth stage, one of the ideas is determined and a prototype is made. And the products produced at the last stage are evaluated on issues such as durability and functionality. On the other hand, no activity similar to STEM or design thinking model was performed in the control group. The control group applied the preschool program implemented in all kindergartens affiliated to the Ministry of National Education in the Republic of Turkey.
Data Collection Tools
Demographic Data Form
A form was prepared by the researchers to collect the information of the children participating in the study and their families. It includes information about the gender of the children, the number of siblings, mother’s educational background, father’s educational background, mother’s employment status and father’s employment status.
21st-Century Skills Scale for Children Aged 5–6 Years (Day-2)
Developed by Yalçın et al., (2020), this scale aims to assess the twenty-first-century skills of 5- to 6-year-old preschool children under three sub-dimensions including 33 items, which are rated on a 4-point Likert scale ranging from “Never” to “Always”. The sub-dimensions in the measurement tool are as follows: learning and innovation skills (4Cs) (items 1 to 15); life and career skills (items 16–28); and information, media and technology skills (items 29–33). The Cronbach’s alpha values for each sub-dimension of the scale are 0.96 for the learning and innovation skills (4Cs) (LIS); 0.94 for the life and career skills (LCS); and 0.92 for the information, media and technology skills (IMTS). Moreover, the scale has proven valid and reliable since the general structure of the “21st-Century Skills Scale for Children Aged 5–6 Years (Day-2)” has a high internal consistency score such as Cronbach’s alpha coefficient of α = 0.97. Since the measurement tool is Likert type, the classroom teacher observed the children and filled the measurement tool separately for each child. A code is given by the teacher to the child to whom the measurement tool will be applied, and the date of that day is assigned to the measurement tool. The teacher observes the children during the day for at least 3 weeks. After the teacher makes sufficient observations, the evaluation process is completed by marking the scoring part of each item in the assessment tool according to the formation of the relevant behaviours and skills in the child. The scale includes items such as “While playing, he evaluates the game and makes simple changes in the game” and “Learns from previous experiences during a new game/activity and produces new solutions”.
Semi-structured Interview Form
The semi-structured teacher interview form prepared by the researcher consists of 12 basic questions and probing questions, which the interviewer uses for trying to reach the details by asking repetitive questions about the subject matter addressed (Kvale, 1994), and the semi-structured interview form consisting of such questions as: “Question 7- Do you think design-oriented STEM activities affect children positively or negatively? (If yes/no) Could you please explain? If there are differences that you have observed in children over the past time, what are they?” At the end of the eight-week practice with the experimental group, the data obtained from the semi-structured teacher interview were entered into the computer and were analysed by using the NVivo 11 package program. These data concern (i) the possible effects of design-oriented STEM activities on the children; (ii) the variations in the children’s activity process; and (iii) the observations and evaluations of the classroom teacher.
Data Analysis
To test the hypothesis, 3 (time: pre-test, post-test and persistence) × 2 (experimental group and control group) mixed factorial analysis of variance (ANOVAs) was used. Simple main effects and interactions between time and group were tested. In addition, Bayesian factor analysis of variances for mixed data was used to determine the effects of design-oriented STEM education on differences between groups and within groups. There are four different dependent variables for mixed ANOVAs in the study. Such a case means that the probability of occurrence of a type 1 error is high (Tabachnick & Fidell, 2014). Bonferroni correction was used to avoid a type 1 error. Bonferroni correction is obtained by dividing the level of significance roughly by the number of analyses to be performed with the same independent variable (Pallant and Manual, 2007). Thus, type I error is taken under control. In the study, the p value of 0.05 was considered 0.0125.
Power analysis was conducted via G*Power (Faul et al., 2009) for the mixed ANOVA. The effect size was estimated based on Cohen’s (1988) guidelines (medium effect size η2 = 0.06). The effect size entered into power analysis was as follows: α = 0.05, power = 0.80 and allocation ratio = 1.1. The results of power analysis suggested that N = 64 participants were required to show the difference between two groups with 80% probability. In similar experimental studies, the total number of subjects ranged from 40 (Sana et al., 2013) to 185 (Rosen et al., 2011). Besides, the number of subjects in different experimental conditions ranged from 20 (Wood et al., 2012) to 76 (Rosen et al., 2011) with a mean of 34.
On the other hand, contemporary studies have mostly been underpowered with ten or fewer participants in each condition (Antonenko & Niederhauser, 2010; Dan & Reiner, 2017). The current study (N: 45) is, likewise, relatively underpowered in comparison to contemporary multitasking experiments, but more powerful than similar experimental studies in the field of early childhood education. As a matter of fact, one of the most critical factors that are likely to negatively impact effective classroom teaching in childhood is crowded classrooms (Güzelyurt et al., 2019; Orçan Kaçan et al., 2021). In this connection, utmost attention was paid in this study in order to ensure that the class size was not large so that its purpose could be fulfilled and that the STEM activities could be practical.
This study was conducted by using IBM SPSS 26 program for classical ANOVAs; the JASP statistics program (JASP Team, 2018) for the Bayesian analysis; and R package program (R Core Team, 2013) as well as the BayesFactor package (Morey et al., 2015) and G*Power for power analysis. Before the data analysis, whether or not the data were normally distributed was tested (see Table 3). As a result, parametric tests were used in the statistical analyses of the study.Table 3 Descriptive statistics of the twenty-first-century skills of the children in the experimental and control groups
Variables Group Valid Mean Std. D Skewness Kurtosis Minimum Maximum
Learning and innovation skills pre-test Experimental group 23 45,304 6306 − 0.262 − 0.752 32 56
Control group 22 45,409 5595 − 0.496 − 0.051 32 54
Life and career skills pre-test Experimental group 23 37,696 3735 − 0.403 − 0.249 30 44
Control group 22 38,182 3737 − 0.608 0.261 29 44
Information, media and technology skills pre-test Experimental group 23 15,217 1126 0.995 0.410 14 18
Control group 22 15,182 1053 0.412 − 0.968 14 17
Twenty-first-century skills pre-test Experimental group 23 98,217 8939 − 0.439 − 1.159 83 111
Control group 22 98,773 7733 − 0.578 − 0.711 83 110
Learning and innovation skills post-test Experimental group 23 52,870 3362 − 1.661 1.755 44 57
Control group 22 44,500 4926 − 0.584 0.488 32 53
Life and career skills post-test Experimental group 23 44,826 2949 − 0.245 0.968 38 51
Control group 22 39,455 4149 − 0.078 − 0.692 32 48
Information, media and technology skills post-test Experimental group 23 17,087 1443 − 0.761 0.011 14 19
Control group 22 16,091 1411 0.272 − 0.625 14 19
Twenty-first-century skills post-test Experimental group 23 114,783 5493 − 1.444 1.078 97 123
Control group 22 100,045 8015 − 0.261 − 0.944 86 114
Learning and innovation skills persistence test Experimental group 23 52,870 3402 − 1.577 1.099 44 57
Control group 22 44,682 4970 − 0.672 0.471 32 53
Life and career skills persistence test Experimental group 23 44,478 2937 0.307 0.124 39 51
Control group 22 39,818 4250 − 0.238 − 0.794 32 48
Information, media and technology skills persistence test Experimental group 23 17,217 1413 − 0.845 0.533 14 19
Control group 22 16,136 1246 0.369 0.255 14 19
Twenty-first-century skills persistence test Experimental group 23 114,565 5341 − 0.807 0.934 100 123
Control group 22 100,636 8156 − 0.240 − 1.017 87 114
When Table 3 is examined, all variables for the times measured in the study show normal distribution in both the experimental group and the control group. The skewness values ranged from − 1.57 to − 0.41, while the kurtosis values ranged from − 1.15 to 1.75. According to George and Mallery (2010), skewness and kurtosis values should be between + 2.0 and − 2.0. Tabachnick and Fidell stated that this value should be between + 1.5 and − 1.5. It can be said that the above-mentioned kurtosis and skewness values are within acceptable normal distribution values according to Tabachnick and Fidell (2013) and George and Mallery (2010). In addition, histograms and Q-Q plots of the variables were examined on the basis of groups, and the analysis supported the assumption of normality.
Results
Quantitative Results of the Research
Comparison of Learning and Innovation Skills of Experimental and Control Group Children by the Total Scores in Pre-tests, Post-tests and Persistence Tests
The first two-way mixed-design ANOVA was conducted for learning and innovation skills on the both groups’ pre-, post- and persistence tests (Table 4). The Levene’s test results indicated that test assumptions were met. On the other hand, the result of the Mauchly’s test of sphericity was found statistically significant (p = 0.001), and then, the Greenhouse–Geisser correction was applied for sphericity correction. The analysis showed that the main effect for testing time (f (1, 43,349) = 22.86, p = 0.001, η2 = 0.069) and the interaction effect of testing time by the group type were all significant (f (1, 43,349) = 35,286, p = 0.001, η2 = 0.107). Between-group effect also appeared to be significant (f (1, 43) = 18,017, p = 0.001, η2 = 0.205). Besides classical statistics, the Bayes factor was also calculated for analysis. The Bayesian model assumes an interaction effect in favour of the alternative model (BF10 = 507,938,765, error % = 3.809). This can also be classified as strong evidence for the alternative model (Jeffreys, 1961). The between-group effect also favoured the alternative model with strong evidence (BF10 = 204,461, error % = 1.089).Table 4 A mixed design for learning and innovation skills (2 × 3) ANOVA summary table
Cases Sum of squares df Mean square F p η2
Within subjects effects
Time 341,436 1008 338,686 22,860 0.001 0.069
Time × group 527,036 1008 522,792 35,286 0.001 0.107
Residuals 642,253 43,349 14,816
Between subjects effects
Group 1,014,575 1 1,014,575 18,017 0.001 0.205
Residuals 2,421,425 43 56,312
To test the main effect of testing time for experimental group and control group, post hoc tests (by Holm’s method) were conducted. These tests showed a significant increase from pre-test to post-test and persistence tests in the experimental group, who were instructed in accordance with STEM education. A post hoc test was conducted on the pre-test, post-test and persistence test scores to investigate the main effect of between-group Holm’s scores. No difference was found among the groups’ pre-test scores, that is, they were equal at the beginning of the study. However, post-test and persistence test scores revealed a statistical significance between the groups, favouring the experimental group in learning and innovation skills (Table 5).Table 5 Post hoc test results for learning and innovation skills
Post hoc comparisons—RM factor 1 × V2
Comparison
RM factor 1 V2 RM factor 1 V2 Mean difference SE df t ptukey pscheffe
Level 1 1 Level 1 2 − 0.105 1.780 43,000 − 0.059 1.000 1.000
Level 1 Level 2 1 − 7.565 0.990 43,000 − 7.641 < 0.001 < 0.001
Level 1 Level 2 2 0.804 1.533 43,000 0.525 0.995 0.998
Level 1 Level 3 1 − 7.565 0.981 43,000 − 7.711 < 0.001 < 0.001
Level 1 Level 3 2 0.623 1.538 43,000 0.405 0.999 0.999
Level 1 2 Level 2 1 − 7.460 1.545 43,000 − 4.830 < 0.001 0.002
Level 1 Level 2 2 0.909 1.012 43,000 0.898 0.945 0.975
Level 1 Level 3 1 − 7.460 1.550 43,000 − 4.814 < 0.001 0.002
Level 1 Level 3 2 0.727 1.003 43,000 0.725 0.978 0.991
Level 2 1 Level 2 2 8.370 1.252 43,000 6.684 < 0.001 < 0.001
Level 2 Level 3 1 0.000 0.073 43,000 0.000 1.000 1.000
Level 2 Level 3 2 8.188 1.259 43,000 6.505 < 0.001 < 0.001
Level 2 2 Level 3 1 − 8.370 1.258 43,000 − 6.651 < 0.001 < 0.001
Level 2 Level 3 2 − 0.182 0.075 43,000 − 2.435 0.167 0.332
Level 3 1 Level 3 2 8.188 1.265 43,000 6.474 < 0.001 < 0.001
Comparison of Life and Career Skills of Experimental and Control Group Children by the Total Scores in Pre-, Post- and Persistence Tests
The second two-way mixed-design ANOVA was conducted for life and career skills on both groups’ pre-, post- and persistence tests. The Levene’s test results indicated that test assumptions were met. On the other hand, the Mauchly’s test of sphericity appeared to be significant (p = 0.001), and then, the Greenhouse–Geisser correction was applied for sphericity correction. The analysis results showed that the main effect for testing time (f (1.1, 47,829) = 60,850, p = 0.001, η2 = 0.188) and the interaction effect of testing time by the group type were all significant (f (1.1, 47,829) = 26,364, p = 0.001, η2 = 0.081) (Table 6). Between-group effect was also significant (f (1, 43) = 10,901, p = 0.002, η2 = 0.121). Besides classical statistics, the Bayes factor was also calculated for analysis. The Bayesian model assumes an interaction effect in favour of the alternative model (BF10 = 2448, error % = 2.358). This can also be classified as moderate evidence for the alternative model (Jeffreys, 1961). The between-group effect also favoured the alternative model with strong evidence (BF10 = 17,312, error % = 1.004).Table 6 Mixed design for life and career skills (2 × 3) ANOVA summary table
Cases Sum of squares Df Mean square F p η2
Within subjects effects
Time 530,335 1112 476,788 60,850 0.001 0.188
Time × group 229,772 1112 206,572 26,364 0.001 0.081
Residuals 374,762 47,829 7835
Between subjects effects
Group 341,515 1 341,515 10,901 0.002 0.121
Residuals 1,347,152 43 31,329
To test the main effect of testing time for the experimental group and control group, post hoc tests (Holm’s) were conducted. There was a significant increase from pre-test to post-test and persistence test results in experimental group, who were instructed in accordance with STEM education. The main effect of Holm’s post hoc tests for the between-group design was analysed in pre-test, post-test and persistence tests scores. No statistical significance was found between the groups in terms of their pre-test scores, that is, they were equal at the beginning of the study. However, post-test and persistence test scores showed a significant difference between the groups in favour of the experimental group in life and career skills (Table 7).Table 7 Post hoc test results for life and career skills
Post hoc comparisons—RM factor 1 × V2
Comparison
RM factor 1 V2 RM factor 1 V2 Mean difference SE df t ptukey pscheffe
Level 1 1 Level 1 2 − 0.486 1.114 43,000 − 0.436 0.998 0.999
Level 2 1 − 7.130 0.731 43,000 − 9.750 < 0.001 < 0.001
Level 2 2 − 1.759 1.091 43,000 − 1.612 0.596 0.760
Level 3 1 − 6.783 0.749 43,000 − 9.054 < 0.001 < 0.001
Level 3 2 − 2.123 1.099 43,000 − 1.931 0.398 0.594
2 Level 2 1 − 6.644 1.092 43,000 − 6.082 < 0.001 < 0.001
Level 2 2 − 1.273 0.748 43,000 − 1.702 0.538 0.715
Level 3 1 − 6.296 1.100 43,000 − 5.725 < 0.001 < 0.001
Level 3 2 − 1.636 0.766 43,000 − 2.136 0.289 0.482
Level 2 1 Level 2 2 5.372 1.069 43,000 5.024 < 0.001 < 0.001
Level 3 1 0.348 0.202 43,000 1.723 0.525 0.705
Level 3 2 5.008 1.077 43,000 4.649 < 0.001 0.003
2 Level 3 1 − 5.024 1.077 43,000 − 4.665 < 0.001 0.003
Level 3 2 − 0.364 0.206 43,000 − 1.762 0.500 0.685
Level 3 1 Level 3 2 4.660 1.085 43,000 4.296 0.001 0.007
Comparison of Information, Media and Technology Skills of Experimental and Control Group Children by the Total Scores in Pre-, Post- and Persistence Tests
The third two-way mixed-design ANOVA was conducted for information, media and technology skills on both groups’ pre-, post- and persistence test scores. The Levene’s test scores indicated that test assumptions were met. However, the Mauchly’s test of sphericity was found statistically significant (p = 0.001), and then, the Greenhouse–Geisser correction was applied for sphericity correction. The analysis showed that the main effect for testing time (f (1.2, 51,196) = 34,505, p = 0.001, η2 = 0.205) was significant, whereas the interaction effect of testing time by the group type was not significant (f (1.2, 51,196 = 4.235, p = 0.038, η2 = 0.025). Between-group effect was also not significant (f (1, 43) = 5.199, p = 0.028, η2 = 0.056) (Table 8). Besides classical statistics, the Bayes factor was also calculated for analysis. The Bayesian model assumes an interaction effect in favour of the alternative model (BF10 = 9449, error % = 1.443). This can also be classified as moderate evidence for the alternative model (Jeffreys, 1961). The between-group effect also favoured the alternative model with weak evidence (BF10 = 1922, error % = 1.228).Table 8 Mixed design for informatıon, media and technology skills (2 × 3) ANOVA summary table
Cases Sum of squares df Mean square F p η2
Within subjects effects
Time 61,774 1191 51,885 34,505 0.001 0.205
Time × group 7581 1191 6368 4235 0.038 0.025
Residuals 76,982 51,196 1504
Between subjects effects
Group 16,729 1 16,729 5199 0.028 0.056
Residuals 138,352 43 3217
In order to test the main effect of testing time for the experimental group and control group, post hoc tests (Holm’s) were conducted. These tests showed a significant increase from pre-test to post-test and persistence tests in the experimental group, who were instructed in accordance with STEM education (Table 9).Table 9 Post hoc test results for information, media and technology
Post hoc comparisons—RM factor 1 × V2
Comparison
RM factor 1 V2 RM factor 1 V2 Mean difference SE df t ptukey pscheffe
Level 1 1 Level 1 2 0.036 0.325 43,000 0.109 1.000 1.000
Level 2 1 − 1.870 0.328 43,000 − 5.699 < 0.001 < 0.001
Level 2 2 − 0.874 0.380 43,000 − 2.299 0.217 0.397
Level 3 1 − 2.000 0.335 43,000 − 5.971 < 0.001 < 0.001
Level 3 2 − 0.919 0.364 43,000 − 2.523 0.140 0.293
2 Level 2 1 − 1.905 0.378 43,000 − 5.043 < 0.001 < 0.001
Level 2 2 − 0.909 0.335 43,000 − 2.710 0.094 0.220
Level 3 1 − 2.036 0.363 43,000 − 5.614 < 0.001 < 0.001
Level 3 2 − 0.955 0.342 43,000 − 2.787 0.079 0.194
Level 2 1 Level 2 2 0.996 0.426 43,000 2.339 0.201 0.377
Level 3 1 − 0.130 0.117 43,000 − 1.114 0.873 0.938
Level 3 2 0.951 0.412 43,000 2.309 0.213 0.392
2 Level 3 1 − 1.126 0.412 43,000 − 2.732 0.089 0.212
Level 3 2 − 0.045 0.120 43,000 − 0.380 0.999 1.000
Level 3 1 Level 3 2 1.081 0.398 43,000 2.718 0.092 0.217
Comparison of Twenty-First-Century Skills of Experimental and Control Group Children by the Total Scores in Pre-, Post- and Persistence Tests
The last two-way mixed-design ANOVA was conducted for a total of twenty-first-century skills on both groups’ pre-, post- and persistence test results. The Levene’s test results indicated that test assumptions were met. On the other hand, the Mauchly’s test of sphericity presented significant results (p = 0.001), and then, the Greenhouse–Geisser correction was applied for sphericity correction. The analysis showed that the main effect for testing time (f (1.1, 45,018) = 78,785, p = 0.001, η2 = 0.173) and the interaction effect of testing time by the group type were all significant (f (1.1, 45,018) = 53,854, p = 0.001, η2 = 0.118). Between-group effect also turned out to be significant (f (1, 43) = 22,259, p = 0.002, η2 = 0.210) (Table 10). Besides classical statistics, the Bayes factor was also calculated for analysis. The Bayesian model assumes an interaction effect in favour of the alternative model (BF10 = 2577, error % = 1.328). This can also be classified as moderate evidence for an alternative model (Jeffreys, 1961). The between-group effect also favoured the alternative model with strong evidence (BF10 = 677,495, error % = 1.279).Table 10 Mixed design for twenty-first-century skills (2 × 3) ANOVA summary table
Cases Sum of squares df Mean square F p η2
Within subjects effects
Time 2,436,256 1047 2,327,026 78,785 0.001 0.173
Time × group 1,665,322 1047 1,590,658 53,854 0.001 0.118
Residuals 1,329,685 45,018 29,536
Between subjects effects
Group 2,961,824 1 2,961,824 22,259 0.001 0.210
Residuals 5,721,702 43 133,063
To test the main effect of testing time for the experimental group and control group, post hoc tests (Holm’s) were conducted. These tests showed a significant increase from pre-test to post-test and persistence tests in the experimental group who were instructed in accordance with STEM education. To investigate the main effect of between-group Holm’s scores, a post hoc analysis was conducted on pre-test, post-test and persistence tests scores. No statistical significance was found between the groups in terms of pre-test scores; that is, they were equal at the onset of the study. However, post-test and persistence test scores showed a significant difference between the groups in favour of the experimental group in total twenty-first-century skills (Table 11).Table 11 Post hoc test results for twenty-first-century skills
Post hoc comparisons—RM factor 1 × V2
Comparison
RM factor 1 V2 RM factor 1 V2 Mean difference SE df t ptukey pscheffe
Level 1 1 Level 1 2 − 0.555 2.497 43,000 − 0.222 1.000 1.000
Level 2 1 − 16.565 1.385 43,000 − 11.958 < 0.001 < 0.001
Level 2 2 − 1.828 2.275 43,000 − 0.804 0.965 0.985
Level 3 1 − 16.348 1.432 43,000 − 11.417 < 0.001 < 0.001
Level 3 2 − 2.419 2.278 43,000 − 1.062 0.894 0.949
2 Level 2 1 − 16.010 2.285 43,000 − 7.007 < 0.001 < 0.001
Level 2 2 − 1.273 1.416 43,000 − 0.899 0.945 0.975
Level 3 1 − 15.792 2.288 43,000 − 6.904 < 0.001 < 0.001
Level 3 2 − 1.864 1.464 43,000 − 1.273 0.798 0.896
Level 2 1 Level 2 2 14.737 2.040 43,000 7.223 < 0.001 < 0.001
Level 3 1 0.217 0.253 43,000 0.860 0.954 0.980
Level 3 2 14.146 2.043 43,000 6.923 < 0.001 < 0.001
2 Level 3 1 − 14.520 2.043 43,000 − 7.106 < 0.001 < 0.001
Level 3 2 − 0.591 0.259 43,000 − 2.286 0.222 0.404
Level 3 1 Level 3 2 13.929 2.046 43,000 6.807 < 0.001 < 0.001
Qualitative Results
This section presents the qualitative results obtained from the interviews and diaries kept by the researcher and the teacher.
The first finding indicated that the children in the experimental group generally improved their twenty-first-century skills. Besides this, the most striking finding in the interview with the classroom teacher was that the children showed improvement in twenty-first-century skills, especially in the learning and innovation skills (4Cs) sub-dimension, which includes very basic skills such as creativity and innovation, critical thinking and problem-solving, communication and collaboration. Regarding creativity and innovation skills, the teacher said in the interview that “Children who have experience on the subject matter immediately transfer their experience to their mates in the group. In this way, children can have preliminary knowledge about the topic and can be creative and productive in coming up with solutions. To me, the reason why more creative activities have emerged, especially towards the final activities, may be that children have gained experience. Small groups seemed to have allowed children to gain self-confidence. Now they can freely express themselves. Perhaps even more important is that they can solve problems within the group without harming each other. I think it is important for them to do this in a group, independently of an adult, to solve problems and communicate, and to generate ideas as a natural result of these, and therefore in terms of creativity”.
Furthermore, the remarks in the diary kept by the researcher for problem-solving skills were as follows: “Children are discussing how they can solve the problem in groups. Almost all of the children are trying to find solutions by acting together with their teams. They are also coming up with quite a few creative ideas. Each child is involved in the group work in some ways. They can express their opinions”, and the remarks in the diary kept by the teacher, “children are quite good at tasks in the implementation process such as understanding the problem, sharing tasks, fulfilling their responsibilities. Now they can empathize better and come up with creative solutions. Not only is the communication within the group, but also the communication between the groups is much better than the early activities”.
Similar to these views, the teacher said “They help each other and communicate very well, especially during the implementation phase. Now they can establish better cause-effect relationships. They have become good at generating ideas for solutions and solving problems”. The teacher also said “They constantly talk during the process and decide on a solution with each other. I had students who had trouble expressing their feelings. I found that this training was particularly beneficial for them. Now they can express themselves more easily in the classroom” and “now the process can be fully completed. Very creative ideas have arisen. They proudly show their product to their friends. Children’s self-confidence has improved over time as they practiced” and “…besides that, children’s communication skills have improved as well, especially since the activities are carried out in small groups. They talk among themselves and decide on a solution with each other. This process has naturally increased their communication”. Based on all the interview and diary notes mentioned above, it can be concluded that design-oriented STEM activities are effective in terms of improving children’s twenty-first-century skills and undoubtedly their “learning and innovation skills (4Cs)”, in particular.
Conclusion and Discussion
This study’s results supported the evidence that STEM activities, based on the design thinking model, are effective in supporting the children to improve and develop skills related to all sub-dimensions of learning and innovation skills; life and career skills; and information, media and technology skills. The STEM activities were effective especially on “learning and innovation skills (4Cs)”. The persistence test revealed that the increase was permanent in general. Similarly, the twenty-first-century skills of the children in the experimental group increased statistically significantly. The increase also proved permanent as seen in the persistence test results. No statistically significant difference was found between the pre-, post- and persistence tests of the children in the control group.
To the best of our knowledge, there is no study that has directly examined the effects of design-oriented STEM activities in early childhood on children’s twenty-first-century skills. Therefore, this study was conducted over the sub-dimensions of the Day-2 scale and the skills were represented by these sub-dimensions.
The reviewed literature has revealed a number of studies focusing on critical thinking and problem-solving, communication, cooperation and creativity (Akçay, 2019; Boyacı & Atalay, 2016; Dwyer, Gkemisi et al., 2016; Hogan & Stewart, 2014; Kyllonen, 2012; P21, 2019; Trilling & Fadel, 2009). Among the twenty-first-century skills, critical thinking should be considered an essential skill that needs to be improved in education (Dwyer et al., 2014). Also, critical thinking and problem-solving are important skills required in every aspect of an individual’s life (Boyacı & Atalay, 2016). On the other hand, communication skills are a priority in business life (Berger, 2016). Similarly, collaboration is among the critical skills for today’s business world, as the workload has increased significantly and individuals are expected to act and work as a team (Lewin & Mcnicol, 2015; Marbach-Ad et al., 2019). Communication and cooperation form the basis of all other twenty-first-century skills, depending on social interaction (Gkemisi et al., 2016). From this point of view, learning and innovation skills are of great importance in terms of raising children in a way to be compatible with the twenty-first century. A research proved that STEM improves the problem-solving skills of individuals (Akçay, 2019). In this respect, Bal (2018) concluded that STEM studies proved to improve the scientific process and problem-solving skills in his study. Yalçın and Erden (2021) argued that STEM activities improved preschool children’s thinking skills such as creative thinking, critical thinking and problem-solving. Durkin (2018) concluded that STEM activities improved children’s collaborative learning skills. Haden et al. (2014) also reported that STEM activities increased the number of questions posed by children. Bagiati (2011) and Ata-Aktürk et al. (2017) concluded that STEM education programs contributed to the development of preschool children’s scientific process skills such as observing and asking questions. Guo, Wang, Breit-Smith and Busch (2016) asserted that STEM activities improved preschool children’s vocabulary skills. Similar to these studies, this study showed that design-oriented STEM education permanently improved the twenty-first-century skills such as critical thinking and problem-solving, communication, cooperation and creativity.
There are a number of studies conducted on flexibility and adaptability; assertiveness and self-management; social and intercultural interaction; productivity and accountability; and leadership and responsibility skills for life and career skills sub-dimensions (Bal, 2018; Carroll et al., 2010; Cavas et al., 2013; Trilling & Fadel, 2009; Wang, 2012). Leadership and responsibility are important attitudes or competencies among twenty-first-century skills. Various studies conducted by P21 (Casner-Lotto & Barrington, 2006) and OECD (2016a, 2016b) have reported that leadership and a sense of responsibility in working life increase productivity. Furthermore, flexibility and adaptability, considered among the twenty-first-century skills, gives individuals the ability to create a balance between differing conditions and personal beliefs and values and to organize the environment in which they work according to new situations (Ceylan, 2019). When considered from this point of view, life and career skills seem to be of major importance in terms of raising twenty-first-century people. STEM activities proved to have increased the self-confidence of the participants, encouraged them to form new ideas and supported the development of empathy skills (Yalçın & Erden, 2021). In addition, STEM studies develop self-efficacy, interest in science, spatial visualization and mental rotation skills (Lamb, Akmal, Petrie, 2015). Similarly, Bagiati (2011) concluded that STEM education improves children’s self-confidence. Consistent with the reviewed literature, in this study, it was concluded that design-oriented STEM education permanently improves the twenty-first-century skills such as flexibility and adaptability; assertiveness and self-management; social and intercultural interaction; productivity and accountability; and leadership and responsibility.
When the literature was examined, many studies on information, media, and technology literacy were found (Carroll et al., 2010; Ceylan & Akcay, 2020; Dishon & Gilead, 2020; Drake & Reid, 2018; Gordon et al., 2010; Konca & Koksalan, 2017; Kyllonen, 2012; Trilling & Fadel, 2009). Getting access to knowledge and information is essential in the twenty-first century, while the capability of using it has become much more critical in the twenty-first century. The reason is that, in the twenty-first century, individuals have to deal with unknown, unpredictable (for example, COVID-19) or uncontrollable problems and encounter new occupations that have never existed before (Dishon & Gilead, 2020). Due to the significant increase in knowledge in the twenty-first century, individuals are not expected to remember the information at a superficial level, but to use it in an effort to solve new problems (Drake & Reid, 2018; Gordon et al., 2010). In summary, in the twenty-first century, there is a need for well-equipped individuals who do not memorize information, question, change and transform existing information with newly learned information (Çevik & ve Şentürk, 2019). However, the advantage of easy and fast access to information can also turn into a disadvantage by causing irrelevant, unnecessary, unwanted and wrong information to spread and be learned quickly (Pandita, 2014). It is, therefore, necessary for individuals to develop their information literacy skills (Bray, 2008). In this study, it is thought that a significant and permanent increase in preschool children’s skills in the information, media, information-communication and technology literacy is of critical importance in terms of raising information-literate individuals for the future.
As a conclusion, the facts that the STEM activities are prepared on the basis of real-life problems, that the activities are conducted in small groups and that child-oriented activities are designed prove to be effective in developing twenty-first-century skills. Based on these results of the study, courses based on theory and practice on STEM education and design thinking model, in particular, can be included in the course catalogue of the universities in order to train prospective teachers of preschool in this regard. Preschool teachers can contribute to the multifaceted development of children by frequently including studies on STEM education and design thinking model in their classrooms.
This research is limited to the children in the experimental and control groups.
The qualitative results of this study are limited to the data obtained from interviews with the teacher, observations and diaries of the researcher and teacher.
Acknowledgements
I would like to thank all of the teachers, families and children who participated in this study.
Declarations
Conflict of Interest
The authors declare no competing interests.
Publisher's Note
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| 0 | PMC9745746 | NO-CC CODE | 2022-12-15 00:02:41 | no | Sci Educ (Dordr). 2022 Dec 13;:1-22 | utf-8 | Sci Educ (Dordr) | 2,022 | 10.1007/s11191-022-00410-7 | oa_other |
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J Technol Behav Sci
J Technol Behav Sci
Journal of Technology in Behavioral Science
2366-5963
Springer International Publishing Cham
287
10.1007/s41347-022-00287-x
Article
Veteran Acceptance of Sleep Health Information Technology: a Mixed-Method Study
http://orcid.org/0000-0001-9098-4012
Kaitz Jenesse [email protected]
1
Robinson Stephanie A. 12
Petrakis Beth Ann 1
Reilly Erin D. 34
Chamberlin Elizabeth S. 5
Wiener Renda Soylemez 26
Quigley Karen S. 7
1 CHOIR/Bedford VA Center for Healthcare Organization and Implementation Research (CHOIR), Bedford Healthcare System, Bedford, MA USA
2 grid.189504.1 0000 0004 1936 7558 The Pulmonary Center, Boston University School of Medicine, Boston, MA USA
3 Mental Illness Research, Education, and Clinical Center (MIRECC), Bedford Healthcare System, Bedford, USA
4 grid.168645.8 0000 0001 0742 0364 University of Massachusetts Medical School, Worcester, MA USA
5 grid.511190.d 0000 0004 7648 112X Geriatric Research Education and Clinical Center (GRECC), Bedford Healthcare System, Bedford, MA USA
6 Center for Healthcare Organization & Implementation Research and Medical Service, Boston Healthcare System, Boston, MA USA
7 grid.261112.7 0000 0001 2173 3359 Department of Psychology, Northeastern University, Boston, MA USA
13 12 2022
112
18 5 2022
7 10 2022
27 10 2022
© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Sleep disturbances, including chronic insomnia and sleep apnea, are major concerns for US veterans, with rising rates and detrimental effects on physical, mental, and social well-being. Sleep disturbances in veterans are also underdiagnosed and undertreated for reasons that include limited sleep clinician availability, long wait times, and the time commitment for treatment. Greater use of sleep health information technologies could improve access to assessment and treatment of sleep disturbances. However, the assessment of acceptance of these technologies among veterans is still ongoing. This mixed-method study combines data from two separate but similar randomized controlled trials to assess acceptance of sleep health information technologies for veterans with chronic insomnia. Sleep health information technologies included in these trials were the following: (1) a WatchPAT sleep monitor for home-based sleep assessment, including detection of sleep apnea, and (2) the VA mobile app Cognitive Behavioral Therapy for Insomnia (CBT-i Coach), which supports self-management of insomnia. The combined sample of 37 veterans receiving care within one New England VA medical center completed a six-week trial using both health information technology tools. Participants completed a survey and interview at the end of the 6 weeks. Overall, participants found the tools acceptable, easy to use, and useful and reported they would use them in the future. Thus, these sleep health information technologies appear to provide an acceptable remote option for assessing and managing sleep issues for veterans. ClinicalTrials.gov NCT02392000; http://clinicaltrials.gov/ct2/show/NCT02392000 and ClinicalTrials.gov NCT03305354; https://clinicaltrials.gov/ct2/show/NCT03305354
Keywords
Cognitive behavioral therapy
Mobile apps
Insomnia
Sleep apnea
http://dx.doi.org/10.13039/100006379 Office of Research and Development PPO 14-144 Quigley Karen S. Boston Roybal Center for Active Lifestyle InterventionsP30 AG048785 Quigley Karen S.
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pmcIntroduction
It is estimated that 50–70 million Americans suffer from sleep disturbance (Institute of Medicine Committee on Sleep & Research, 2006) and rates continue to rise (Caldwell et al., 2017). Compared to non-veterans, veterans have even higher rates of sleep disturbance (Alexander et al., 2016; Caldwell et al., 2017) with chronic insomnia and sleep apnea two of the most common sleep disorders in veterans (Alexander et al., 2016). Almost one quarter of veterans receiving care at the Department of Veterans Affairs (VA) have a documented diagnosis of sleep apnea, and 12% have been diagnosed with insomnia (Folmer et al., 2020). Furthermore, these two disorders are highly comorbid, with approximately 30–40% of patients with insomnia meeting additional criteria for sleep apnea and vice versa (Sweetman et al., 2021). Sleep disturbances have broader health and functional impact than is often appreciated, including being risk factors for a multitude of mental health conditions, including PTSD, depression, and suicidal behavior (Neckelmann et al., 2007; Picchioni et al., 2010; Tae et al., 2019; Wright et al., 2011). Additionally, chronic sleep disturbances can negatively impact overall quality of life by affecting work performance, social activities, and interpersonal relationships (Garbarino et al., 2016). Furthermore, sleep disturbances are associated with the development of serious health conditions such as cardiovascular disease, diabetes, and dementia (Liew & Aung, 2021). Patients with comorbid insomnia and sleep apnea also exhibit more negative mood, poorer quality of life, and worse treatment outcomes than those with either disorder alone (Sweetman et al., 2021).
Given these major negative impacts, it is concerning that these sleep disorders are both underdiagnosed and undertreated. The VA healthcare system has continued to increase its focus on assessing sleep disturbance and diagnoses continue to increase, suggesting the possibility of historical underdiagnosis of sleep disturbance in veterans (Folmer et al., 2020; Weaver et al., 2020). The VA has also aimed to increase access to cognitive behavioral therapy for insomnia (CBT-I), the gold-standard treatment for chronic insomnia, launching a national provider training program to increase the number of clinicians who can deliver CBT-I (Folmer et al., 2020). Despite these efforts, CBT-I remains underutilized within the VA (Koffel et al., 2018a). A recent review suggests that this under-utilization may arise from long wait times for veterans wanting to access in-clinic CBT-I and the difficulty of arranging frequent clinical appointments into their busy lives (Koffel et al., 2018a). Additionally, given the high rates of comorbid sleep apnea and insomnia, and their negative impact on treatment, it is important to assess for sleep apnea in those with chronic insomnia (Ong et al., 2021). However, access barriers remain to sleep apnea testing, especially for those who need to travel long distances for in-lab sleep testing (Weaver et al., 2020).
Health information technologies (HITs), including home sleep apnea testing and mobile health applications (apps), could help to increase access to sleep assessments and treatments. Consumer-facing HITs support health care for patients by enhancing access to health communication, self-management, support, and treatment. Two reviews noted that patients found HITs for a variety of conditions and goals to be highly acceptable (Or & Karsh, 2009; Tao et al., 2020). Multiple types of HITs for sleep have been developed, including sleep-tracking apps (Choi et al., 2018) and internet-based and mobile-enabled CBT-I treatments (Erten Uyumaz et al., 2021; Horsch et al., 2015). Additionally, home sleep testing helps overcome barriers to in-lab assessments (Weaver et al., 2020). Veterans prefer having multiple options for their sleep care, including the possibility of first using at-home self-management options, or internet and mobile options before engaging with in-person treatment (Epstein et al., 2012; Koffel et al., 2021). Given this preference and long wait times for in-clinic care, there is a growing need to increase our understanding of veterans’ experiences with and acceptance of specific sleep HITs, especially given the quick adoption and expansion of virtual care options in recent years due to the COVID-19 pandemic.
Several theoretical models of technology acceptance have been proposed, including the Unified Theory of Acceptance of Technology (UTAUT; Venkatesh et al., 2002, 2003) and Wilson and Lankton’s model (2004), which combined the Technology Acceptance Model (Davis, 1989) and the motivational model (Davis et al., 1992). These models posit that users’ acceptance and use of HITs are determined by multiple interrelated factors including individual differences, motivation, perceived usability (i.e., ease of use), perceived usefulness, and intent to use HITs (Venkatesh et al., 2003; Wilson & Lankton, 2004). Experts recommend acceptance testing for HITs before implementation (Dabbs et al., 2009); however, acceptance has not yet been widely explored for already-deployed sleep HITs with veterans. Studies have shown good feasibility and acceptability for the use of sleep HITs in veterans for the treatment and self-management of insomnia (Koffel et al., 2018b; Kuhn et al., 2022). Although sleep HITs for assessing sleep apnea have been validated (Pillar et al., 2020), no known studies have assessed their acceptance in veterans. Furthermore, given high rates of comorbidity, it would be useful to assess the use of multiple sleep HITs concurrently, including HIT-based assessments of sleep apnea in a population with chronic insomnia. Thus, in the current study, we used a mixed-method approach to assess the acceptance of HITs for sleep assessment and self-management within a veteran sample with chronic insomnia.
Methods
The current study used a convergent parallel mixed-method design, where quantitative and qualitative data were collected and analyzed simultaneously (Fetters et al., 2013). The current analysis combines sample data from two separate, but similar, randomized controlled trial studies. Sample 1 examined sleep outcomes from pre- to post-intervention of sleep HITs (Reilly et al., 2019). Sample 2 extended the work of Sample 1 and added a physical activity intervention (Reilly et al., 2021). Similarities and differences between the two are described in greater detail below.
Participants
For both samples, veterans at one small New England VA Medical Center were recruited for participation via flyers, outreach at VA and community events, referrals from VA behavioral and sleep health providers, and recruitment letters to veterans. Interested veterans were screened for study eligibility by phone. Veterans were eligible to participate if they had the following: (1) military service after 2001 in Iraq and/or Afghanistan, (2) Insomnia Severity Index (ISI) score greater than 10 with a duration of at least one month, and (3) impaired daytime functioning measured by item 7 of the ISI. Exclusion criteria included the following: (1) moderate-to-severe cognitive impairment based on scores on the Telephone Mini Mental State Exam (Norton et al., 1999), (2) excessive alcohol use on the Alcohol Use Disorders Identification Test-Concise (Bush et al., 1998), or (3) self-report of other sleep disorders including sleep apnea, circadian rhythm disorder, or restless leg syndrome. In Sample 1, participants were excluded from the study if they had moderate to severe sleep apnea as measured by the WatchPAT home sleep monitor (see below for details); in Sample 2, participants were excluded if they had severe sleep apnea based on a WatchPAT-based assessment. Participants with severe sleep apnea were excluded because of the contraindication for CBT-I and they were referred for further assessment and treatment. In Sample 1, 50 veterans were assessed, 38 were enrolled, 18 were withdrawn due to sleep apnea, and 11 completed the full study (8 with mild sleep apnea; Reilly et al., 2019). In Sample 2, 48 veterans were assessed, 33 enrolled, 2 were withdrawn due to severe sleep apnea, and 26 completed (16 with mild or moderate sleep apnea; Reilly et al., 2021). Full information on participant inclusion and attrition has been previously published for each sample (Reilly et al., 2019, 2021). For both studies, participants were compensated $15 for each of the first two visits and $40 for the final visit for a total of $70 for study completion. Sample 1 was collected from October 2015 to November 2016 and Sample 2 was collected from January 2018 to June 2019.
Study Design
This paper analyzes survey and semi-structured interview data from Sample 1 and Sample 2. Questions focused on use of two sleep HIT tools: the CBT-i Coach app and the WatchPAT. Sample 2 participants also received an activity tracker (Fitbit; San Francisco, CA) and were randomized to a CBT-i Coach-only group or CBT-i Coach plus physical activity group. Participants in this study were not instructed to use the Fitbit to track sleep. Methods and primary clinical outcomes of Sample 1 and Sample 2 are reported respectively in Reilly et al. (2019, 2021). Both studies were approved by the Institutional Review Board of the VA Bedford Healthcare System.
Health Information Technologies (HITs)
Participants in both studies received an iPod Touch loaded with the CBT-i Coach app. The CBT-i Coach app is a free, publicly available app created by the VA National Center for PTSD and DoD (Hoffman et al., 2013; Kuhn et al., 2016). The app provides sleep psychoeducation, a diary for tracking sleep duration, sleep hygiene recommendations, relaxation tools, and graphs of user data over time. The app was supplemented by worksheets based on the Quiet Your Mind and Get to Sleep manual (Carney & Manber, 2009), including Wakeful Activities, Coping Self-Statements, Constructive Worry, and a Relaxation Log. Participants were also provided a self-management guide with suggestions for using the app and instructions for each week on what to access and complete within the app. The supplemental worksheets and self-management guide were designed to be used in conjunction with the app. Most of the sleep health education topics were materials that participants read or tools they used within the CBT-i Coach app. The CBT-i Coach app was originally developed to be used alongside treatment with a provider. These topics and tools correspond with those standardly used in CBT-I. A newer app, Insomnia Coach, is now available, which includes similar sleep health education and tools (such as relaxation strategies) along with a self-management guide.
All participants received a WatchPAT home sleep monitor (Model WP200U; Itamar Medical, Inc.) for use during the study. The WatchPAT sleep monitor is an FDA-approved device that has been shown to provide valid screening for sleep apnea (Yalamanchali et al., 2013) and to provide objective data on broad sleep stage measures (e.g., rapid eye movement [REM] vs non-REM) that have been validated against gold-standard polysomnography (Herscovici et al., 2007). The WatchPAT is worn like a wristwatch with an attached cable leading to a plethysmographic-based finger-mounted probe and a thin wire leading to a small sensor on the chest to measure snoring. Participants can use the device at home using simple instructions, which were provided via a laminated pamphlet and a video on the iPod Touch. Participants viewed the video during their first visit and the video was available on their iPod Touch for later reference. The WatchPAT was used three times by each participant who completed the full study, twice within the first week of the study and once after 6 weeks of using the CBT-i Coach app. Each time the WatchPAT was used, participants were provided a sleep study report which study staff reviewed with them. The report showed total study time (calculated from when they turned on the device to when they took it off), total sleep time, an apnea–hypopnea index (AHI), respiratory disturbance index (RDI), oxygen desaturation index (ODI), and the percentage of time in REM sleep, with definitions and normal ranges of each. The AHI and RDI measures are used to provide a proxy assessment of sleep apnea.
Quantitative Survey Measures
Demographics
Participants reported their age, gender, race, ethnicity, education, military service, and income at the first visit. Participants’ height and weight were measured at the first visit.
Acceptance Measure
Participants received a measure of acceptance at the end of the study adapted from Wilson and Lankton (2004) including the following factors: intrinsic motivation to use, perceived ease of use, perceived usefulness, and behavioral intention to use HITs. Separate items for each sleep HIT tool (CBT-i Coach app and WatchPAT) were assessed using 7-point Likert scales. Participants were asked to indicate their level of agreement with each item on a scale from 1 (strongly disagree) to 7 (strongly agree). Scale scores (agreement ratings averaged across items for each construct) were calculated for each HIT for the following constructs: Intrinsic Motivation, Ease of Use, Perceived Usefulness, and Behavioral Intention to use the HIT. All subscales had moderate to high internal consistency with Cronbach’s αs ranging from 0.74–0.97 for the scales applied to the CBT-i Coach app and 0.83–0.99 for the scales applied to the WatchPAT. Intrinsic motivation was assessed with three items (α = 0.84–0.96): I found [HIT] to be enjoyable; the actual process of using [HIT] was pleasant; I had fun using [HIT]. Perceived ease of use was assessed with three items (αs = 0.74–0.91 across the two samples): my interaction with [HIT] was clear and understandable; [HIT] was easy to use; I found it easy to get [HIT] to do what I wanted it to do. Perceived usefulness was assessed with three items (αs = 0.83–0.98): using [HIT] supported critical aspects of my health care; using [HIT] enhanced my effectiveness in managing my health care; overall, [HIT] was useful in managing my health care. Behavioral intention was assessed with two items (αs = 0.84–0.99): I intend to use [HIT]; I predict I will use [HIT].
Qualitative Interviews
Following completion of the intervention, each participant completed a semi-structured qualitative interview. Participants were asked about their experiences using the sleep HITs. Interviews lasted approximately 45–60 min. Interviews included questions about the perceived effects of the sleep HITs in terms of their perceived ease of use, perceived usefulness, intentions for future use, and suggestions for improvement. The interview guide can be found in Appendix A.
Data Analysis
Quantitative survey data was cleaned, summary scores calculated, and descriptive analyses conducted using SPSS Version 26 (IBM Corp, 2019) with descriptive statistics calculated for each usability survey subscale. For qualitative interview data, we used a deductive approach, specifically, a qualitative directed content analysis (Hsieh & Shannon, 2005), using a priori codes based on theories of technology acceptance as well as inductive coding to capture themes that emerged from the data. We used an iterative process to develop a codebook, and several interviews were co-coded to ensure inter-coder reliability. The coding team (BAP, SR, ER, KQ) used NVivo 11 (QSR International, 2015) to code the interviews. The coders met to discuss emerging findings, resolve discrepancies, and reach consensus on coding passages where codes were discrepant. The codebook was developed using Sample 1 data and was revised as needed for Sample 2.
Results
Participant Demographics
Table 1 presents participant demographic information from both samples. Participants were primarily male (75%) with a mean age of 41 (SD = 10).Table 1 Descriptive statistics for participants in both samples
Combined samples (n = 37) Sample 1
(n = 11) Sample 2
(n = 26)
Mean age (SD) 41 (10) 48 (10) 38 (9)
Gender (male)
n (%) 33 (75%) 8 (73%) 20 (77%)
Race, n (could select > 1)
White 35 10 21
Black 3 0 3
Other race 7 2 5
Ethnicity
Hispanic/Latino 8 3 5
Quantitative Results
All 37 participants who completed the 6-week mobile intervention also completed the post-intervention acceptance survey. Overall, participants’ acceptance ratings were similar across the two samples, with no statistically significant differences (Table 2). On average, participants rated the acceptance of both the CBT-i Coach app and the WatchPAT highly. For both the CBT-i Coach app and the WatchPAT, participants largely agreed that they had high intrinsic motivation to use the HITs, that they were easy to use, useful, and that they intended to use them after the study. Compared to other domains, intrinsic motivation to use was the lowest rated for both the CBT-i Coach app (Sample 1 mean = 5.03 [1.44], Sample 2 mean = 5.08 [1.67]) and the WatchPAT (Sample 1 mean = 4.58 [1.21], Sample 2 mean = 4.41 [1.83]). The highest rated domain was intent to use in the future for both the CBT-i Coach app (Sample 1 mean = 6.05 [0.93], Sample 2 mean = 5.50 [1.54]) and the WatchPAT (Sample 1 mean = 6.46 [0.72], Sample 2 mean = 6.54 [1.07]). Across the two HITs, participants rated the WatchPAT somewhat easier to use, more useful, and more likely that they would use it in the future than the CBT-i Coach app, but they had less intrinsic motivation to use it.Table 2 Acceptance of sleep HITs in both samples
Total sample (n = 37) Sample 1 (N = 11) Sample 2 (N = 26)
Mean (SD) Median Range Mean (SD) Median Range Mean (SD) Median Range p Cohen’s d
CBT-i Coach app
Intrinsic motivation to use 5.06 (1.58) 5.33 1.00–7.00 5.03 (1.44) 5.33 2.00–7.00 5.08 (1.67) 5.50 1.00–7.00 0.93 −0.03
Perceived ease of use 5.58 (1.38) 6.00 2.00–7.00 5.42 (1.29) 5.67 2.00–7.00 5.64 (1.44) 6.00 2.00–7.00 0.66 −0.16
Perceived usefulness 5.14 (1.73) 5.33 1.00–7.00 5.18 (1.41) 5.00 1.67–6.67 5.12 (1.87) 5.68 1.00–7.00 0.90 0.04
Behavioral intention to use 5.66 (1.40) 6.00 2.00–7.00 6.05 (0.93) 6.50 4.50–7.00 5.50 (1.54) 6.00 2.00–7.00 0.19 0.39
WatchPAT
Intrinsic motivation to use 4.46 (1.65) 4.67 1.00–7.00 4.58 (1.21) 4.00 3.00–7.00 4.41 (1.83) 5.00 1.00–7.00 0.75 0.10
Perceived ease of use 6.14 (0.95) 6.33 3.33–7.00 6.00 (0.75) 6.00 4.67–7.00 6.21 (1.03) 6.67 3.33–7.00 0.50 −0.21
Perceived usefulness 5.53 (1.68) 6.00 1.00–7.00 5.64 (1.32) 6.00 3.00–7.00 5.49 (1.83) 6.00 1.00–7.00 0.78 0.09
Behavioral intention to use 6.51 (0.97) 7.00 2.50–7.00 6.46 (0.72) 7.00 5.00–7.00 6.54 (1.07) 7.00 2.50–7.00 0.81 −0.09
p values reflect comparisons across the two samples
Qualitative Results
The qualitative coding resulted in several HIT acceptance themes, which we categorized as the following: (1) usability, (2) usefulness, (3) intended future use, and (4) suggestions for improvement.
Usability: Sleep HITs Are Easy to Use
The vast majority of participants found that these sleep HITs were easy to use. Participants noted that the CBT-i Coach app was straightforward and self-explanatory. Participants also stated that it was easy to input their sleep diaries and to self-correct earlier input errors:“There was a help button if you had a question of what it [sleep diary] was actually asking you… So, I would go into the help for a minute and be like, oh, okay. That’s what it’s asking. And then I’d go back, and I’d be able to do whatever it asked for.”
The WatchPAT was similarly easy to use for all participants. Participants described the WatchPAT as simple and the instructions easy to follow. Even participants who had complaints, such as the device being uncomfortable, said they were easily able to endure the potential minor discomfort for a few nights:“A little uncomfortable at first just because I’m not used to it and the actual watch part of it is pretty heavy. The first time I was like, oh, this is kind of weird with the wires and everything. And the second time it was like, okay, I’m used to this. Third time it was like, I don’t even feel it.”
Usefulness: Sleep HITs Are Useful
Three sub-themes appeared around usefulness: (1) gaining new knowledge and awareness, (2) making behavioral changes, and (3) positive sleep-related and health-related outcomes.
Sleep HITs help to gain new knowledge and awareness. Participants found sleep HITs useful for helping them gain new knowledge and awareness of their sleep. This often helped to increase acceptance and reduce anxiety around sleep for participants:“Now I’m understanding the difference between light sleep, and so I’m not getting as stressed about when I feel like I’m awake during the night because I came to realize that I’m actually getting some sleep. It’s just not as deep as at other times.”
Participants found the wakeful activity assessment at the start of the study particularly useful for deciding where to make changes and implementing them. For example, setting a regular sleep schedule:“And actually, it’s made me aware that I need a regular schedule, and I knew that, but it definitely reminded me, and it absolutely made me change my job and get just a certain schedule, whether it’s nine o’clock at night every night or just the same every week.”
Participants reported the usefulness of objective data in the sleep HITs, such as the sleep diary data visualizations in both the CBT-i Coach and WatchPAT. Some participants remarked that by using the sleep HITs, they had a new awareness of their sleep patterns, which in and of itself was helpful. For example, some participants were relieved to find out via the WatchPAT that they did not have sleep apnea:“Gave myself that piece of mind knowing that I don’t have sleep apnea. So, it’s nothing that I should have a concern about being, the numbers being so low. That I'm not even close to like maybe being dangerous. It’s like no, you’re really healthy.”
Others noted that the WatchPAT helped them realize that they slept more than they expected:“It was reassuring that, though I perceive my sleep as being abnormally short, the scientific data says I’m sleeping longer than I think.”
Additionally, the visualizations of the sleep diary data in the app helped participants see how their sleep improved over time:“You can actually see how your sleep, I mean like where your sleep went up and how it hasn't gone up. I mean like I noticed that my sleep has gone up since I started, even since the beginning of this month. Just that I sleep better than I did before. It’s achievement, like meeting a goal.”
Finally, participants considered it helpful to have objective data when interacting with their medical providers. Participants shared or planned to share the results of the WatchPAT testing with their primary care or other providers to inform their care in the future:“When I go to my doctor, she can look at it. We can discuss the results and, if she thinks it’s warranted, set up a game plan.”
Sleep HITs encourage behavior change. For most participants, new knowledge, awareness, and motivation through HITs led to behavior changes that positively impacted their sleep. Participants reported engaging in a range of recommended behavior changes to improve their sleep including changing their sleep environment or bedtime routine, regulating, or changing their sleep schedule, avoiding electronics before bed, changing the timing of caffeine intake, changing stimulus control activities (e.g., avoiding activities other than sleep or sex in bed), and relaxation strategies (e.g., deep breathing exercises). For example, one participant described the changes they made as follows:“And I think what kind of really helped me, especially to get to fall asleep, was some of the wakeful activities that were in there. I pretty much eliminated about I would say over 90% of them before I was getting ready to go to bed. So, I wouldn’t watch TV, wouldn’t do anything on my phone, wouldn’t read. I’d just have a light conversation with my spouse, and then bedtime was bedtime.”
Others had more difficulty making behavior changes, even with increased knowledge about what changes might be helpful for their sleep. These participants talked about making these changes as a lower priority in their lives:“I wasn’t going to stop watching TV two hours. I’m not going to lay in bed and read. Like, I'm not going to do stuff like that. That’s, the hour a day to myself I get, that’s what I choose to do. And unfortunately, I can’t put that hour anywhere else.”
Most of these participants recognized that these behavior changes were necessary to improve their sleep but expressed that they were not ready yet. One participant spoke specifically about motivation and readiness: “I’m just not at that stage of action yet.”
Another spoke of recognizing the need for their own agency and change:“So it’s ultimately up to me to maybe take in less caffeine or things like, you know, going to bed later, being less stressed that will, I’ll have to be responsible for my own sleep... So, I have to be the one to change them.”
Participants associated using sleep HITs with positive changes in their sleep and other outcomes. Participants found the CBT-i Coach app particularly useful for seeing positive changes in their sleep and their lives overall. They associated many of these improvements with changing their sleep habits and how they thought about sleep. One participant described the change in their sleep as “longer and uninterrupted.” Participants reported improvements in physical health, pain, stress, energy and fatigue, memory, concentration, overall quality of life, and social interactions. Several participants noted the potential connection between sleeping more and feeling better physically or having less pain. As one participant noted: “I think sleeping more has been helping my body heal more.” Many participants felt their moods were better, with less irritability, as one participant noted: “I think I feel happier, more joyful I guess, during the day, now that I'm sleeping better.” When participants slept better, they could engage in more quality-of-life activities, as one participant illuminated: “I’ve become more engaged in outside activities, like the baseball camp.”
A few participants connected their lower use of sleep HITs with less ideal outcomes. For example, for one participant:“I didn’t really use it all that much. It’s really just getting out of it what you put into it. And seeing how, unfortunately, as far as just the app goes, I didn’t put that much into it, and yeah, I didn’t get that much out of it.”
Intended Future Use of Sleep HITs
Most participants expressed positive sentiments about using sleep HITs in the future and would recommend them to others. Most participants said they would or already had downloaded the CBT-i Coach app onto their personal devices. Some felt that they needed more time to see further improvements in their sleep:“I might, actually [download it], just because I don’t feel like I had enough time with it. But I do, from what I did see, I do feel like it is beneficial. I just wish I had more time with it, so I probably will, yeah.”
Other participants felt that their time using the sleep app was sufficient and planned to stop using the app. One participant described how they had gotten what they could out of it:“[The app] just being static information, I think I got the information I needed off of that, so. And then to me, information starts becoming old.”
Some of these participants stated that they would consider using the app in the future if needed:“Well, now that I know it’s there, if I feel like I start seeing issues again, then I will definitely do that. So I’ll just start monitoring myself.”
Suggestions for Improvement
Participants’ suggestions for improvements of sleep HITs fell into three main areas: (1) suggestions for the CBT-i Coach app, (2) suggestions for the WatchPAT, and (3) integration across devices. First, suggestions for the CBT-i Coach app often were technical improvements, including adding a military time option or the ability to choose sleep diary durations in other than 10-min intervals. Some participants would have preferred printed materials, including sleep diaries, educational materials, and progress charts. Finally, several participants suggested adding game and community elements to the CBT-i Coach app. For example:“Maybe you could put a picture of your pajamas you’re wearing for the night or the movie you’re watching before bed to put you to sleep. And it might pull people in a little more. And you could have goals and maybe have little achievements. I slept eight hours yesterday. I can hit the button and ding! You get six, seven hours in a row, you get a little trophy, and then everybody knows it, and it motivates you.
Suggestions related to the WatchPAT were primarily focused on increasing comfort and ease of use, including making it wireless. Additionally, participants suggested that the WatchPAT should be easier to access for veterans outside the study so that more people could be screened for sleep apnea. Finally, participants suggested that sleep HITs could be better integrated across devices and sources of information. They wanted information from both the CBT-i Coach app and the WatchPAT to be combined and automatically sent to their health care providers.
Discussion
Overall, the combined results of these studies suggested that sleep HITs are generally acceptable, usable, and useful for veterans with chronic insomnia. The quantitative and qualitative results from these two samples were aligned and showed that veterans had broadly positive experiences with the CBT-i Coach app and the WatchPAT sleep monitor. By the end of their participation, most participants expressed that both sleep HITs were easy to use, useful, and that they intended to use them in the future, if needed. These results are expected given that the participants voluntarily agreed to enroll in a clinical trial using these HITs. Additionally, sleep HITs helped some participants receive sleep assessment and management that was more accessible (e.g., it fit with their schedule), thereby overcoming a documented barrier to engagement in CBT-I treatment (Koffel et al., 2018a). These findings are valuable to the literature that assesses the acceptance of multiple sleep HITs. The CBT-i Coach app and the WatchPAT provided complementary tools and information that are helpful to use together. The WatchPAT was a key assessment tool in providing initial feedback on sleep apnea and baseline objective sleep data, which is important given the high comorbidity of sleep apnea and insomnia and its impact on insomnia treatment (Ong et al., 2021; Sweetman et al., 2021). The CBT-i Coach app education and tools were likely more helpful in the self-management of sleep disturbance and in supporting behavior change.
The qualitative results provide additional information on why participants found these technologies to be useful. They provided new knowledge and awareness, and support for making behavioral changes and improvements in their sleep and other areas of their lives. These findings are aligned with the key components of CBT-I: psychoeducation, cognitive restructuring, and behavior change, including stimulus control and sleep hygiene (Manber et al., 2012). It appeared that sleep HITs were most helpful at building knowledge and awareness, which then often led to behavior change. The sleep diary was a key component of building awareness of participants’ sleep patterns, which participants felt guided them on how to make behavior changes. This finding reinforces previous research on self-monitoring as a health behavior intervention, including the prior use of sleep diaries that led to changes in sleep patterns (Goelema et al., 2016). Also aligned with the goals of CBT-I (Thakral et al., 2020), it appeared that learning about normal sleep patterns through psychoeducation and their own WatchPAT results reduced misconceptions about sleep, which may have helped participants make behavior changes.
A small number of participants spoke about the difficulties of making behavior changes despite acquiring new knowledge and awareness. Lack of motivation appeared as a barrier to making behavioral changes. This finding was echoed in the quantitative results, where we saw that motivation to use sleep HITs, while still relatively high, was generally lower than for other domains. Motivation is a key factor in HIT use (Venkatesh et al., 2003) and HIT effectiveness (Baretta et al., 2019). CBT-I outcomes depend on adherence to behavioral change recommendations, which are greatly impacted by the motivation to change behavior (Trockel et al., 2014). Some individuals with sleep disturbance with lower motivation for behavior change may benefit from increased support from a healthcare provider. They may also benefit from motivational interviewing (MI) strategies, which can increase motivation for change. Research on delivering MI through technology, including mobile apps, is promising (Shingleton & Palfai, 2016), and additional research would be beneficial on the addition of MI components to further boost the usefulness of existing sleep HITs. Individuals with more difficulty making behavior changes may have also faced environmental barriers such as shift work, young children, or comorbid medical conditions, which also might be better addressed by using a more supported approach.
These findings show good acceptance, usability, and perceived usefulness of sleep HITs for veterans with sleep disturbance, but as with any study, we note several limitations. First, these studies used two small samples of veterans at a single site, and therefore, we cannot generalize to all veterans with chronic insomnia. Additionally, those individuals who elected to participate and completed the study may be more drawn to using sleep HITs and thus, more likely to find them acceptable. The findings of this study could have also been impacted by confounding variables that were spontaneously reported in interviews, such as shift work and young children, and that were not assessed systematically across all participants. Since CBT-I is contraindicated in cases involving shift work (Smith & Perlis, 2006), participants working night or rotating shifts may see minimal benefit from self-management sleep HITs. Additionally, questions about intrinsic motivation to use was not included in qualitative interviews; future qualitative work could include this factor as it was the lowest scoring aspect of acceptance of sleep HITs from our quantitative findings. Finally, these data were primarily self-report and there was no follow-up beyond the immediate post-intervention assessment. In interviews, participants often commented on their experience in the study overall and did not necessarily differentiate between information learned from different components, such as the worksheets used early in the trial versus use of the CBT-i Coach app. Similarly, a few participants in Sample 2 used the Fitbit to track their sleep, which may have impacted their perception of each HIT. Participants who used both found the WatchPAT to have more in-depth, and what they felt was more accurate feedback compared to the Fitbit, which could have resulted in a more positive view of the WatchPAT. Thus, this study primarily provides a picture of the acceptance of these sleep HITs as they worked as part of a single intervention, and thus, we have less information about the acceptance of each HIT alone. In the future, it will be important to combine self-reported app use with in-app usage data, longer-term follow-ups, and dismantling studies to further assess the best combinations of sleep HITs.
Overall, sleep HITs may help increase access to assessment and treatment for sleep disorders, which are under-diagnosed and under-treated, especially among veterans. Sleep self-management using sleep HITs may also align well with a stepped-care approach, in which self-management methods can be used before the delivery of provider-delivered treatments. Some veterans may find these self-management approaches more accessible and even preferred (Koffel et al., 2021). This stepped-care approach can help stretch valuable healthcare provider resources, enabling care for more patients (Alessi et al., 2016). Additionally, this study confirms veteran patients’ acceptance of delivering CBT-I via non-clinicians (Alessi et al., 2016). Clearly, some veterans will benefit from the additional support of working with a clinician. Future research could focus on predictive factors indicative of which patients may most benefit from an initial (or solely) self-management approach and which patients will need more support for sleep assessments or treatments.
Appendix A: Interview Guide
Past treatment experience—sleep and CBT
Have you seen a healthcare provider for your sleep problems before?[If no] Why not?
[If yes] What did you try previously to improve your sleep? Did you ever try using technology before to improve your sleep? How did using the WatchPAT and the CBT-i Coach compare with what you tried before? [Interviewer: we want to know about what they tried previously including HOW it was delivered and by whom.]
Have you ever had cognitive behavioral therapy for insomnia before and, if so, was it helpful?
During the course of the study did you change anything about your medications? (Any new medications, changes in dosage, time you took them?)If yes, did you change this as part of the study or was it just something that occurred during the study
Experience/usability with WatchPAT and CBT-i Coach and Sleep Help apps
Could you describe what it was like using the WatchPAT sleep monitor?Did you have any specific sensations while wearing the WatchPAT? Did you have any discomfort while wearing it? Did you think that it changed how you slept (in other words, did it make your sleep either better or worse)?
Was it easy to use? Was anything confusing?
How can the instructions for using the WatchPAT that we gave you at your first visit be improved?
Did you refer to the information brochure or video? [If yes] Can you tell me about a time when you looked at it? Do you have any suggestions for how the informational brochure or video could be changed?
Did you have any problems with the WatchPAT and if so, how did you solve the problem?(i) Did you call anyone for assistance? [If yes] Please tell me about that experience.
(ii) f. How could the WatchPAT itself be changed to make it easier to use or more useful?
What was your overall opinion of or experience with the CBT-i app?What feature(s) did you like the most and why?
Which components did you find less useful, and why?
How could the CBT-I app be changed to make it easier to use or more useful?
Was it what you expected?
How easy was it to use?
Did you have any problems with it?(i) [If yes] Can you tell me about what they were and how you solved them?
Did you enjoy using it? Why/why not?
What was your overall opinion of or experience with the Sleep Help app which had the worksheets on wakeful activities, coping self-statements, behavioral plan, constructive worrying and a relaxation log?How easy was it to use?
Did you have any problems with it?(i) [If yes] Can you tell me about what they were and how you solved them?
What worksheet(s) did you like the most and why?
Which parts did you find less useful, and why?
How could the Sleep Help app be changed to make it easier to use or more useful?
Was it what you expected?
Did you enjoy using it? Why/why not?
Perceived impact of intervention
4. How would you describe how your sleep has changed since beginning this study? What changes, if any, have you noticed? (Examples? Ascertain if better/worse)
5. Could you tell me about any other changes to your health, or in your life since beginning this study?Could you tell me about any changes you experienced in… (if yes, how so or is there a specific example you can share with me?) [If not mentioned, probe for:](i) Pain?
(ii) Stress?
(iii) Fatigue?
(iv) Memory?
(v) Concentration/focus?
(vi) Daily life in general?
(vii) Interactions with my partner/spouse/friends?
What do you think caused these improvements? (Getting more sleep? Use of CBT for insomnia or Sleep Help worksheets? Feedback from WatchPAT? Talking with your physician about your sleep?)
6. Did you change any of your sleep behaviors since beginning the study? If so, what did you change?
7. Did you change anything about the way you thought about your sleep since beginning the study? If so, what changed?
Patient engagement
8. Have you spoken with your provider about your sleep since you began this research study?[If yes] What were his/her reactions to your using the CBT-i Coach?
What other suggestions has your doctor/clinician had to help you with your sleep?
Do you have a follow-up visit with your provider to discuss your sleep?
Behavioral intention for HIT
9. What other cell phone tools or apps do you use? How regularly do you use them?[If yes] Can you tell me a little bit about the things you use them for?(i) Do you use any apps for health purposes? (e.g., those for tracking fitness, diet, smoking, or other health behaviors) [If yes] Can you tell me about some things you’ve done using health-related apps before?
(ii) [If yes] How did using the CBT-i app for your sleep compare with those experiences?
(iii) [If no] You said you don’t use (health) apps very much. Can you tell me a little about why you don’t use them?
10. How often do you use the Internet?[If user] Can you tell me about what you typically do on the internet?
How often do you use the internet for health-related reasons or to get answers to health-related questions? Can you give me some examples of when you have done this recently?
11. Do you plan to continue using the CBT-i app now that the research study is done? (why/why not?)
12. Would you consider using mobile apps for other health issues and if so, which health issue(s) do you think would be most helpful to you?
Final thoughts
13. Would you recommend using technology like the WatchPAT and/or CBT-i Coach to other Veterans with sleep problems? [Why/why not?]
14. Is there something else I should have asked but didn’t?
Funding
Dr. Kaitz’s writing of this manuscript was supported by the US Department of Veterans Affairs, Office of Academic Affiliations, Advanced Fellowship Program in Health Services Research, Center for Healthcare Organization and Implementation Research, Veterans Affairs Bedford Healthcare System. This material is based on work supported by the Department of VA, VHA, Office of Research and Development, Health Services Research and Development (PPO 14–144) to KSQ and a pilot grant to KSQ, under the Boston Roybal Center for Active Lifestyle Interventions grant (principal investigator: Margie Lachman; grant number P30 AG048785) supported by the National Institute on Aging, the Department of Veterans Affairs VISN1 Clinical Trials Network, and the Veterans Affairs Rehabilitation Research and Development-funded Center for Social and Community Reintegration Research (principal investigator: KSQ). The findings and interpretations of the data expressed in the paper are the sole responsibility of the authors and do not necessarily represent the views of the Department of VA.
Declarations
Competing Interests
The authors declare no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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| 0 | PMC9745770 | NO-CC CODE | 2022-12-15 00:02:42 | no | J Technol Behav Sci. 2022 Dec 13;:1-12 | utf-8 | J Technol Behav Sci | 2,022 | 10.1007/s41347-022-00287-x | oa_other |
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